Use of CNP or CNP conjugates such as navepegritide to treat leg curvature in patients with skeletal dysplasia

Abstract

The present invention relates to a CNP or CNP conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such CNP or CNP conjugate or a pharmaceutically acceptable salt thereof for use in the treatment of a lower extremity deformity in a subject with a skeletal dysplasia and wherein the subject has or is at risk of developing said lower extremity deformity and related aspects.

Description

[0001] Ascendis Pharma Growth Disorders A / S 1 22 December 2025

[0002] CPX75232PC

[0003] Improvements in leg curvature in patients with skeletal dysplasia

[0004] The present invention relates to a CNP or CNP conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such CNP or CNP conjugate or a pharmaceutically acceptable salt thereof for use in the treatment of a lower extremity deformity in a subject with a skeletal dysplasia and wherein the subject has or is at risk of developing said lower extremity deformity and related aspects.

[0005] Lower leg deformities are a hallmark of achondroplasia, reported in 40% of children upon standing and progressing to 93% in adulthood (Kopits, Clin. Orthop. Rel. Res. (1976), 114:153-79). Although the literature is sparse regarding the impact of these lower limb deformities on other comorbidities, they have been associated with pain, impaired physical functioning and the need for corrective surgery.

[0006] In achondroplasia, lower extremity deformities are primarily reflected in outward leg bowing (genu varum), with curvature evident in both the femur and / or tibia in addition to malalignment at the knee. Genu varum is present at birth in all children, transitioning to a slight valgus (inward) stance by age 2. In achondroplasia, genu varum progresses during childhood, an effect considered primarily a result of overgrowth of the fibula relative to the tibia (Ponseti, J. Bone Joint Surg. Am. (1970), 52(4): 701-16). The elongated fibula limits eversion of the foot, which increases pressure on the medial distal tibial physis, thus slowing its growth and contributing to increased tibial curvature. Varus curvature of the tibia places additional stress on the lateral collateral ligament, creating laxity in the knee that may also contribute to progressive varus deformation of the whole leg (Stanley, J. Pediatr. Orthop. (2002), 22(1): 112-6)

[0007] Recurrent periods of leg pain and discomfort affect 70% of children with leg deformities between 4-10 years of age, an age when the incidence of spinal stenosis, which can also cause leg pain, is low. Pain in the knee and ankle joints has been attributed to direct bony pressure due to an elongated fibula, which may also contribute to ligament strain and irritation of the peroneal nerve (Kopits, Clin. Orthop. Rel. Res. (1976), 114:153-79).Ascendis Pharma Growth Disorders A / S 2 22 December 2025

[0008] CPX75232PC

[0009] Although studies have not directly linked lower limb deformities with objective measures of physical function or comorbidities in achondroplasia, their common prevalence suggests association. Children and adults with achondroplasia walk with reduced gait speed and stride length and increased cadence compared to normal sized individuals. Much of these differences can be attributed to decreased leg length, however, other changes in gait such as higher internal knee valgus moments (0.49 Nm / kg in patients with achondroplasia vs 0.19 Nm / kg in average stature) suggest there are specific differences that may be attributable to differences in leg morphology (Brostrbm et al., BMC Musculoskelet. Disord. (2022), 23(1): 397; Sims et al., J. Appl. Physiol. (1985), 124(3): 396-703).

[0010] In an average- stature population, genu varum has been associated with poorer mediolateral static and dynamic stability (Samaei et al., Int. J. Sports Med. (2012), 33(6): 469-73) as well as altered postural control strategies during single leg stance (Nyland et al., Med. Sci. Sports Exerc. (2002), 34(7): 1150-7). During a single leg jump-landing test, individuals with genu varum deformities took significantly longer time to stabilize the knee in the medio-lateral direction following landing, compared to individuals with no observed knee deformities (Joni et al., Physical Treatments - Specific Physical Therapy Journal (2017), 7: 79-88). Although no such studies have been caried out in the achondroplasia population, it can be speculated that achondroplasia patients have poor knee joint stability in the medio-lateral direction due to their often large degree of varus deformity in the lower extremities.

[0011] Leg bracing is contraindicated in achondroplasia, as it tends to deform the epiphyses, rather than straightening the bones (Kopits, Clin. Orthop. Rel. Res. (1976), 114:153-79), therefore corrective surgery is common. Natural history studies have suggested that between 25% and 50% of achondroplasia patients have had lower extremity surgery (Nahm et al., Orphanet J Rare Dis. (2023), 18(1): 139). In the CLARITY study spanning children and adults with achondroplasia, the mean age for osteotomy was 9.1 ± 5.8 years with a median age of 7.9 years (1.1-36.9). The most common indications for the lower extremity surgery were malalignment followed by pain and fracture, and the majority of subjects had more than one procedure. A history of both shunting and CMD was associated an increased risk for a lower extremity procedure (1.93, p = 0.031), suggesting that early delays in motor function may contribute to future varus deformity.Ascendis Pharma Growth Disorders A / S 3 22 December 2025

[0012] CPX75232PC

[0013] Thus, there is a need to at least partially overcome the shortcomings of current treatment options of lower leg deformity in patients with skeletal dysplasia.

[0014] This object is achieved with a CNP or CNP conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such CNP or CNP conjugate or a pharmaceutically acceptable salt thereof for use in the treatment of a lower extremity deformity in a subject with a skeletal dysplasia and wherein the subject has or is at risk of developing said lower extremity deformity.

[0015] Without wishing to be bound by theory, this treatment effect may be achieved by at least one of (i) normalization of fibular overgrowth, (ii) a normalization of condylar growth and / or (iii) improved muscle strength.

[0016] In patients with achondroplasia tibial growth is more truncated than in the fibula, which contributes to the varus deformity. Applicant surprisingly found a statistically significant decrease in the fibula-to-tibia ratio upon treatment with navepegritide in a clinical trial with children having achondroplasia.

[0017] Altered mechanical forces due to malalignment or other aspects of dysplasia result in asymmetric growth of the condyles. It is believed that treatment with CNP or a CNP conjugate may normalize condylar growth through its direct effects at the asymmetrical growth plate and / or through improved leg kinematics caused by improved skeletal muscle function. In a clinical trial with navepegritide, applicant surprisingly found that the lateral distal femoral angle showed a numerical improvement compared to placebo.

[0018] Patients with achondroplasia have impaired muscle strength (WO 2024 / 104922 Al), which may contribute to malalignment via increased laxity at the hip and knee joints. CNP or a CNP conjugate through improving muscle strength may improve mechanical alignment and force transmission in the lower extremities, thus improving leg curvature.

[0019] Within the present invention the terms are used having the meaning as follows.Ascendis Pharma Growth Disorders A / S 4 22 December 2025

[0020] CPX75232PC

[0021] As used herein, the term “CNP” refers to CNP polypeptides, such as from mammalian species, such as from human, that are characterized by regulating the growth, proliferation and differentiation of cartilaginous growth plate chondrocytes.

[0022] As used herein, the term “ring moiety” or short “ring” 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. Preferably, 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. Independently of the length of the CNP moiety, the sequence of the ring moiety of wild-type CNP is FGLKLDRIGSMSGLG (SEQ ID NO: 96).

[0023] As used herein the term “tibia-to-femoral angle” (TFA) refers to the angle between the tibia and femur on a standing lower extremity X-ray.

[0024] As used herein the term “mechanical axis deviation” (MAT) refers to the distance from the centre of the knee to the mechanical axis, i.e., to the line drawn between the femur head and the ankle, on a standing lower extremity X-ray.

[0025] As used herein the term “fibular-to-tibia ratio” refers to the ratio of the fibular length to the tibia length as assessed on a standing lower extremity X-ray.

[0026] As used herein the terms “release half-life” and “half-life” refer to the time required under physiological conditions (i.e. aqueous buffer, pH 7.4, 37°C) until half of all CNP molecules of a reversible CNP conjugate are released.

[0027] The term “peptide” as used herein refers to a chain of at least 2 and up to and including 50 amino acid monomer moieties, which may also be referred to as “amino acid residues”, linked by peptide (amide) linkages. The amino acid monomers may be selected from the group consisting of proteinogenic amino acids and non-proteinogenic amino acids and may be D- or L-amino acids. The term “peptide”Ascendis Pharma Growth Disorders A / S 5 22 December 2025

[0028] CPX75232PC

[0029] also includes peptidomimetics, such as peptoids, beta-peptides, cyclic peptides and depsipeptides and covers such peptidomimetic chains with up to and including 50 monomer moieties.

[0030] As used herein, the term “protein” refers to a chain of more than 50 amino acid monomer moieties, which may also be referred to as “amino acid residues”, linked by peptide linkages, in which no more than 12000 amino acid monomers are linked by peptide linkages. For simplification, CNP moieties and CNP molecules are generally referred to herein as “peptide”, even if the certain embodiments would be considered proteins due to their size.

[0031] As used herein the term “physiological conditions” refers to aqueous buffer at pH 7.4, 37°C.

[0032] As used herein the term “pharmaceutical composition” refers to a composition containing one or more active ingredients, such as for example at least one CNP or CNP conjugate, 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. Accordingly, a pharmaceutical composition for use of the present invention encompasses any composition made by admixing one or more CNP or CNP conjugate and a pharmaceutically acceptable excipient.

[0033] As used herein, the term “excipient” refers to a diluent, adjuvant, or vehicle with which the therapeutic, such as a drug or prodrug, is administered. Such pharmaceutical excipient may 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 an example for an excipient when the pharmaceutical composition is administered orally. Saline and aqueous dextrose are examples of excipients when the pharmaceutical composition is administered intravenously. 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 composition, if desired, can also contain minor amounts of wetting or emulsifying agents, pH buffering agents, like, forAscendis Pharma Growth Disorders A / S 6 22 December 2025

[0034] CPX75232PC

[0035] example, acetate, succinate, tris, carbonate, phosphate, HEPES (4-(2 -hydroxy ethyl)- 1-piperazineethanesulfonic acid), MES (2-(A-morpholino)ethanesulfonic acid), or can contain detergents, like Tween®, poloxamers, poloxamines, CHAPS, Igepal®, or amino acids like, for example, glycine, lysine, or histidine. These pharmaceutical compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, or sustained-release formulations. The pharmaceutical composition may 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 compositions will contain a therapeutically effective amount of the drug or biologically active moiety, together with a suitable amount of excipient so as to provide the form for proper administration to the subject. The formulation should suit the mode of administration.

[0036] As used herein, the term “liquid composition” refers to a mixture comprising a water-soluble CNP or CNP conjugate and one or more solvents, such as water.

[0037] As used herein, the term “suspension composition” relates to a mixture comprising a water-insoluble CNP or CNP conjugate and one or more solvents, such as water.

[0038] As used herein, the term “dry composition” means that a pharmaceutical composition is provided in a dry form. Suitable methods for drying are spray-drying and lyophilization, i.e., freeze-drying. Such dry composition has a residual water content of a maximum of 10%, determined according to Karl Fischer. In certain embodiments such dry pharmaceutical composition is dried by lyophilization.

[0039] The term “drug” as used herein refers to a substance, such as CNP, used in the treatment, cure, prevention, or diagnosis of a disease or used to otherwise enhance physical or mental well-being. If a drug is conjugated to another moiety, the moiety of the resulting product that originated from the drug is referred to as “drug moiety”.

[0040] As used herein, the term “prodrug” refers to a covalent conjugate in which a drug moiety is reversibly and covalently connected to a specialized protective group through a reversible linker moiety, also referred to as “reversible prodrug linker moiety” or “reversible linker moiety”, which is conjugated through a reversible linkage to the biologically active moiety and wherein the specialized protectiveAscendis Pharma Growth Disorders A / S 7 22 December 2025

[0041] CPX75232PC

[0042] group alters or eliminates undesirable properties in the parent molecule. This also includes the enhancement of desirable properties in the drug and the suppression of undesirable properties. The specialized non-toxic protective group is referred to as “carrier”. A prodrug releases the reversibly and covalently bound drug moiety in the form of its corresponding drug. In other words, a prodrug is a conjugate comprising a drug moiety which is covalently and reversibly conjugated to a carrier moiety via a reversible linker moiety, which covalent and reversible conjugation of the carrier to the reversible linker moiety is either directly or through a spacer. Such conjugate releases the formerly conjugated drug moiety in the form of a free unmodified drug.

[0043] As used herein, the term “reversible linkage” is a linkage that is degradable, i.e. 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 three months. Accordingly, a stable linkage is a linkage having a half-life under physiological conditions (aqueous buffer at pH 7.4, 37°C) in the absence of enzymes of more than three months.

[0044] As used herein, the terms “traceless prodrug linker” or “traceless linker” mean a reversible prodrug linker, i.e. a linker moiety reversibly and covalently connecting a drug moiety with a carrier, which upon cleavage releases the drug in its free form. As used herein, the term “free form” of a drug means the drug in its unmodified, pharmacologically active form.

[0045] As used herein, the term “reagent” means a chemical compound which comprises at least one functional group for reaction with the functional group of another chemical compound or drug. It is understood that a drug comprising a functional group, such as a primary or secondary amine or hydroxyl functional group is also a reagent.

[0046] As used herein, the term “moiety” means a part of a molecule, which lacks one or more atom(s) compared to the corresponding reagent. If, for example, a reagent of the formula “H-X-H” reacts with another reagent and becomes part of the reaction product, the corresponding moiety of the reaction product has the structure “H-X-” or “-X-”, whereas each indicates attachment to another moiety. Accordingly, a drug moiety is released from a prodrug as a drug and also a drug is a reagent if it has a functional group.Ascendis Pharma Growth Disorders A / S 22 December 2025

[0047] CPX75232PC

[0048] It is understood that if the chemical structure of a group of atoms is provided which group of atoms is attached to at least one other moiety or is interrupting a moiety, said chemical structure may be attached to the at least one further or interrupted moiety in either orientation, unless explicitly stated otherwise. For example, a moiety “-C(O)N(R1)-” may be attached to two moieties or interrupting a moiety either as “-C(O)N(R1)-” or as “-N(R1)C(O)-”. Similarly, a moiety

[0049]

[0050] may be attached to two moieties or can interrupt a moiety either as

[0051]

[0052] or as

[0053] As used herein, the term “functional group” means a group of atoms which can react with other groups of atoms. Functional groups are for example a carboxylic acid, primary amine, secondary amine, maleimide, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isocyanate, isothiocyanate, phosphoric acid, phosphonic acid, haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, disulfide, sulfonamides, sulfuric acid, vinyl sulfone, vinyl ketone, diazoalkane, oxirane and aziridine.

[0054] In case a CNP or CNP conjugate comprises one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the CNP or CNP conjugate comprising acidic groups may be used according to the invention, 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. A CNP or CNP conjugate comprising one or more basic groups, i.e. groups which can be protonated, may be present and may be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples for suitableAscendis Pharma Growth Disorders A / S 9 22 December 2025

[0055] CPX75232PC

[0056] 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. For the person skilled in the art further methods are known for converting the basic group into a cation like the alkylation of an amine group resulting in a positively-charge ammonium group and an appropriate counterion of the salt. If the CNP or CNP conjugate simultaneously comprises acidic and basic groups, the invention also includes, in addition to the salt forms mentioned above, inner salts or betaines (zwitterions). The respective salts may be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these compounds with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds 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.

[0057] As used herein, the term “pharmaceutically acceptable” means a substance that does not cause harm when administered to a subject and in certain embodiments 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, in particular for use in humans.

[0058] As used herein the terms “about” or “approx.” 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. For example, the phrases “about 200” or “approx. 200” is used to mean a range ranging from and including 200 + / - 10%, i.e. ranging from and including 180 to 220. It is understood that a percentage given as “about 20%” or “approx. 20%” does not mean “20% + / - 10%”, i.e. ranging from and including 10 to 30%, but “about 20%” or “approx. 20%” means ranging from and including 18 to 22%, i.e. plus and minus 10% of the numerical value which is 20.

[0059] As used herein, the term “polymer” means a molecule comprising repeating structural units, i.e., the monomers, connected by chemical bonds in a linear, circular, branched, crosslinked or dendrimericAscendis Pharma Growth Disorders A / S 10 22 December 2025

[0060] CPX75232PC

[0061] 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. If the polymer is soluble, it in certain embodiments has a molecular weight of at most 1000 kDa. It is understood that for water-insoluble polymers, such as hydrogels, no meaningful molecular weight ranges can be provided. It is understood that also a peptide or protein 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.

[0062] As used herein, the term “polymeric” 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:

[0063] • 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

[0064] • linkages selected from the group comprising

[0065]

[0066] wherein

[0067] dashed lines indicate attachment to the remainder of the moiety or reagent, and

[0068] -R and -Raare independently of each other selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3 -methylpentyl, 2,2-dimethylbutyl, 2,3- dimethylbutyl and 3, 3 -dimethylpropyl.Ascendis Pharma Growth Disorders A / S 11 22 December 2025

[0069] CPX75232PC

[0070] The person skilled in the art understands that the polymerization products obtained from a polymerization reaction do not all have the same molecular weight, but rather exhibit a molecular weight distribution. Consequently, 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.

[0071] Accordingly, in a polymeric moiety comprising “x” monomer units 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 lie. An integer for “x” given as “about x” means that the arithmetic mean numbers of monomers lie in a range of integers of x + / - 10%.

[0072] As used herein, the term “number average molecular weight” means the ordinary arithmetic mean of the molecular weights of the individual polymers.

[0073] As used herein, the term “water-soluble” with reference to the CNP or CNP conjugate means that at least 1 g of the CNP or CNP conjugate can be dissolved in one liter of water at 20°C to form a homogeneous solution. Accordingly, the term “water-insoluble” with reference to the CNP conjugate means that less than 1 g of the CNP conjugate can be dissolved in one liter of water at 20°C to form a homogeneous solution.

[0074] As used herein, the term “PEG-based” in relation to a moiety or reagent means that said moiety or reagent comprises PEG. In certain embodiments a PEG-based moiety or reagent comprises at least 10% (w / w) PEG. The remaining weight percentage of the PEG-based moiety or reagent are other moi eties that in certain embodiments are selected from the following moi eties and linkages:

[0075] • 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 • linkages selected from the group comprisingAscendis Pharma Growth Disorders A / S 12 22 December 2025

[0076] CPX75232PC

[0077]

[0078] wherein

[0079] dashed lines indicate attachment to the remainder of the moiety or reagent, and

[0080] -R and -Raare independently of each other selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3 -methylpentyl, 2,2-dimethylbutyl, 2,3- dimethylbutyl and 3, 3 -dimethylpropyl.

[0081] The term “hyaluronic acid-based” is defined accordingly.

[0082] The term “substituted” as used herein 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”.

[0083] In certain embodiments the one or more further optional substituents are independently of each other selected from the group consisting of halogen, -CN, -COORxl, -ORxl, -C(O)Rxl, -C(O)N(RxlRxla), -S(O)2N(RxlRxla), -S(O)N(RxlRxla), -S(O)2Rxl, -S(O)Rxl, -N(Rxl)S(O)2N(RxlaRxlb), -SRxl, -N(RxlRxla), -NO2, -OC(O)RX1, -N(Rxl)C(O)Rxla, -N(Rxl)S(O)2Rxla, -N(Rxl)S(O)Rxla, -N(Rxl)C(O)ORxla, -N(Rxl)C(O)N(RxlaRxlb), -OC(O)N(RxlRxla), -T°, C1-50 alkyl, C2.5o alkenyl and C2-5o alkynyl; wherein -T°, C1-50 alkyl, C2-so alkenyl, and C2-so alkynyl are optionally substituted with one or more -Rx2, which are the same or different, and wherein C1-50 alkyl, C2-so alkenyl and C2-so 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(Rx3)-, -S(O)2N(RX3)-, -S(O)N(RX3)-, -S(O)2-, -S(O)-, -N(Rx3)S(O)2N(Rx3a)-, -S-, -N(Rx3)-, -OC(ORx3)(Rx3a)-, -N(Rx3)C(O)N(Rx3a)- and -OC(O)N(Rx3)-;Ascendis Pharma Growth Disorders A / S 13 22 December 2025

[0084] CPX75232PC

[0085] -Rxl, -Rxlaand -Rxlbare independently of each other selected from the group consisting of -H, -T°, Ci-50 alkyl, C2-50 alkenyl and C2-50 alkynyl; wherein -T°, C1-50 alkyl, C2-50 alkenyl and C2-50 alkynyl are optionally substituted with one or more -Rx2, 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(Rx3)-, -S(O)2N(Rx3)-, -S(O)N(Rx3)-; -S(O)2-, -S(O)-, -N(Rx3)S(O)2N(Rx3a)-, -S-, -N(Rx3)-, -OC(ORx3)(Rx3a)-, -N(Rx3)C(O)N(Rx3a)-and -OC(O)N(Rx3)-;

[0086] each T° is independently 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 each T° is independently optionally substituted with one or more -Rx2, which are the same or different;

[0087] each -Rx2is independently selected from the group consisting of halogen, -CN, oxo (=0), -COORx4, -ORx4, -C(O)Rx4, -C(O)N(Rx4Rx4a), -S(O)2N(Rx4Rx4a), -S(O)N(Rx4Rx4a), -S(O)2RX4, -S(O)RX4, -N(Rx4)S(O)2N(Rx4aRx4b), -SRx4, -N(Rx4Rx4a), -NO2, -OC(O)Rx4, -N(Rx4)C(O)Rx4a, -N(Rx4)S(O)2Rx4a, -N(Rx4)S(O)Rx4a, -N(Rx4)C(O)ORx4a, -N(Rx4)C(O)N(Rx4aRx4b), -OC(O)N(Rx4Rx4a) and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;

[0088] each -Rx3, -Rx3a, -Rx4, -Rx4aand -Rx4bis independently selected from the group consisting of -H and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.

[0089] In certain embodiments the one or more further optional substituents are independently of each other selected from the group consisting of halogen, -CN, -COORxl, -ORxl, -C(O)Rxl, -C(O)N(RxlRxla), -S(O)2N(RxlRxla), -S(O)N(RxlRxla), -S(O)2Rxl, -S(O)Rxl, -N(Rxl)S(O)2N(RxlaRxlb), -SRxl, -N(RxlRxla), -NO2, -OC(O)RX1, -N(Rxl)C(O)Rxla, -N(Rxl)S(O)2Rxla, -N(Rxl)S(O)Rxla, -N(Rxl)C(O)ORxla, -N(Rxl)C(O)N(RxlaRxlb), -OC(O)N(RxlRxla), -T°, C1-10 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 -Rx2, 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°-,Ascendis Pharma Growth Disorders A / S 14 22 December 2025

[0090] CPX75232PC

[0091] -C(O)O-, -O-, -C(O)-, -C(O)N(Rx3)-, -S(O)2N(Rx3)-, -S(O)N(RX3)-, -S(O)2-, -S(O)-, -N(Rx3)S(O)2N(Rx3a)-, -S-, -N(Rx3)-, -OC(ORx3)(Rx3a)-, -N(Rx3)C(O)N(Rx3a)- and -OC(O)N(Rx3)-;

[0092] each -Rxl, -Rxla, -Rxlb, -Rx3and -Rx3ais independently selected from the group consisting of -H, halogen, Ci-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;

[0093] each T° is independently 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 each T° is independently optionally substituted with one or more -Rx2, which are the same or different;

[0094] each -Rx2is independently selected from the group consisting of halogen, -CN, oxo (=0), -COORx4, -ORx4, -C(O)Rx4, -C(O)N(Rx4Rx4a), -S(O)2N(Rx4Rx4a), -S(O)N(Rx4Rx4a), -S(O)2RX4, -S(O)RX4, -N(Rx4)S(O)2N(Rx4aRx4b), -SRx4, -N(Rx4Rx4a), -NO2, -OC(O)Rx4, -N(Rx4)C(O)Rx4a, -N(Rx4)S(O)2Rx4a, -N(Rx4)S(O)Rx4a, -N(Rx4)C(O)ORx4a, -N(Rx4)C(O)N(Rx4aRx4b), -OC(O)N(Rx4Rx4a) and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;

[0095] each -Rx4, -Rx4aand -Rx4bis independently selected from the group consisting of -H, halogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;

[0096] In certain embodiments the one or more further optional substituents are independently of each other selected from the group consisting of halogen, -CN, -COORxl, -ORxl, -C(O)Rxl, -C(O)N(RxlRxla), -S(O)2N(RxlRxla), -S(O)N(RxlRxla), -S(O)2Rxl, -S(O)Rxl, -N(Rxl)S(O)2N(RxlaRxlb), -SRxl, -N(RxlRxla), -NO2, -OC(O)RX1, -N(Rxl)C(O)Rxla, -N(Rxl)S(O)2Rxla, -N(Rxl)S(O)Rxla, -N(Rxl)C(O)ORxla, -N(Rxl)C(0)N(RxlaRxlb), -OC(O)N(RxlRxla), -T°, Ci-6alkyl, C2.6alkenyl and C2.6alkynyl; wherein -T°, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted with one or more -Rx2, which are the same or different; and wherein C1-6 alkyl, C2-6 alkenyl and C2-6 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(Rx3)-, -S(O)2N(RX3)-, -S(O)N(RX3)-, -S(O)2-, -S(O)-, -N(Rx3)S(O)2N(Rx3a)-, -S-, -N(Rx3)-, -OC(ORx3)(Rx3a)-, -N(Rx3)C(O)N(Rx3a)- and -OC(O)N(Rx3)-;Ascendis Pharma Growth Disorders A / S 15 22 December 2025

[0097] CPX75232PC

[0098] each -Rxl, -Rxla, -Rxlb, -Rx2, -Rx3and -Rx3ais independently selected from the group consisting of -H, halogen, Ci-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;

[0099] each T° is independently 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 each T° is independently optionally substituted with one or more -Rx2, which are the same or different.

[0100] In certain embodiments a maximum of six -H atoms of an optionally substituted molecule are independently replaced by a substituent, e.g. five -H atoms are independently replaced by a substituent, four -H atoms are independently replaced by a substituent, three -H atoms are independently replaced by a substituent, two -H atoms are independently replaced by a substituent, or one -H atom is replaced by a substituent.

[0101] As used herein, the term “interrupted” means that a moiety is inserted 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.

[0102] As used herein, the term “C1-4 alkyl” alone or in combination means a straight-chain or branched alkyl moiety having 1 to 4 carbon atoms. If present at the end of a molecule, examples of straightchain 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 C1-4 alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. Each hydrogen of a C1-4 alkyl carbon may optionally be replaced by a substituent as defined above. Optionally, a C1-4 alkyl may be interrupted by one or more moieties as defined elsewhere herein.

[0103] As used herein, the term “C1-6 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 straightchain and branched C1-6 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, tert-butyl, n-pentyl, 2-m ethylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-m ethylpentyl, 3-m ethylpentyl, 2,2-dimethylbutyl, 2,3 -dimethylbutyl and 3, 3 -dimethylpropyl. When two moieties of a molecule are linked by the C1-6 alkyl group, then examples for such C1-6 alkyl groups are -CH2-,Ascendis Pharma Growth Disorders A / S 16 22 December 2025

[0104] CPX75232PC

[0105] -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)- and -C(CH3)2-. Each hydrogen atom of a Ci-6carbon may optionally be replaced by a substituent as defined above. Optionally, a C1-6 alkyl may be interrupted by one or more moieties as defined elsewhere herein.

[0106] Accordingly, “C1-10 alkyl”, “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 C1-50 carbon may optionally be replaced by a substituent as defined above. Optionally, a C1-10 or C1-50 alkyl may be interrupted by one or more moieties as defined elsewhere herein.

[0107] As used herein, the term “C2-6 alkenyl” alone or in combination means a straight-chain or branched hydrocarbon moiety comprising at least one carbon-carbon double bond having 2 to 6 carbon atoms. If present at the end of a molecule, examples are -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CHCH2-CH3and -CH=CH-CH=CH2. When two moieties of a molecule are linked by the C2-6 alkenyl group, then an example for such C2-6 alkenyl is -CH=CH-. Each hydrogen atom of a C2-6 alkenyl moiety may optionally be replaced by a substituent as defined above. Optionally, a C2-6 alkenyl may be interrupted by one or more moieties as defined elsewhere herein.

[0108] Accordingly, the term “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. Optionally, a C2-10 alkenyl, C2-20 alkenyl or C2-50 alkenyl may be interrupted by one or more moieties as defined elsewhere herein.

[0109] As used herein, the term “C2-6 alkynyl” alone or in combination means straight-chain or branched hydrocarbon moiety comprising at least one carbon-carbon triple bond having 2 to 6 carbon atoms. If present at the end of a molecule, examples are -C=CH, -CH2-OCH, CH2-CH2-OCH and CH2-C=C-CH3. When two moieties of a molecule are linked by the alkynyl group, then an example is -C=C-. Each hydrogen atom of a C2-6 alkynyl group may optionally be replaced by a substituent as defined above. Optionally, one or more double bond(s) may occur. Optionally, a C2-6 alkynyl may be interrupted by one or more moieties as defined elsewhere herein.Ascendis Pharma Growth Disorders A / S 17 22 December 2025

[0110] CPX75232PC

[0111] Accordingly, as used herein, 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 carboncarbon 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. Optionally, one or more double bond(s) may occur. Optionally, a C2-10 alkynyl, C2-20 alkynyl or C2-50 alkynyl may be interrupted by one or more moieties as defined elsewhere herein.

[0112] As mentioned above, a Ci-4 alkyl, Ci-6 alkyl, Ci-io alkyl, C1-20 alkyl, C1-50 alkyl, C2-6 alkenyl, C2-10 alkenyl, C2-20 alkenyl, C2-50 alkenyl, C2-6 alkynyl, C2-10 alkynyl, C2-20 alkenyl or C2-50 alkynyl may optionally be interrupted by one or more moieties which in certain embodiments are selected from the group consisting of

[0113]

[0114] wherein

[0115] dashed lines indicate attachment to the remainder of the moiety or reagent; and

[0116] -R and -Raare independently of each other selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3 -methylpentyl, 2,2-dimethylbutyl, 2,3- dimethylbutyl and 3, 3 -dimethylpropyl.

[0117] As used herein, the term “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 cycloalkyf’also includes bridged bicycles like norbornane or norbornene.Ascendis Pharma Growth Disorders A / S 18 22 December 2025

[0118] CPX75232PC

[0119] As used herein, the term “8- to 30-membered carbopolycyclyl” or “8- to 30-membered carbopoly cycle” 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). In certain embodiments 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.

[0120] As used herein, the term “3- to 10-membered heterocyclyl” or “3- to 10-membered heterocycle” means a ring with 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 4 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for 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, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine and homopiperazine. Each hydrogen atom of a 3 - to 10-membered heterocyclyl or 3- to 10-membered heterocyclic group may be replaced by a substituent as defined elsewhere herein.

[0121] As used herein, the term “8- to 11 -membered heterobicyclyl” or “8- to 11 -membered heterobicycle” means a heterocyclic moiety of two rings with 8 to 11 ring atoms, where at least one ring atom is shared by both rings and that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 6 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for an 8- to 11 -membered heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline,Ascendis Pharma Growth Disorders A / S 19 22 December 2025

[0122] CPX75232PC

[0123] dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine and pteridine. The term 8- to 11-membered heterobicycle also includes spiro structures of two rings like l,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles like 8-aza-bicyclo[3.2.1]octane. Each hydrogen atom of an 8- to 11 -membered heterobicyclyl or 8- to 11 -membered heterobicycle carbon may be replaced by a substituent as defined elsewhere herein.

[0124] Similary, the term “8- to 30-membered heteropolycyclyl” or “8- to 30-membered heteropolycycle” means a heterocyclic moiety of more than two rings with 8 to 30 ring atoms, in certain embodiments of three, four or five rings, 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 unsaturated), wherein at least one ring atom up to 10 ring atoms are replaced by a heteroatom selected from the group of sulfur (including -S(O)- and -S(O)2-), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of a molecule via a carbon or nitrogen atom.

[0125] It is understood that the phrase “the pair Rx / Ryis joined together with the atom to which they are attached to form a C3-10 cycloalkyl or a 3- to 10-membered heterocyclyl” in relation with a moiety of the structure

[0126]

[0127] means that Rxand Ryform the following structure:

[0128]

[0129] wherein R is C3-10 cycloalkyl or 3- to 10-membered heterocyclyl.

[0130] It is also understood that the phrase “the pair Rx / Ryis joint together with the atoms to which they are attached to form a ring A” in relation with a moiety of the structureAscendis Pharma Growth Disorders A / S 20 22 December 2025

[0131] CPX75232PC

[0132]

[0133] means that Rxand Ryform the following structure:

[0134]

[0135] As used herein, the term “halogen” means fluoro, chloro, bromo or iodo. In certain embodiments halogen is fluoro or chloro.

[0136] As used herein, the term “albumin-binding moiety” refers to a moiety that binds to albumin, such as serum albumin, under physiological conditions (aqueous buffer at pH 7.4, 37°C). An albumin-binding moiety may be a small molecule, peptide or lipid that interacts non-covalently or covalently with albumin to enable or enhance binding, association or complex formation. Such moieties can be naturally occurring or engineered and may include fatty acids or fatty acid derivatives, hydrophobic groups or peptides known in the art to bind albumin.

[0137] As used herein, the term “asymmetric growth of condyles” refers to a condition in which the medial and lateral condylar growth plates of the knee develop at different rates, resulting in lower leg bowing.

[0138] As used herein, the term “gait speed” refers to the time that a subject takes to walk a specific distance at a comfortable pace. Gait speed may be expressed as a measure of distance per unit time (e.g., meters per second) and can be determined using standardized walking tests, sensor-based systems or other suitable measurement techniques.

[0139] As used herein, the term “stride length” refers to the distance covered by a subject during one complete gait cycle, measured from the point of initial contact of one foot to the subsequent point of initial contact of the same foot.

[0140] As used herein, the term “knee valgus moments” refers to the rotational force or torque applied to the knee joint in the frontal plane. They are typically expressed in units of torque (e.g., Newton-meters)Ascendis Pharma Growth Disorders A / S 21 22 December 2025

[0141] CPX75232PC

[0142] and may be calculated based on ground reaction forces, limb kinematics or segmental inertial properties during walking, running, or landing.

[0143] As used herein, the term “mediolateral static stability” refers to the ability of a subject to maintain the body's center of gravity within the boundaries of the base of support in the frontal plane while minimizing mediolateral movement of the center of pressure during quiet standing. Mediolateral static stability may be quantified by parameters such as the displacement of the center of pressure, sway amplitude or load distribution between lower extremities during a standing position.

[0144] As used herein, the term “and / or” is to be taken as specific disclosure of each of the specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,” “A or B,” “A” (alone) and “B” (alone). Likewise, the term “and / or” as used in a phrase such as “A, B and / or C” is intended to encompass each of the following aspects: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0145] As used herein, the term “dose” or “unit 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.

[0146] As used herein, the term “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.Ascendis Pharma Growth Disorders A / S 22 22 December 2025

[0147] CPX75232PC

[0148] As used herein, the term “patient” refers to a subject amenable to treatment or prophylaxis according to the invention, particularly a human subject.

[0149] In general, the term “comprise” or “comprising” also encompasses “consist of’ or “consisting of’.

[0150] In another aspect the present invention relates to the use of a CNP or CNP conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such CNP or CNP conjugate or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a lower extremity deformity in a subject having a skeletal dysplasia.

[0151] In another aspect the present invention relates to a method of treating, preventing or decreasing a lower extremity deformity in a subject suffering from a skeletal dysplasia, the method comprising the step of administering a pharmaceutically effective amount of a CNP or CNP conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such CNP or CNP conjugate or a pharmaceutically acceptable salt thereof to said subject.

[0152] In another aspect the present invention relates to a method of improving a lower extremity deformity in a subject suffering from a skeletal dysplasia, the method comprising:

[0153] i) assessing the lower extremity deformity, at least once, in the subject suffering from the skeletal dysplasia, and

[0154] ii) administering a therapeutically effective amount of a CNP or CNP conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such CNP or CNP conjugate or a pharmaceutically acceptable salt thereof to said subject.

[0155] Said assessment of the lower extremity deformity may provide a baseline value or determination of the lower extremity deformity, optionally wherein said assessment is carried out within a month before initiating the administering step.

[0156] Said assessment of the lower extremity deformity comprises the step of measuring one or more parameters indicative of said lower extremity deformity as described elsewhere herein.Ascendis Pharma Growth Disorders A / S 23 22 December 2025

[0157] CPX75232PC

[0158] In certain embodiments the lower extremity deformity is lower leg bowing, also referred to as genu varum. In certain embodiments such lower leg bowing is caused by an increased relative length of the fibula compared to the tibia compared to subjects without skeletal dysplasia. In certain embodiments such lower leg bowing is caused by asymmetric growth of condyles. In certain embodiments such lower log bowing is caused by increased laxity at the hip and / or knee joints.

[0159] In certain embodiments the skeletal dysplasia is a skeletal dysplasia that results in leg bowing. In certain embodiments the skeletal dysplasia is caused by decreased mineralization, such as for example X-linked hypophosphatemia (XLH) or perinatal hypophosphatasia (HPP). In certain embodiments the skeletal dysplasia is achondroplasia.

[0160] In certain embodiments the subject has a lower extremity deformity. In certain embodiments the subject has a lower extremity deformity at the start of the treatment. In certain embodiments the treatment reduces the tibia-to-femoral angle. In certain embodiments such reduction in the tibia-to-femoral angle is a reduction of at least one degree compared to baseline within the first year of treatment. In certain embodiments the reduction in the tibia-to-femoral angle is a reduction of the tibia-to-femoral Z-score, such as the tibia-to-femoral angle Z-score, of at least one degree compared to baseline within the first year of treatment. In certain embodiments the treatment reduces the mechanical axis deviation. In certain embodiments such reduction in mechanical axis deviation is a reduction of at least one mm compared to baseline within the first year of treatment. In certain embodiments the reduction in the mechanical axis deviation is a reduction of the mechanical axis deviation Z-score of at least one mm compared to baseline within the first year of treatment. In certain embodiments the treatment reduces the fibula-to-tibia ratio.

[0161] In certain embodiments the subject is at risk of developing lower extremity deformity. In certain embodiments the treatment prevents the formation of the lower extremity deformity in such subject or may result in a less severe lower extremity deformity than without the treatment.

[0162] In certain embodiments the treatment comprises the step of measuring one or more parameters indicative of the lower extremity deformity, which may be prior to the initiation of the treatment, during and / or after the treatment. Suitable parameters may be the tibia-to-femoral angle, theAscendis Pharma Growth Disorders A / S 24 22 December 2025

[0163] CPX75232PC

[0164] mechanical axis deviation or the fibula-to-tibia ratio, which may be measured by taking X-rays of the lower extremities while standing.

[0165] In certain embodiments treatment starts upon birth and / or prior to the manifestation of the lower extremity deformity. In such case the treatment may prevent the manifestation of a lower extremity deformity or may result in a less severe form of lower extremity deformity.

[0166] In certain embodiments the subject is a mammalian subject, such as a human subject. The human subject is in certain embodiments a pediatric subject. In certain embodiments the subject is an infant. In certain embodiments the subject is a newborn. In certain embodiments the subject is a pediatric subject of less than 8 years of age.

[0167] In certain embodiments the subject has a TFA angle of >5 degrees.

[0168] In certain embodiments the treatment is accompanied by corrective surgery of a lower extremity. In certain embodiments the treatment eliminates the need for corrective surgery, in particular if the treatment starts prior to the manifestation of the lower extremity deformity, such as at birth.

[0169] In certain embodiments the treatment starts upon diagnosis of the skeletal dysplasia. If the skeletal dysplasia is detected in utero, the treatment may start in utero or upon birth. Treatment may be for one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, eleven years, twelve years, thirteen years, fourteen years, fifteen years, for more than fifteen years or until bone epiphyses are closed. In certain embodiments treatment may continue beyond closure of bone epiphyses.

[0170] The treatment comprises successive administrations of the CNP or CNP conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such CNP or CNP conjugate or a pharmaceutically acceptable salt thereof. Such successive administrations may be daily, weekly, once every two weeks, once every three weeks, monthly or once every two months. Administration may occur via external application, injection or infusion, including intraarticular, periarticular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intraorbital, intravitreal, intratympanic, intravesical, intracardiac,Ascendis Pharma Growth Disorders A / S 25 22 December 2025

[0171] CPX75232PC

[0172] transtracheal, subcuticular, subcapsular, subarachnoid, intraspinal, intraventricular, intrastemal injection and infusion; direct delivery to the brain via implanted device allowing delivery of the invention or the like to brain tissue or brain fluids (e.g., Ommaya reservoir), direct intracerebroventricular injection or infusion, injection or infusion into brain or brain associated regions, injection into the subchoroidal space, retro-orbital injection and ocular instillation. In certain embodiments administration is via subcutaneous injection, which may be done with a pen injector or via a syringe.

[0173] In certain embodiments the treatment increases gait speed. In certain embodiments the treatment increases stride length. In certain embodiments the treatment increases cadence. In certain embodiments the treatment reduces internal knee valgus moments. In certain embodiments the treatment increases mediolateral static stability. In certain embodiments the treatment increases dynamic stability. In certain embodiments the treatment increases knee joint stability in the mediolateral direction.

[0174] In certain embodiments the CNP is selected from the group consisting of

[0175] SEQ ID NO: 1 (CNP-22):

[0176] GLSKGCFGLKLDRIGSMSGLGC,

[0177] SEQ ID NO:2 (CNP-53):

[0178] DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:3 (G-CNP-53):

[0179] GDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:4 (M-CNP-53):

[0180] MDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:5 (P-CNP-53):

[0181] PDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:6 (CNP-53 M48N):

[0182] DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC,

[0183] SEQ ID NO:7 (CNP-53 Al 5-31):

[0184] DLRVDTKSRAAWARGLSKGCFGLKLDRIGSMSGLGC,

[0185] SEQ ID NO: 8 (CNP-52):

[0186] LRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC,Ascendis Pharma Growth Disorders A / S 26 22 December 2025

[0187] CPX75232PC

[0188] SEQ ID NO: 9 (CNP-51):

[0189] RVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO: 10 (CNP-50):

[0190] VDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO: 11 (CNP-49):

[0191] DTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO: 12 (CNP -48):

[0192] TKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO: 13 (CNP-47):

[0193] KSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO: 14 (CNP -46):

[0194] SRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO: 15 (CNP-45):

[0195] RAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC,

[0196] SEQ ID NO: 16 (CNP -44):

[0197] AAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC,

[0198] SEQ ID NO: 17 (CNP-44 A 14-22):

[0199] AAWARLLQEHPNAGLSKGCFGLKLDRIGSMSGLGC,

[0200] SEQ ID NO: 18 (CNP-44 Al 5-22):

[0201] AAWARLLQEHPNARGLSKGCFGLKLDRIGSMSGLGC,

[0202] SEQ ID NO: 19 (CNP -43):

[0203] AWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC,

[0204] SEQ ID NO:20 (CNP-42):

[0205] WARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ IDNO:21 (CNP-41):

[0206] ARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC,

[0207] SEQ ID NO:22 (CNP-40):

[0208] RLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ IDNO:23 (CNP-39):

[0209] LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ IDNO:24 (CNP-38):

[0210] LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC,Ascendis Pharma Growth Disorders A / S 27 22 December 2025

[0211] CPX75232PC

[0212] SEQ IDNO:25 (CNP-37):

[0213] QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:26 (CNP-37 QlpQ, wherein pQ = pyroglutamate): pQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:27 (G-CNP-37):

[0214] GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:28 (P-CNP-37):

[0215] PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:29 (M-CNP-37):

[0216] MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:30 (PG-CNP-37):

[0217] PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ IDNO:31 (MG-CNP-37):

[0218] MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:32 (CNP-37 M32N):

[0219] QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC, SEQ ID NO:33 (G-CNP-37 M32N):

[0220] GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC, SEQ ID NO:34 (G-CNP-37 K14Q):

[0221] GQEHPNARKYKGANQKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:35 (G-CNP-37 K14P):

[0222] GQEHPNARKYKGANPKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:36 (G-CNP-37 K14Q, Al 5):

[0223] GQEHPNARKYKGANQGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:37 (G-CNP-37 K14Q, K15Q):

[0224] GQEHPNARKYKGANQQGLSKGCFGLKLDRIGSMSGLGC, SEQ IDNO:38 (CNP-36):

[0225] EHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:39 (CNP-35):

[0226] HPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ IDNO:40 (CNP-34):

[0227] PNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC,Ascendis Pharma Growth Disorders A / S 28 22 December 2025

[0228] CPX75232PC

[0229] SEQ IDNO:41 (CNP-33):

[0230] NARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ IDNO:42 (CNP-32):

[0231] ARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ IDNO:43 (CNP-31):

[0232] RKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ IDNO:44 (CNP-30):

[0233] KYKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ IDNO:45 (CNP-29):

[0234] YKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ IDNO:46 (CNP-28):

[0235] KGANKKGLSKGCFGLKLDRIGSMSGLGC,

[0236] SEQ ID NO:47 (GHKSEVAHRF-CNP-28) GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ IDNO:48 (CNP-27):

[0237] GANKKGLSKGCFGLKLDRIGSMSGLGC,

[0238] SEQ ID NO:49 (CNP-27 K4Q, K5Q):

[0239] GANQQGLSKGCFGLKLDRIGSMSGLGC,

[0240] SEQ ID NO:50 (CNP-27 K4R, K5R):

[0241] GANRRGLSKGCFGLKLDRIGSMSGLGC,

[0242] SEQ ID NO: 51 (CNP-27 K4P, K5R):

[0243] GANPRGLSKGCFGLKLDRIGSMSGLGC,

[0244] SEQ ID NO:52 (CNP-27 K4S, K5S):

[0245] GANSSGLSKGCFGLKLDRIGSMSGLGC,

[0246] SEQ ID NO 53 (CNP-27 K4P, K5R):

[0247] GANGANPRGLSRGCFGLKLDRIGSMSGLGC,

[0248] SEQ ID NO: 54 (CNP-27 K4R, K5R, K9R):

[0249] GANRRGLSRGCFGLKLDRIGSMSGLGC,

[0250] SEQ ID NO 55 (CNP-27 K4R, K5R, K9R, M22N):

[0251] GANRRGLSRGCFGLKLDRIGSNSGLGC,

[0252] SEQ ID NO:56 (P-CNP-27 K4R, K5R, K9R):

[0253] PGANRRGLSRGCFGLKLDRIGSMSGLGC,Ascendis Pharma Growth Disorders A / S 29 22 December 2025

[0254] CPX75232PC

[0255] SEQ ID NO:57 (M-CNP-27 K4R, K5R, K9R):

[0256] MGANRRGLSRGCFGLKLDRIGSMSGLGC,

[0257] SEQ ID NO: 58 (HSA fragment-CNP-27):

[0258] GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:59 (HSA fragment-CNP-27 M22N):

[0259] GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSNSGLGC, SEQ ID NO: 60 (M-HSA fragment-CNP-27):

[0260] MGHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:61 (P-HSA fragment-CNP-27):

[0261] PGHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO: 62 (CNP-26):

[0262] ANKKGLSKGCFGLKLDRIGSMSGLGC,

[0263] SEQ ID NO: 63 (CNP-25):

[0264] NKKGLSKGCFGLKLDRIGSMSGLGC,

[0265] SEQ ID NO: 64 (CNP-24):

[0266] KKGLSKGCFGLKLDRIGSMSGLGC,

[0267] SEQ IDNO:65 (CNP-23):

[0268] KGLSKGCFGLKLDRIGSMSGLGC,

[0269] SEQ ID NO: 66 (R-CNP-22):

[0270] RGLSKGCFGLKLDRIGSMSGLGC,

[0271] SEQ ID NO: 67 (ER-CNP-22):

[0272] ERGLSKGCFGLKLDRIGSMSGLGC,

[0273] SEQ ID NO: 68 (R-CNP-22 K4R):

[0274] RGLSRGCFGLKLDRIGSMSGLGC,

[0275] SEQ ID NO: 69 (ER-CNP-224KR):

[0276] ERGLSRGCFGLKLDRIGSMSGLGC,

[0277] SEQ ID NO: 70 (RR-CNP-22):

[0278] RRGLSRGCFGLKLDRIGSMSGLGC,

[0279] SEQ ID NO:71 (HRGP fragment-CNP-22):

[0280] GHHSHEQHPHGANQQGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO: 72 (HRGP fragment-CNP-22):

[0281] GAHHPHEHDTHGANQQGLSKGCFGLKLDRIGSMSGLGC,Ascendis Pharma Growth Disorders A / S 30 22 December 2025

[0282] CPX75232PC

[0283] SEQ ID NO: 73 (HRGP fragment-CNP-22):

[0284] GHHSHEQHPHGANPRGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO: 74 (IgGi(Fc) fragment-CNP-22):

[0285] GQPREPQVYTLPPSGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO: 75 (HSA fragment-CNP-22):

[0286] GQHKDDNPNLPRGANPRGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO: 76 (HSA fragment-CNP-22):

[0287] GERAFKAWAVARLSQGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO:77 (osteocrin NPR C inhibitor fragment-CNP-22): FGIPMDRIGRNPRGLSKGCFGLKLDRIGSMSGLGC,

[0288] SEQ ID NO:78 (FGF2 heparin-binding domain fragment-CNP-22): GKRTGQYKLGSKTGPGPKGLSKGCFGLKLDRIGSMSGLGC, SEQ ID NO: 79 (IgGi(Fc) fragment-CNP-22 K4R):

[0289] GQPREPQVYTGANQQGLSRGCFGLKLDRIGSMSGLGC, SEQ ID NO: 80 (HSA fragment-CNP-22 K4R):

[0290] GVPQVSTSTGANQQGLSRGCFGLKLDRIGSMSGLGC, SEQ ID NO: 81 (fibronectin fragment-CNP-22 K4R):

[0291] GQPSSSSQSTGANQQGLSRGCFGLKLDRIGSMSGLGC, SEQ ID NO: 82 (fibronectin fragment-CNP-22 K4R):

[0292] GQTHSSGTQSGANQQGLSRGCFGLKLDRIGSMSGLGC, SEQ ID NO: 83 (fibronectin fragment-CNP-22 K4R):

[0293] GSTGQWHSESGANQQGLSRGCFGLKLDRIGSMSGLGC, SEQ ID NO: 84 (zinc finger fragment-CNP-22 K4R):

[0294] GS S SS S S S SSGANQQGLSRGCFGLKLDRIGSMSGLGC, SEQ IDNO:85 (CNP-21):

[0295] LSKGCFGLKLDRIGSMSGLGC,

[0296] SEQ ID NO: 86 (CNP-20):

[0297] SKGCFGLKLDRIGSMSGLGC,

[0298] SEQ ID NO: 87 (CNP-19):

[0299] KGCFGLKLDRIGSMSGLGC,

[0300] SEQ IDNO:88 (CNP-18):

[0301] GCFGLKLDRIGSMSGLGC,Ascendis Pharma Growth Disorders A / S 31 22 December 2025

[0302] CPX75232PC

[0303] SEQ ID NO: 89 (CNP-17):

[0304] CFGLKLDRIGSMSGLGC,

[0305] SEQ ID NO: 90 (BNP fragment-CNP-17-BNP fragment):

[0306] SPKMVQGSGCFGLKLDRIGSMSGLGCKVLRRH,

[0307] SEQ ID NO:91 (CNP-38 L1G):

[0308] GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC,

[0309] SEQ ID NO: 92 (Ac-CNP-37; wherein Ac= acetyl):

[0310] Ac-QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC,

[0311] SEQ ID NO: 93:

[0312] QEHPNARXI¥X2GANX3X4GLSX5GCFGLX6LDRIGSMSGLGC,

[0313] wherein Xi, X2, X3, X4, X5 and Xe 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 Xe 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,

[0314] SEQ ID NO: 94:

[0315] QEHPNARKYKGANX1X2GLSX3GCFGLX4LDRIGSMSGLGC,

[0316] wherein 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,

[0317] SEQ ID NO: 95:

[0318] QEHPNARKYKGANX1X2GLSKGCFGLKLDRIGSMSGLGC,

[0319] wherein X1X2 are selected from the group consisting of KR, RK, KP, PK, SS, RS, SR, QK, QR, KQ, RQ, RR and QQ,

[0320] SEQ ID NO:97 (CNP-38 N6Q, N14Q):

[0321] LQEHPQARKYKGAQKKGLSKGCFGLKLDRIGSMSGLGC,

[0322] SEQ ID NO: 98:

[0323] PGQEHPQARRYRGAQRRGLSRGCFGLKLDRIGSMSGLGC (SEQ ID NO:98)

[0324] SEQ ID NO: 99:

[0325] PGQEHPNARRYRGANRRGLSRGCFGLKLDRIGSMSGLGC,

[0326] SEQ ID NO: 100:Ascendis Pharma Growth Disorders A / S 32 22 December 2025

[0327] CPX75232PC

[0328] PGQEHPQARKYKGAQKKGLSKGCFGLKLDRIGSMSGLGC,

[0329] SEQ ID NO: 101 (Ac= acetyl):

[0330] Ac-PGQEHPQARRYRGAQRRGLSRGCFGLKLDRIGSMSGLGC,

[0331] SEQ ID NO: 102 (Ac= acetyl):

[0332] Ac-PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC-NIh,

[0333] SEQ ID NO: 103 (Ac= acetyl):

[0334] Ac-PGQEHPNARRYRGANRRGLSRGCFGLKLDRIGSMSGLGC,

[0335] SEQ ID NO: 104 (Ac= acetyl):

[0336] AC-PGQEHPNARRYRGANRRGLSRGCFGLKLDRIGSMSGLGC-NH2, and

[0337] SEQ ID NO: 105 (Ac= acetyl):

[0338] AC-PGQEHPQARRYRGAQRRGLSRGCFGLKLDRIGSMSGLGC-NH2;

[0339] wherein in all peptides the cysteines are connected through a disulfide-bridge.

[0340] In certain embodiments the CNP is a peptide having the sequence of SEQ ID NO:30, which is also known as vosoritide and marketed as VOXZOGO®. In certain embodiments the CNP has the sequence of SEQ ID NO:24. In certain embodiments the CNP has the sequence of SEQ ID NO:25. In certain embodiments the CNP has the sequence of SEQ ID NO:26.

[0341] In certain embodiments the CNP conjugate is a CNP of SEQ ID NO:30, which is covalently conjugated to an albumin-binding moiety. The structure of such albumin-binding moiety is as described elsewhere herein. In certain embodiments the albumin-binding moiety is of formula (w-i)

[0342]

[0343] wherein

[0344] the dashed line indicates attachment to the CNP having the sequence of SEQ ID NO:30, such as to the N-terminal amine functional group or to an amine functional group on the ring of said CNP.

[0345] In certain embodiments the albumin-binding moiety is of formula (w-ii) or (w-ii)’Ascendis Pharma Growth Disorders A / S 33 22 December 2025

[0346] CPX75232PC

[0347]

[0348] wherein

[0349] the dashed line indicates attachment to the CNP having the sequence of SEQ ID NO:30, such as to the N-terminal amine functional group or to an amine functional group on the ring of said CNP.

[0350] In certain embodiments the albumin-binding moiety is of formula (w-i)’

[0351]

[0352] (w-i)’,

[0353] wherein

[0354] the dashed line indicates attachment to the CNP having the sequence of SEQ ID NO:30, such as to the N-terminal amine functional group or to an amine functional group on the ring of said CNP.

[0355] In certain embodiments the albumin-binding moiety is of formula (w-i)”

[0356]

[0357] (w-i)”,

[0358] whereinAscendis Pharma Growth Disorders A / S 34 22 December 2025

[0359] CPX75232PC

[0360] the dashed line indicates attachment to the CNP having the sequence of SEQ ID NO:30, such as to the N-terminal amine functional group or to an amine functional group on the ring of said CNP.

[0361] In certain embodiments the CNP conjugate is a reversible conjugate, in which at least one CNP moiety -D is reversibly conjugated to at least one moiety -Z. In certain embodiments such conjugate releases an unmodified CNP.

[0362] In certain embodiments the CNP conjugate is of formula (la) or (lb):

[0363]

[0364] wherein

[0365] -D is a CNP moiety;

[0366] -L1- is a reversible linker moiety;

[0367] -L2- is absent or a spacer moiety;

[0368] -Z is a polymeric moiety or an albumin-binding moiety;

[0369] 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; and

[0370] y is an integer selected from the group consisting of 2, 3, 4 and 5.

[0371] In certain embodiments the CNP conjugate is formula (la). In certain embodiments x of formula (la) is 1. In certain embodiments x of formula (la) is 2. In certain embodiments x of formula (la) is 3. In certain embodiments x of formula (la) is 4. In certain embodiments x of formula (la) is 5. In certain embodiments x of formula (la) is 6. In certain embodiments x of formula (la) is 7. In certain embodiments x of formula (la) is 8.

[0372] In certain embodiments the CNP conjugate is formula (lb). In certain embodiments y of formula (lb) is 1. In certain embodiments y of formula (lb) is 2. In certain embodiments y of formula (lb) is 3. In certain embodiments y of formula (lb) is 4. In certain embodiments y of formula (lb) is 5.Ascendis Pharma Growth Disorders A / S 35 22 December 2025

[0373] CPX75232PC

[0374] If a conjugate comprises more than one moiety -D, they are in certain embodiments of the same type, i.e., all moieties -D of the conjugate have the same structure. In certain embodiments a conjugate comprises more than one moiety -D and these moieties -D have a different structure. There may be two different types of -D, three different types of -D, four different types of -D or five different types of -D in such a conjugate. These different types of -D may be conjugated to the same or to a different type of -L1-.

[0375] In certain embodiments -D of formula (la) or (lb) is a CNP moiety having the sequence of SEQ ID NOT, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NOT, SEQIDNO: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 NOTO, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NOTO, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NOTO, SEQ ID NOT 1, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NOTO, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NOTO, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104 or SEQ ID NO: 105.

[0376] In certain embodiments -D of formula (la) or (lb) has the sequence of SEQ ID NO:24. In certain embodiments -D of formula (la) or (lb) has the sequence of SEQ ID NO:25. In certain embodiments -D of formula (la) or (lb) has the sequence of SEQ ID NO:26. In certain embodiments -D of formula (la) or (lb) has the sequence of SEQ ID NOTO.Ascendis Pharma Growth Disorders A / S 36 22 December 2025

[0377] CPX75232PC

[0378] In certain embodiments -D is a CNP moiety conjugated to an albumin-binding moiety, i.e., the drug released from a conjugate of formula (la) or (lb) comprises a CNP peptide, that is stably conjugated to an albumin-binding moiety. Such albumin-binding moiety is described in more detail elsewhere herein. In certain embodiments the CNP conjugate is of formula (la) with x = 1, -D has the sequence of SEQ ID NO:30 to which an albumin-binding moiety is covalently, such as covalently and stably conjugated, and -Z is a further albumin-binding moiety. It is understood that such CNP conjugate comprises two albumin-binding moieties, one that remains conjugated to the CNP upon release, and one albumin-binding moiety that is reversibly conjugated, namely -Z.

[0379] If a conjugate comprises more than one moiety -L1-, they are in certain embodiments of the same type, i.e., all moieties -L1- of the conjugate have the same structure. In certain embodiments a conjugate comprises more than one moiety -L1- and these moieties -L1- have a different structure. There may be two different types of -L1-, three different types of -L four different types of -L1- or five different types of -L1- in such a conjugate. These different types of -L1- may be conjugated to the same or different type of -L2- and may be conjugated to the same or to a different type of -D.

[0380] -L1- of formula (la) or (lb) may be conjugated to a functional group of the side chain of an amino acid residue of the CNP peptide, to the N-terminal amine functional group or to the C-terminal carboxyl functional group of the CNP peptide. In certain embodiments -L1- of formula (la) or (lb) is conjugated to the N-terminal amine functional group of the CNP peptide. In certain embodiments -L1- of formula (la) or (lb) is conjugated to the C-terminal carboxyl functional group of the CNP peptide. In certain embodiments -L1- of formula (la) or (lb) is conjugated to a functional group of a side chain of an amino acid residue of the CNP peptide.

[0381] -L1- of formula (la) or (lb) is conjugated to a functional group of a CNP peptide, which in certain embodiments is selected from the group consisting of primary amine, secondary amine, carboxylic acid, maleimide, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isocyanate, isothiocyanate, phosphoric acid, phosphonic acid, haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, sulfate, disulfide, vinyl sulfone, vinyl ketone, diazoalkane, oxirane, guanidine and aziridine. In certain embodiments the functional group of the CNP peptide to which -L1- is conjugated is selected from the group consisting of primary amine, secondary amine, hydroxyl and guanidine. In certain embodiments -L1- is conjugated to a primary amine or to aAscendis Pharma Growth Disorders A / S 37 22 December 2025

[0382] CPX75232PC

[0383] secondary amine of the CNP peptide. In certain embodiments -L1- is conjugated to a primary amine functional group of the CNP peptide.

[0384] If the moiety -L1- of formula (la) or (lb) is conjugated to a functional group of the side chain of an amino acid residue of the CNP peptide, said amino acid residue is selected from the group consisting of proteinogenic amino acid residues and non-proteinogenic amino acid residues. It is understood that such non-proteinogenic amino acids are not found in the sequence of native CNP.

[0385] -L1- of formula (la) or (lb) can be connected to -D through any type of linkage, provided that it is reversible. In certain embodiments -L1- of formula (la) or (lb) is connected to -D through a linkage selected from the group consisting of amide, ester, carbamate, acetal, aminal, imine, oxime, hydrazone, disulfide and acylguanidine. In certain embodiments -L1- of formula (la) or (lb) 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 -L1- may render the linkage reversible. In certain embodiments -L1- is connected to -D through an amide linkage.

[0386] In certain embodiments -L1- of formula (la) or (lb) is conjugated to a functional group of the side chain of a proteinogenic amino acid residue of CNP. In certain embodiments this amino acid is selected from the group consisting of lysine, histidine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid and arginine. In certain embodiments said amino acid is selected from the group consisting of lysine, aspartic acid, arginine and serine. In certain embodiments said amino acid is selected from the group consisting of lysine, arginine and serine. In certain embodiments -L1- of formula (la) or (lb) is conjugated to the amine functional group the side chain of a lysine residue of CNP. In certain embodiments such lysine is located within the ring moiety of the CNP. In certain embodiments -L1- of formula (la) or (lb) is conjugated to the equivalent position of the lysine at position 4 of the ring moiety of SEQ ID NO:96. In certain embodiments -L1- of formula (la) or (lb) is conjugated to a lysine residue outside the ring structure. In certain embodiments -L1- of formula (la) or (lb) is conjugated to the amine functional group of the side chain of the lysine residue located within the ring moiety of CNP.Ascendis Pharma Growth Disorders A / S 38 22 December 2025

[0387] CPX75232PC

[0388] The moiety -L1- is a reversible prodrug linker from which the drug, i.e., H-D, is released in its free form, i.e. it is a traceless prodrug linker. It is understood that the “H-” in “H-D” is a hydrogen. Suitable prodrug linkers are known in the art, such as for example the reversible prodrug linker moieties disclosed in W02002 / 089789A1, W02005 / 099768A2, WO2006 / 136586A2, WO2011 / 089216A1, WO2013 / 024053 Al, US7585837B2 and WO2016 / 020373 Al, which are incorporated by reference herewith in their entirety.

[0389] In certain embodiments -L1- is disclosed in W02009 / 095479A2. Accordingly, in certain embodiments -L1- is of formula (II):

[0390]

[0391] wherein

[0392] the dashed line indicates attachment to a nitrogen, hydroxyl or thiol of -D;

[0393] -X- is selected from the group consisting of -C(R4R4a)-, -N(R4)-. -O-, -C(R4R4a)-C(R5R5a)-, -C(R5R5a)-C(R4R4a)-, -C(R4R4a)-N(R6)-, -N(R6)-C(R4R4a)-, -C(R4R4a)-O-, -O-C(R4R4a)- and -C(R7R7a)-;

[0394] >X1=is selected from the group consisting of >C= and >S(O)=;

[0395] -X2- is selected from the group consisting of -C(R8R8a)- and -C(R8R8a)-C(R9R9a)-;

[0396] =X3is selected from the group consisting of =0, =S and =N-CN;

[0397] -R1, -Rla, -R2, -R2a, -R4, -R4a, -R5, -R5a, -R6, -R8, -R8a, -R9and -R9aare independently selected from the group consisting of -H and Ci-6 alkyl;

[0398] -R3and -R3aare independently selected from the group consisting of -H and Ci-6 alkyl, provided that in case one of -R3and -R3aor both are other than -H they are connected to N to which they are attached through an sp3-hybridized carbon atom;

[0399] -R7is selected from the group consisting of -N(R10R10a) and -NR10-(C=O)-R11;

[0400] -R7a, -R10, -R10aand -R11are independently of each other selected from the group consisting of -H and Ci-6 alkyl;

[0401] optionally one or more of the pairs -Rla / -R4a, -Rla / -R5a, -Rla / -R7a, -R4a / -R5aand -R8a / -R9aform a chemical bond;Ascendis Pharma Growth Disorders A / S 39 22 December 2025

[0402] CPX75232PC

[0403] optionally one or more of the pairs -RJ / -Rla, -R2 / -R2a, -R4 / -R4a, -R5 / -R5a, -R8 / -R8aand -R9 / -R9aare joined together with the atom to which they are attached to form a C3-10 cycloalkyl or 3- to 10-membered heterocyclyl;

[0404] optionally one or more of the pairs -RV-R4, -RV-R5, -RV-R6, -RJ / -R7a, -R4 / -R5,-R4 / -R6, -R8 / -R9and -R2 / -R3are joined together with the atoms to which they are attached to form a ring A;

[0405] optionally -R3 / -R3aare joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycle;

[0406] 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 -L1- is substituted with -L2- and wherein -L1- is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (II) is not replaced by -L2- or a substituent.

[0407] In certain embodiments -L1- of formula (II) is not further substituted.

[0408] It is understood that if -R3 / -R3aof formula (II) are joined together with the nitrogen atom to which they are attached to form a 3 - to 10-membered heterocycle, only such 3- to 10-membered heterocycles may be formed in which the atoms directly attached to the nitrogen are sp3-hybridized carbon atoms. In other words, such 3- to 10-membered heterocycle formed by -R3 / -R3atogether with the nitrogen atom to which they are attached has the following structure:

[0409]

[0410] wherein

[0411] the dashed line indicates attachment to the rest of -L1-;

[0412] the ring comprises 3 to 10 atoms comprising at least one nitrogen; and

[0413] R#and R##represent an sp3-hydridized carbon atom.

[0414] It is also understood that the 3- to 10-membered heterocycle may be further substituted.Ascendis Pharma Growth Disorders A / S 40 22 December 2025

[0415] CPX75232PC

[0416] Exemplary embodiments of suitable 3- to 10-membered heterocycles formed by -R3 / -R3aof formula (II) together with the nitrogen atom to which they are attached are the following:

[0417]

[0418] wherein

[0419] dashed lines indicate attachment to the rest of the molecule; and

[0420] -R is selected from the group consisting of -H and Ci-6 alkyl.

[0421] -L1- of formula (II) may optionally be further substituted. In general, 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

[0422]

[0423] of formula (II) remains part of a primary, secondary or tertiary amine, i.e. -R3and -R3aare independently of each other -H or are connected to -N< through an sp3-hybridized carbon atom.

[0424] In certain embodiments -R1or -Rlaof formula (II) is substituted with -L2-. In certain embodiments -R2or -R2aof formula (II) is substituted with -L2-. In certain embodiments -R3or -R3aof formula (II) is substituted with -L2-. In certain embodiments -R4or -R4aof formula (II) is substituted with -L2-. In certain embodiments -R5or -R5aof formula (II) is substituted with -L2-. In certain embodiments -R6of formula (II) is substituted with -L2In certain embodiments -R7or -R7aof formula (II) is substituted with -L2-. In certain embodiments -R8or -R8aof formula (II) is substituted with -L2-. In certain embodiments -R9or -R9aof formula (II) is substituted with -L2-. In certain embodiments -R10or -R10aof formula (II) is substituted with -L2-. In certain embodiments -R11of formula (II) is substituted with -L2-.Ascendis Pharma Growth Disorders A / S 41 22 December 2025

[0425] CPX75232PC

[0426] In certain embodiments -X- of formula (II) is selected from the group consisting of -C(R4R4a)-, -N(R4)- and -C(R7R7a)-. In certain embodiments -X- of formula (II) is -C(R4R4a)-. In certain embodiments -X- of formula (II) is -C(R7R7a)-. In certain embodiments -R7of formula (II) is -N(R10R10a). In certain embodiments -R7of formula (II) is -NR10-(C=O)-R11.

[0427] In certain embodiments -R7of formula (II) is -N(R10R10a) with -R10being -H and -R10abeing methyl. In certain embodiments -R7of formula (II) is -N(R10R10a) with both-R10and -R10abeing -H. In certain embodiments -R7of formula (II) is -N(R10R10a) with both -R10and -R10abeing methyl. In certain embodiments -R7of formula (II) is -NR10-(C=O)-R11with -R10being -H and -R11being methyl. In certain embodiments -R7of formula (II) is -NR10-(C=O)-R11with -R10being methyl and -R11being -H. In certain embodiments -R7of formula (II) is -NR10-(C=O)-R11with -R10and -R11being methyl. In certain embodiments -R7of formula (II) is -NR10-(C=O)-R11with -R10and -R11being -H. In certain embodiments -R7aof formula (II) is -H. In certain embodiments -R7aof formula (II) is methyl.

[0428] In certain embodiments >X1=of formula (II) is >C=.

[0429] In certain embodiments =X3of formula (II) is =0.

[0430] In certain embodiments -X2- of formula (II) is -C(R8R8a)-.

[0431] In certain embodiments -R8and -R8aof formula (II) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments at least one of -R8and -R8aof formula (II) is -H. In certain embodiments both -R8and -R8aof formula (II) are -H.

[0432] In certain embodiments -R1and -Rlaof formula (II) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments at least one of -R1and -Rlaof formula (II) is -H. In certain embodiments both -R1and -Rlaof formula (II) are -H.

[0433] In certain embodiments -R2and -R2aof formula (II) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments at least one of -R2and -R2aof formula (II) is -H. In certain embodiments both -R2and -R2aof formula (II) are H.Ascendis Pharma Growth Disorders A / S 42 22 December 2025

[0434] CPX75232PC

[0435] In certain embodiments -R3and -R3aof formula (II) are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. In certain embodiments at least one of -R3and -R3aof formula (II) is methyl. In certain embodiments -R3and -R3aof formula (II) are both -H. In certain embodiments -R3and -R3aof formula (II) are both methyl. In certain embodiments -R3of formula (II) is -H and -R3aof formula (II) is methyl.

[0436] In certain embodiments -R4and -R4aof formula (II) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments at least one of -R4and -R4aof formula (II) is -H. In certain embodiments both -R4and -R4aof formula (II) are -H.

[0437] In certain embodiments the moiety -L1- is of formula (Ila):

[0438] > >

[0439]

[0440] wherein the dashed line indicates the attachment to a nitrogen of -D;

[0441] -R1, -Rla, -R2, -R2a, -R3, -R3a, -R7, -R7aand -X2- are used as defined in formula (II); and wherein -L1- is substituted with -L2- and wherein -L1- is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (Ila) is not replaced by -L2- or a substituent.

[0442] In certain embodiments -L1- of formula (Ila) is not further substituted.

[0443] In certain embodiments -R1and -Rlaof formula (Ila) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments at least one of -R1and -Rlaof formula (Ila) is -H. In certain embodiments both -R1and -Rlaof formula (Ila) are -H.

[0444] In certain embodiments -R7of formula (Ila) is -NR10-(C=O)-R11. In certain embodiments -R7of formula (Ila) is -NR10-(C=O)-R11with -R10being -H and -R11being methyl. In certain embodiments -R7of formula (Ila) is -NR10-(C=O)-R11with -R10being methyl and -R11being -H. In certain embodiments -R7of formula (Ila) is -NR10-(C=O)-R11with -R10and -R11being methyl. In certain embodiments -R7of formula (Ila) is -NR10-(C=O)-R11with -R10and -R11being -H.Ascendis Pharma Growth Disorders A / S 43 22 December 2025

[0445] CPX75232PC

[0446] In certain embodiments -R7aof formula (Ila) is -H. In certain embodiments -R7aof formula (Ila) is methyl.

[0447] In certain embodiments -X2- of formula (Ila) is -C(R8R8a)-.

[0448] In certain embodiments -R8and -R8aof formula (Ila) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments at least one of -R8and -R8aof formula (Ila) is -H. In certain embodiments both -R8and -R8aof formula (Ila) are -H.

[0449] In certain embodiments -R2and -R2aof formula (Ila) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments at least one of -R2and -R2aof formula (Ila) is -H. Even more preferably both -R2and -R2aof formula (Ila) are H.

[0450] In certain embodiments -R3and -R3aof formula (Ila) are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. In certain embodiments at least one of -R3and -R3aof formula (Ila) is methyl. In certain embodiments -R3and -R3aof formula (Ila) are both -H. In certain embodiments -R3and -R3aof formula (Ila) are both methyl. In certain embodiments -R3of formula (Ila) is -H and -R3aof formula (Ila) is methyl.

[0451] In certain embodiments the moiety -L1- is of formula (lib) :

[0452]

[0453] wherein the dashed line indicates the attachment to a nitrogen of -D;

[0454] -R2, -R2a, -R3, -R3a, -R10, -R11and -X2- are used as defined in formula (II); and

[0455] wherein -L1- is substituted with -L2- and wherein -L1- is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (lib) is not replaced by -L2- or a substituent.

[0456] In certain embodiments -L1- of formula (lib) is not further substituted.Ascendis Pharma Growth Disorders A / S 44 22 December 2025

[0457] CPX75232PC

[0458] In certain embodiments -X2- of formula (lib) is -C(R8R8a)-.

[0459] In certain embodiments -R8and -R8aof formula (lib) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments at least one of -R8and -R8aof formula (lib) is -H. In certain embodiments both -R8and -R8aof formula (lib) are -H.

[0460] In certain embodiments -R2and -R2aof formula (lib) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments at least one of -R2and -R2aof formula (lib) is -H. In certain embodiments both -R2and -R2aof formula (lib) are H.

[0461] In certain embodiments -R3and -R3aof formula (lib) are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. In certain embodiments at least one of -R3and -R3aof formula (lib) is methyl. In certain embodiments -R3and -R3aof formula (lib) are both -H. In certain embodiments -R3and -R3aof formula (lib) are both methyl. In certain embodiments -R3of formula (lib) is -H and -R3aof formula (lib) is methyl.

[0462] In certain embodiments -R10of formula (lib) is methyl. In certain embodiments -R10of formula (lib) is -H.

[0463] In certain embodiments -R11of formula (lib) is methyl. In certain embodiments -R11of formula (lib) is -H. In certain embodiments -R11of formula (lib) is -H, which is substituted with -L2-.

[0464] In certain embodiments -L1- is of formula (lie):

[0465]

[0466] (lie),

[0467] wherein the unmarked dashed line indicates the attachment to a nitrogen of -D;

[0468] the dashed line marked with the asterisk indicates attachment to -L2-; andAscendis Pharma Growth Disorders A / S 45 22 December 2025

[0469] CPX75232PC

[0470] wherein -L1- is substituted with -L2- and wherein -L1- is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (lie) is not replaced by -L2- or a substituent.

[0471] In certain embodiments the moiety -L1- of formula (lie) is not further substituted.

[0472] In certain embodiments -L1- is as disclosed in US8946405B2 and US8754190B2, which are herewith incorporated by reference in their entirety. Accordingly, in certain embodiments -L1- is of formula (III):

[0473]

[0474] (III),

[0475] wherein

[0476] the dashed line indicates attachment to nitrogen, oxygen or sulfur of -D;

[0477] m is 0 or 1;

[0478] at least one or both of -R1and -R2is / 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)R3, -S(O)R3, -S(O)2R3and -SR4,

[0479] one and only one of -R1and -R2is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted arylalkyl and optionally substituted heteroaryl alkyl; -R3is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR9and -N(R9)2;

[0480] -R4is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

[0481] each -R5is independently selected from the group consisting of -H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

[0482] -R9is selected from the group consisting of -H and optionally substituted alkyl;Ascendis Pharma Growth Disorders A / S 46 22 December 2025

[0483] CPX75232PC

[0484] -Y- is absent and -X- is -O- or -S-; or

[0485] -Y- is -N(Q)CH2- and -X- is -O-;

[0486] Q is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

[0487] optionally -R1and -R2may be joined to form a 3 to 8-membered ring; and

[0488] optionally both -R9together with the nitrogen to which they are attached form a heterocyclic ring;

[0489] wherein -L1- is substituted with -L2- and wherein -L1- is optionally further substituted.

[0490] Only in the context of formula (III) the terms used have the following meaning:

[0491] The term “alkyl” as used herein includes linear, branched or cyclic saturated hydrocarbon groups of 1 to 8 carbons, or in certain embodiments 1 to 6 or 1 to 4 carbon atoms.

[0492] The term “alkoxy” includes alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy and similar.

[0493] The term “alkenyl” includes non-aromatic unsaturated hydrocarbons with carbon-carbon double bonds.

[0494] The term “alkynyl” includes non-aromatic unsaturated hydrocarbons with carbon-carbon triple bonds.

[0495] The term “aryl” includes aromatic hydrocarbon groups of 6 to 18 carbons, such as 6 to 10 carbons, including groups such as phenyl, naphthyl and anthracenyl. The term “heteroaryl” includes aromatic rings comprising 3 to 15 carbons containing at least one N, O or S atom, such as 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.

[0496] In some instance, alkenyl, alkynyl, aryl or heteroaryl moieties may be coupled to the remainder of the molecule through an alkylene linkage. Under those circumstances, the substituent will be referredAscendis Pharma Growth Disorders A / S 47 22 December 2025

[0497] CPX75232PC

[0498] 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.

[0499] The term “halogen” includes bromo, fluoro, chloro and iodo.

[0500] The term “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.

[0501] When a ring system is optionally substituted, 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, -NR2, -OCOR, -NRCOR, -COOR, -CONR2, -SOR, -SO2R, -SONR2, -SO2NR2, 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.

[0502] In certain embodiments -L1- of formula (III) is not further substituted.

[0503] In certain embodiments -L1- is as disclosed in WO2013 / 036857A1, which is herewith incorporated by reference in its entirety. Accordingly, in certain embodiments -L1- is of formula (IV):

[0504]

[0505] wherein

[0506] the dashed line indicates attachment to a nitrogen of -D;

[0507] -R1is selected from the group consisting of optionally substituted Ci-Ce linear, branched, or cyclic alkyl; optionally substituted aryl; optionally substituted heteroaryl; alkoxy; and -NR5?; -R2is selected from the group consisting of -H; optionally substituted Ci-Ce alkyl; optionally substituted aryl; and optionally substituted heteroaryl;Ascendis Pharma Growth Disorders A / S 48 22 December 2025

[0508] CPX75232PC

[0509] -R3is selected from the group consisting of -H; optionally substituted Ci-Ce alkyl; optionally substituted aryl; and optionally substituted heteroaryl;

[0510] -R4is selected from the group consisting of -H; optionally substituted Ci-Ce alkyl; optionally substituted aryl; and optionally substituted heteroaryl;

[0511] each -R5is 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 -R5can be cycloalkyl or cycloheteroalkyl;

[0512] wherein -L1- is substituted with -L2- and wherein -L1- is optionally further substituted.

[0513] Only in the context of formula (IV) the terms used have the following meaning:

[0514] “Alkyl”, “alkenyl”, and “alkynyl” include linear, branched or cyclic hydrocarbon groups of 1-8 carbons or 1-6 carbons or 1-4 carbons wherein alkyl is a saturated hydrocarbon, alkenyl includes one or more carbon-carbon double bonds and alkynyl includes one or more carbon-carbon triple bonds. Unless otherwise specified these contain 1-6 C.

[0515] “Aryl” includes aromatic hydrocarbon groups of 6-18 carbons, such as 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, such as 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.

[0516] The term “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; thiocarbamate; thiourea; ketone; sulfone; sulfonamide; aryl including phenyl, naphthyl, and anthracenyl; heteroaryl including 5-member heteroaryls including as pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole, and tetrazole, 6-Ascendis Pharma Growth Disorders A / S 22 December 2025

[0517] CPX75232PC

[0518] member heteroaryls including pyridine, pyrimidine, pyrazine, and fused heteroaryls including benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzisoxazole, and benzisothi azole.

[0519] In certain embodiments -L1- of formula (IV) is not further substituted.

[0520] In certain embodiments -L1- has a structure as disclosed in W02005 / 099768A2. Accordingly, in certain embodiments the moiety -L1- is of formula (V-a) or (V-b):

[0521]

[0522] (V-b),

[0523] wherein

[0524] the unmarked dashed line indicates attachment to a nitrogen of -D;

[0525] the dashed line marked with the asterisk indicates attachment to -L2-;

[0526] n is 0, 1, 2, 3 or 4;

[0527] =Yi is =0, =S or =NR6;

[0528] -Y2- is -O-, -S- or -NR6-;

[0529] -Y3- is -O- or -S-;

[0530] -Y4- is -O-, -NR6- or -C(R7)(R8)-;

[0531] =Ys is =0 or =S;

[0532] -R2, -R3, -R5and -R6are independently of each other selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2- methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-m ethylpentyl, 3 -methylpentyl, 2,2- dimethylbutyl, 2, 3 -dimethylbutyl and 3, 3 -dimethylpropyl;Ascendis Pharma Growth Disorders A / S 50 22 December 2025

[0533] CPX75232PC

[0534] -R4is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3 -methylpentyl, 2,2-dimethylbutyl, 2,3 -dimethylbutyl and 3,3-dimethylpropyl; -W- is selected from the group consisting of C1-20 alkyl optionally interrupted by one or more groups selected from the group consisting of C3-10 cycloalkyl, 8- to 30-membered carbopolycyclyl, 3- to 10-membered heterocyclyl, -C(O)-, -C(O)N(R7)-, -O-, -S- and -N(R7)-; -Nu is a nucleophile selected from the group consisting of -N(R7R7a), -N(R70H), -N(R7)-N(R7aR7b), -S(R7), -COOH,

[0535]

[0536] -Ar- is selected from the group consisting ofAscendis Pharma Growth Disorders A / S 51 22 December 2025

[0537] CPX75232PC

[0538]

[0539] dashed lines indicate attachment to the rest of the prodrug,

[0540] -Z1- is selected from the group consisting of -O-, -S- and -N(R7)-, and

[0541] -Z2- is -N(R7)-; and

[0542] -R7, -R7aand -R7bare independently of each other selected from the group consisting of -H, Ci-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; and

[0543] wherein -L1- is substituted with -L2- and wherein -L1- is optionally further substituted.

[0544] In certain embodiments -L1- is of formula (V-a). In certain embodiments -L1- of formula (V-b) is not further substituted.

[0545] In certain embodiments -L1- is of formula (V-b). In certain embodiments -L1- of formula (V-a) is not further substituted.

[0546] In certain embodiments =Yi of formula (V-a) or (V-b) is =0. In certain embodiments =Yi of formula (V-a) or (V-b) is =S. In certain embodiments =Yi of formula (V-a) or (V-b) is =NR6. In certain embodiments -R6is methyl. In certain embodiments -R6is -H.Ascendis Pharma Growth Disorders A / S 52 22 December 2025

[0547] CPX75232PC

[0548] In certain embodiments -Y2- of formula (V-a) or (V-b) is -O-. In certain embodiments -Y2- of formula (V-a) or (V-b) is -S-. In certain embodiments -Y2- of formula (V-a) or (V-b) is -NR6-. In certain embodiments -R6is methyl. In certain embodiments -R6is -H.

[0549] In certain embodiments -Y3- of formula (V-a) or (V-b) is -O-. In certain embodiments -Y3- of formula (V-a) or (V-b) is -S-.

[0550] In certain embodiments -Y4- of formula (V-a) or (V-b) is -NR6-. In certain embodiments -R6is methyl. In certain embodiments -R6is -H. In certain embodiments -Y4- of formula (V-a) or (V-b) is -O-. In certain embodiments -Y4- of formula (V-a) or (V-b) is -C(R7)(R8)-. In certain embodiments -R7of formula (V-a) or (V-b) is -H. In certain embodiments -R7of formula (V-a) or (V-b) is methyl. In certain embodiments -R8of formula (V-a) or (V-b) is -H. In certain embodiments -R8of formula (V-a) or (V-b) is methyl. In certain embodiments both -R7and -R8of formula (V-a) or (V-b) are -H.

[0551] In certain embodiments =Ys of formula (V-a) or (V-b) is =0. In certain embodiments =Ys of formula (V-a) or (V-b) is =S.

[0552] In certain embodiments -R2of formula (V-b) is -H. In certain embodiments -R2of formula (V-b) is methyl.

[0553] In certain embodiments -R3of formula (V-a) or (V-b) is -H. In certain embodiments -R3of formula (V-a) or (V-b) is methyl.

[0554] In certain embodiments n of formula (V-a) or (V-b) is 0. In certain embodiments n of formula (V-a) or (V-b) is 1. In certain embodiments n of formula (V-a) or (V-b) is 2.

[0555] In certain embodiments -R4of formula (V-a) or (V-b) is methyl. In certain embodiments -R4of formula (V-a) or (V-b) is ethyl. In certain embodiments -R4of formula (V-a) or (V-b) is propyl. In certain embodiments -R4of formula (V-a) or (V-b) is isopropyl.Ascendis Pharma Growth Disorders A / S 53 22 December 2025

[0556] CPX75232PC

[0557] In certain embodiments Ar of formula (V-a) or (V-b) is phenyl. In certain embodiments Ar of formula

[0558]

[0559] In certain embodiments -W- of formula (V-a) or (V-b) is Ci-io alkyl. In certain embodiments -W- of formula (V-a) or (V-b) is Ci-6 alkyl. In certain embodiments -W- of formula (V-a) or (V-b) is Ci alkyl. In certain embodiments -W- of formula (V-a) or (V-b) is C2 alkyl. In certain embodiments -W- of formula (V-a) or (V-b) is C3 alkyl. In certain embodiments -W- of formula (V-a) or (V-b) is C4 alkyl.

[0560] In certain embodiments Nu- of formula (V-a) or (V-b) is -N(R7R7a). In certain embodiments one of -R7and -R7ais methyl. In certain embodiments both -R7and -R7aare methyl.

[0561] In certain embodiments -L1- has a structure as disclosed in W02020 / 206358A1. Accordingly, in certain embodiments the moiety -L1- is of formula (VI):

[0562]

[0563] wherein

[0564] the unmarked dashed line indicates attachment to -D;

[0565] the dashed line marked with the asterisk indicates attachment to -L2-;

[0566] n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6;

[0567] -R1and -R2are independently an electron-withdrawing group, alkyl, or -H, and wherein at least one of -R1or -R2is an electron-withdrawing group;

[0568] each -R4is independently C1-C3 alkyl or the two -R4are taken together with the carbon atom to which they are attached to form a 3- to 6-membered ring; and

[0569] -Y- is absent when -D is a drug moiety connected through an amine, or

[0570] -Y- is -N(R6)CH2- when -D is a drug moiety connected through a phenol, alcohol, thiol, thiophenol, imidazole or non-basic amine; wherein -R6is optionally substituted Ci-Ce alkyl, optionally substituted aryl or optionally substituted heteroaryl.Ascendis Pharma Growth Disorders A / S 54 22 December 2025

[0571] CPX75232PC

[0572] In certain embodiments n of formula (VI) is an integer selected from 1, 2, 3, 4, 5 and 6. In certain embodiments n of formula (VI) is an integer selected from 1, 2 and 3. In certain embodiments n of formula (VI) is an integer from 0, 1, 2 and 3. In certain embodiments n of formula (VI) is 1. In certain embodiments n of formula (VI) is 2. In certain embodiments n of formula (VI) is 3.

[0573] In certain embodiments the electron-withdrawing group of -R1and -R2of formula (VI) is selected from the group consisting of -CN; -NO2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted alkenyl; optionally substituted alkynyl; -COR3, -SOR3or -SO2R3, wherein -R3is -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR8or -NR82, wherein each -R8is independently -H or optionally substituted alkyl, or both -R8groups are taken together with the nitrogen to which they are attached to form a heterocyclic ring or -SR9, wherein -R9is optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.

[0574] In certain embodiments the electron-withdrawing group of -R1and -R2of formula (VI) is -CN. In certain embodiments the electron-withdrawing group of -R1and -R2of formula (VI) is -NO2. In certain embodiments the electron-withdrawing group of -R1and -R2of formula (VI) is optionally substituted aryl comprising 6 to 10 carbons. In certain embodiments the electron-withdrawing group of -R1and -R2of formula (VI) is optionally substituted phenyl, naphthyl or anthracenyl. In certain embodiments the electron-withdrawing group of -R1and -R2of formula (VI) is optionally substituted heteroaryl comprising 3 to 7 carbons and comprising at least one N, O or S atom. In certain embodiments the electron-withdrawing group of -R1and -R2of formula (VI) is optionally substituted pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl or indenyl. In certain embodiments the electron-withdrawing group of -R1and -R2of formula (VI) is optionally substituted alkenyl containing 2 to 20 carbon atoms. In certain embodiments the electron-withdrawing group of -R1and -R2of formula (VI) is optionally substituted alkynyl comprising 2 to 20 carbon atoms. In certain embodiments the electron-withdrawing group of -R1and -R2of formula (VI) is -COR3, -SOR3or -SO2R3, wherein -R3is -H, optionally substituted alkyl comprising 1 to 20 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR8or -NR82, wherein each -R8is independently -H or optionally substituted alkyl comprising 1 to 20 carbon atoms, orAscendis Pharma Growth Disorders A / S 55 22 December 2025

[0575] CPX75232PC

[0576] both -R8groups are taken together with the nitrogen to which they are attached to form a heterocyclic ring. In certain embodiments the electron-withdrawing group of -R1and -R2of formula (VI) is -SR9, wherein -R9is optionally substituted alkyl comprising 1 to 20 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.

[0577] In certain embodiments at least one of -R1or -R2of formula (VI) is -CN, -SOR3or -SO2R3. In certain embodiments at least one of -R1and -R2of formula (VI) is -CN or -SO2R3. In certain embodiments at least one of -R1and -R2of formula (VI) is -CN or -SO2R3, wherein -R3is optionally substituted alkyl, optionally substituted aryl or -NR82. In certain embodiments at least one of -R1and -R2of formula (VI) is -CN, -SO2N(CH3)2, -SO2CH3, phenyl substituted with -SO2, phenyl substituted with -SO2 and -Cl, -SO2N(CH2CH2)2O, -SO2CH(CH3)2, -SO2N(CH3)(CH2CH3) or -SO2N(CH2CH2OCH3)2.

[0578] In certain embodiments each -R4of formula (VI) is independently C1-C3 alkyl. In certain embodiments both -R4are methyl.

[0579] In certain embodiments -Y- of formula (VI) is absent. In certain embodiments -Y- of formula (VI) is -N(R6)CH2-.

[0580] In certain embodiments -L1- is of formula (VI), wherein n is 1, -R1is -CN, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 1, -R1is -SO2N(CH3)2, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 1, -R1is SO2CH3, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 1, -R1is -SO2N(CH2CH2)2CHCH3, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 1, -R1is phenyl substituted with -SO2, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 1, -R1is phenyl substituted with -SO2 and -Cl, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 1, -R1is -SO2N(CH2CH2)2O, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 1, -R1is -SO2CH(CH3)2, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 1, -R1is -SO2N(CH3)(CH2CH3), -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 1, -R1is -SO2N(CH2CH2OCH3)2, -R2is -H and -R4Ascendis Pharma Growth Disorders A / S 56 22 December 2025

[0581] CPX75232PC

[0582] is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 1, -R1is phenyl substituted with-SCh and -CH3, -R2is -H and -R4is -CH3.

[0583] In certain embodiments -L1- is of formula (VI), wherein n is 2, -R1is -CN, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 2, -R1is -SO2N(CH3)2, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 2, -R1is SO2CH3, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 2, -R1is -SO2N(CH2CH2)2CHCH3, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 2, -R1is phenyl substituted with -SO2, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 2, -R1is phenyl substituted with -SO2 and -Cl, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 2, -R1is -SO2N(CH2CH2)2O, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 2, -R1is -SO2CH(CH3)2, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 2, -R1is -SO2N(CH3)(CH2CH3), -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 2, -R1is -SO2N(CH2CH2OCH3)2, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 2, -R1is phenyl substituted with -SO2 and -CH3, -R2is -H and -R4is -CH3.

[0584] In certain embodiments -L1- is of formula (VI), wherein n is 3, -R1is -CN, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 3, -R1is -SO2N(CH3)2, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 3, -R1is SO2CH3, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 3, -R1is -SO2N(CH2CH2)2CHCH3, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 3, -R1is phenyl substituted with -SO2, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 3, -R1is phenyl substituted with -SO2 and -Cl, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 3, -R1is -SO2N(CH2CH2)2O, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 3, -R1is -SO2CH(CH3)2, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 3, -R1is -SO2N(CH3)(CH2CH3), -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 3, -R1is -SO2N(CH2CH2OCH3)2, -R2is -H and -R4is -CH3. In certain embodiments -L1- is of formula (VI), wherein n is 3, -R1is phenyl substituted with -SO2 and -CH3, -R2is -H and -R4is -CH3.Ascendis Pharma Growth Disorders A / S 57 22 December 2025

[0585] CPX75232PC

[0586] Only in the context of formula (VI) the terms used have the following meaning:

[0587] The term "alkyl" refers to linear, branched, or cyclic saturated hydrocarbon groups of 1 to 20, 1 to 12, 1 to 8, 1 to 6 or 1 to 4 carbon atoms. In certain embodiments an alkyl is linear or branched. Examples of linear or branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n- octyl, n-nonyl and n-decyl. In certain embodiments an alkyl is cyclic. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl and cyclohexyl.

[0588] The term "alkoxy" refers to alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy and cyclobutoxy.

[0589] The term "alkenyl" refers to non-aromatic unsaturated hydrocarbons with carbon-carbon double bonds and 2 to 20, 2 to 12, 2 to 8, 2 to 6 or 2 to 4 carbon atoms.

[0590] The term "alkynyl" refers to non-aromatic unsaturated hydrocarbons with carbon-carbon triple bonds and 2 to 20, 2 to 12, 2 to 8, 2 to 6 or 2 to 4 carbon atoms.

[0591] The term "aryl" refers to aromatic hydrocarbon groups of 6 to 18 carbons, preferably 6 to 10 carbons, including groups such as phenyl, naphthyl and anthracenyl. The term "heteroaryl" refers to aromatic rings comprising 3 to 15 carbons comprising at least one N, O or S atom, preferably 3 to 7 carbons comprising at least one N, O or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl and indenyl.

[0592] In certain embodiments alkenyl, alkynyl, aryl or heteroaryl moieties may be coupled to the remainder of the molecule through an alkyl linkage. Under those circumstances, 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.

[0593] The term "halogen" or "halo" refers to bromo, fluoro, chloro and iodo.Ascendis Pharma Growth Disorders A / S 58 22 December 2025

[0594] CPX75232PC

[0595] The term "heterocyclic ring" or "heterocyclyl" refers to a 3- to 15-membered aromatic or nonaromatic ring comprising at least one N, O or S atom. Examples include piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine and tetrahydrofuranyl, as well as the exemplary groups provided for the term "heteroaryl" above. In certain embodiments a heterocyclic ring or heterocyclyl is nonaromatic. In certain embodiments a heterocyclic ring or heterocyclyl is aromatic.

[0596] The term "optionally substituted" refers to a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents which may be the same or different. Examples of substituents include alkyl, alkenyl, alkynyl, halogen, -CN, -ORaa, -SRaa, -NRaaRbb, -NO2, -C=NH(ORaa), -C(O)Raa, -OC(O)Raa, -C(O)ORaa, -C(O)NRaaRbb, -OC(O)NRaaRbb, -NRaaC(O)Rbb, -NRaaC(O)ORbb, -S(O)Raa, -S(O)2Raa, -NRaaS(O)Rbb, -C(O)NRaaS(O)Rbb, -NRaaS(O)2Rbb, -C(O)NRaaS(O)2Rbb, -S(O)NRaaRbb, -S(O)2NRaaRbb, -P(O)(ORaa)(ORbb), heterocyclyl, heteroaryl, or aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl are each independently optionally substituted by -Rcc, wherein -Raaand -Rbbare each independently -H, alkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl, or aryl, or -Raaand -Rbbare taken together with the nitrogen atom to which they attach to form a heterocyclyl, which is optionally substituted by alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy or -CN, and wherein: each -Rccis independently alkyl, alkenyl, alkynyl, halogen, heterocyclyl, heteroaryl, aryl, -CN or -NO2.

[0597] In certain embodiments -L1- has a structure as disclosed in formula I of WO2021 / 242756A1, which is hereby incorporated by reference in its entirety. Accordingly, in certain embodiments the moiety -L1- is of formula (VII):

[0598]

[0599] wherein

[0600] the unmarked dashed line indicates attachment to -D;

[0601] the dashed line marked with the asterisk indicates attachment to -L2-;

[0602] -R2, -R4and -R8are independently selected from the group consisting of -H or Ci-4 alkyl;

[0603] -R3is Ci-4 alkyl or -R3and -R4together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring;Ascendis Pharma Growth Disorders A / S 59 22 December 2025

[0604] CPX75232PC

[0605] -R5is -NH2;

[0606] with the proviso that when -R4and -R3together with the atoms to which they are attached from a 5- or 6-membered heterocyclic ring -R2is not -H; and

[0607] wherein the -L1- of formula (VII) is optionally substituted.

[0608] In certain embodiments both -R4and -R8of formula (VII) are -H.

[0609] In certain embodiments -R3is methyl. In certain embodiments -R3is -H.

[0610] In certain embodiments -R2is -H.

[0611] In certain embodiments -L1- is of formula (Vll-i)

[0612]

[0613] the unmarked dashed line indicates attachment to -D; and

[0614] the dashed line marked with the asterisk indicates attachment to -L2-.

[0615] In certain embodiments -L1- is of formula (Vll-ii)

[0616]

[0617] -ii),

[0618] the unmarked dashed line indicates attachment to -D; and

[0619] the dashed line marked with the asterisk indicates attachment to -L2-.

[0620] In certain embodiments -L1- is of formula (Vll-iii)

[0621]

[0622] -iii),

[0623] the unmarked dashed line indicates attachment to -D; and

[0624] the dashed line marked with the asterisk indicates attachment to -L2-.Ascendis Pharma Growth Disorders A / S 60 22 December 2025

[0625] CPX75232PC

[0626] In certain embodiments -L1- has a structure as disclosed in formula II of WO2022 / 096636A1, which is herewith incorporated by reference. Accordingly, in certain embodiments the moiety -L1- is of formula (Vll-b):

[0627]

[0628] wherein

[0629] the unmarked dashed line indicates attachment to -D; and

[0630] the dashed line marked with the asterisk indicates attachment to -L2-.

[0631] A moiety -L2- may be either absent or a spacer moiety connecting -L1- to -Z. In certain embodiments -L2- is absent. When -L2- is absent, -L1- is directly conjugated to -Z. In certain embodiments -L2- is a spacer moiety.

[0632] If a conjugate comprises more than one moiety -L2-, they are in certain embodiments of the same type, i.e., all moieties -L2- of the conjugate have the same structure. In certain embodiments a conjugate comprises more than one moiety -L2- and these moieties -L2- have a different structure. There may be two different types of -L2-, three different types of -L2-, four different types of -L2- or five different types of -L2- in such a conjugate. These different types of -L2- may be conjugated to the same or to a different type of -L1- and may be conjugated to the same or different type of -Z, if applicable.

[0633] In general, -L2- may be attached to -L1- at any position where a hydrogen is present, unless where explicitly excluded.

[0634] In certain embodiments the linkage between -Z and -L2- is a stable linkage.

[0635] When -L2- is a spacer moiety, it may have a molecular weight of less than or equal to about 1000 g / mol, about 900 g / mol, about 800 g / mol, about 750 g / mol, about 700 g / mol, about 650 g / mol, or about 600 g / mol. In certain embodiments -L2- may have a molecular weight of more than or equal to 14 g / mol, more than or equal to about 28 g / mol, more than or equal to about 42 g / mol, more than or equal to about 100 g / mol, or more than or equal to about 200 g / mol, while at the same time having aAscendis Pharma Growth Disorders A / S 61 22 December 2025

[0636] CPX75232PC

[0637] molecular weight of less than or equal to about 1000 g / mol, less than or equal to about 900 g / mol, less than or equal to about 800 g / mol, less than or equal to about 750 g / mol, less than or equal to about 700 g / mol, less than or equal to about 650 g / mol, or less than or equal to about 600 g / mol. In certain embodiments -L2- has a molecular ranging from 14 g / mol to 750 g / mol. In certain embodiments -L2- has a molecular weight ranging from 14 g / mol to 500 g / mol.

[0638] In certain embodiments -L2- consists of chemical elements selected from the group consisting of H, C, Si, N, P, O, S, F and Cl. In certain embodiments -L2- consists of chemical elements selected from the group consisting of H, C, N, O and S.

[0639] In certain embodiments -L2- has a chain length of 1 to 20 atoms.

[0640] As used herein the term “chain length” with regard to the moiety -L2- refers to the number of atoms of -L2- present in the shortest connection between -L1- and -Z.

[0641] In certain embodiments -L2- is a spacer moiety selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ryl)S(O)2N(Ryla)-, -S-, -N(Ry1)-, -OC(ORyl)(Ryla)-, -N(Ryl)C(O)N(Ryla)-, -OC(O)N(Ry1)-, C1-50 alkyl, C2.5o alkenyl, and C2-5o alkynyl; wherein -T-, C1-50 alkyl, C2-so alkenyl, and C2-so alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-50 alkyl, C2-so alkenyl, and C2-so 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(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a)-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a)-, -N(Ry3)C(O)N(Ry3a)-, and -OC(O)N(Ry3)-;

[0642] -Ryland -Rylaare independently of each other selected from the group consisting of -H, -T, C1-50 alkyl, C2-5o alkenyl, and C2-so alkynyl; wherein -T, C1-50 alkyl, C2-so alkenyl, and C2-so alkynyl are optionally substituted with one or more -Ry2, which are the same or different, and wherein C1-50 alkyl, C2-5o alkenyl, and C2-so 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(Ry4)-, -S(O)2N(Ry4)-, -S(O)N(Ry4)-, -S(O)2-, -S(O)-, -N(Ry4)S(O)2N(Ry4a)-, -S-, -N(Ry4)-, -OC(ORy4)(Ry4a)-, -N(Ry4)C(O)N(Ry4a)-, and -OC(O)N(Ry4)-;Ascendis Pharma Growth Disorders A / S 62 22 December 2025

[0643] CPX75232PC

[0644] 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 heteropoly cyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different;

[0645] each -Ry2is independently selected from the group consisting of halogen, -CN, oxo (=0), -COORy5, -ORy5, -C(O)Ry5, -C(O)N(Ry5Ry5a), -S(O)2N(Ry5Ry5a), -S(O)N(Ry5Ry5a), -S(O)2Ry5, -S(O)Ry5, -N(Ry5)S(O)2N(Ry5aRy5b), -SRy5, -N(Ry5Ry5a), -NO2, -OC(O)Ry5, -N(Ry5)C(O)Ry5a, -N(Ry5)S(O)2Ry5a, -N(Ry5)S(O)Ry5a, -N(Ry5)C(O)ORy5a, -N(Ry5)C(O)N(Ry5aRy5b), -OC(O)N(Ry5Ry5a), and Ci-6alkyl; wherein Ci-6alkyl is optionally substituted with one or more halogen, which are the same or different; and

[0646] each -Ry3, -Ry3a, -Ry4, -Ry4a, -Ry5, -Ry5aand -Ry5bis 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.

[0647] In certain embodiments -L2- selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ry1)-, S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ryl)S(O)2N(Ryla)-, -S-, -N(Ry1)-, -OC(ORyl)(Ryla)-, -N(Ryl)C(0)N(Ryla)-, -OC(O)N(Ry1)-, C1-50 alkyl, C2.5o alkenyl, and C2.5o alkynyl; wherein -T-, C1-20 alkyl, C2.2o alkenyl, and C2.2o alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-20 alkyl, C2.2o alkenyl, and C2.2o 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(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a)-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a)-, -N(Ry3)C(O)N(Ry3a)-, and -OC(O)N(Ry3)-;

[0648] -Ryland -Rylaare independently of each other selected from the group consisting of -H, -T, C1-10 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 -Ry2, 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(Ry4)-, -S(O)2N(Ry4)-, -S(O)N(Ry4)-, -S(O)2-, -S(O)-, -N(Ry4)S(O)2N(Ry4a)-, -S-, -N(Ry4)-, -OC(ORy4)(Ry4a)-, -N(Ry4)C(O)N(Ry4a)-, and -OC(O)N(Ry4)-;Ascendis Pharma Growth Disorders A / S 63 22 December 2025

[0649] CPX75232PC

[0650] 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 heteropoly cyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different;

[0651] -Ry2is selected from the group consisting of halogen, -CN, oxo (=0), -COORy5, -ORy5, -C(O)Ry5, -C(O)N(Ry5Ry5a), -S(O)2N(Ry5Ry5a), -S(O)N(Ry5Ry5a), -S(O)2Ry5, -S(O)Ry5, -N(Ry5)S(O)2N(Ry5aRy5b), -SRy5, -N(Ry5Ry5a), -NO2, -OC(O)Ry5, -N(Ry5)C(O)Ry5a, -N(Ry5)S(O)2Ry5a, -N(Ry5)S(O)Ry5a, -N(Ry5)C(O)ORy5a, -N(Ry5)C(O)N(Ry5aRy5b), -OC(O)N(Ry5Ry5a), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and

[0652] each -Ry3, -Ry3a, -Ry4, -Ry4a, -Ry5, -Ry5aand -Ry5bis independently of each other selected from the group consisting of -H, and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.

[0653] In certain embodiments -L2- is selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ryl)S(O)2N(Ryla)-, -S-, -N(Ry1)-, -OC(ORyl)(Ryla)-, -N(Ryl)C(0)N(Ryla)-, -OC(O)N(Ry1)-, C1-50 alkyl, C2.5o alkenyl, and C2-5o alkynyl; wherein -T-, C1-50 alkyl, C2-so alkenyl, and C2-so alkynyl are optionally substituted with one or more -Ry2, 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(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a)-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a)-, -N(Ry3)C(O)N(Ry3a)-, and -OC(O)N(Ry3)-;

[0654] -Ryland -Rylaare independently selected from the group consisting of -H, -T, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl;

[0655] 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 heteropoly cyclyl;Ascendis Pharma Growth Disorders A / S 64 22 December 2025

[0656] CPX75232PC

[0657] each -Ry2is independently selected from the group consisting of halogen, and C1-6 alkyl; and

[0658] each -Ry3, -Ry3a, -Ry4, -Ry4a, -Ry5, -Ry5aand -Ry5bis independently of each other selected from the group consisting of -H, and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.

[0659] In certain embodiments -L2- is a C1-20 alkyl chain, which is optionally interrupted by one or more groups independently selected from -O-, -T- and -C(O)N(Ry1)-; and which C1-20 alkyl chain is optionally substituted with one or more groups independently selected from -OH, -T and -C(O)N(Ry6Ry6a); wherein -Ryl, -Ry6, -Ry6aare independently selected from the group consisting of -H and C1-4 alkyl and wherein T is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropoly cyclyl.

[0660] In certain embodiments -L2- comprises a moiety selected from

[0661]

[0662] Ascendis Pharma Growth Disorders A / S 65 22 December 2025

[0663] CPX75232PC

[0664]

[0665] wherein

[0666] dashed lines indicate attachment to the rest of -L2-, -L1- and / or -Z, respectively; and

[0667] -R and -Raare independently of each other selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3 -methylpentyl, 2,2-dimethylbutyl, 2,3- dimethylbutyl and 3, 3 -dimethylpropyl.

[0668] In certain embodiments -L2- is of formula (i):

[0669]

[0670] wherein

[0671] the dashed line marked with the asterisk indicates attachment to -L1-;Ascendis Pharma Growth Disorders A / S 66 22 December 2025

[0672] CPX75232PC

[0673] the unmarked dashed line indicates attachment to -Z;

[0674] -R1is 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

[0675] wherein the moiety of formula (i) is optionally further substituted.

[0676] In certain embodiments the moiety -L'-L2- is selected from the group consisting of

[0677]

[0678] wherein

[0679] the unmarked dashed line indicates the attachment to a nitrogen of -D; and

[0680] the dashed line marked with the asterisk indicates attachment to -Z.

[0681] In certain embodiments the moiety -L1-! - is of formula (Ild-ii).

[0682] If a conjugate comprises more than one moiety -Z, they are in certain embodiments of the same type, i.e., all moieties -Z of the conjugate have the same structure. In certain embodiments a conjugate comprises more than one moiety -Z and these moieties -Z have a different structure. There may be two different types of -Z, three different types of -Z, four different types of -Z or five different types of -Z in such a conjugate. These different types of -Z may be conjugated to the same or different type of -L2-.Ascendis Pharma Growth Disorders A / S 67 22 December 2025

[0683] CPX75232PC

[0684] In certain embodiments -Z of formula (la) or (lb) has a molecular weight ranging from 5 to 200 kDa. In certain embodiments -Z of formula (la) or (lb) has a molecular weight ranging from 8 to 100 kDa. In certain embodiments -Z of formula (la) or (lb) has a molecular weight ranging from 10 to 80 kDa. In certain embodiments -Z of formula (la) or (lb) has a molecular weight ranging from 12 to 60 kDa. In certain embodiments -Z of formula (la) or (lb) has a molecular weight ranging from 15 to 40 kDa. 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.

[0685] The polymeric moiety -Z of formula (la) or (lb) comprises a polymer. In certain embodiments -Z of formula (la) or (lb) comprises a polymer selected from the group consisting of poly(2-methacryloyloxyethyl phosphorylcholine), poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(hydroxymethacrylates), poly(hydroxypropylmethacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyloxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(ortho esters), poly(oxazolines), polypropylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinylmethylethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, xylans and copolymers thereof.

[0686] In certain embodiments -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 / alanineAscendis Pharma Growth Disorders A / S 68 22 December 2025

[0687] CPX75232PC

[0688] 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.

[0689] In certain embodiments -Z of formula (la) or (lb) is an albumin-binding moiety. In certain embodiments such albumin-binding moiety is an albumin-binding moiety as described for moiety -AB in WO2024 / 184351, page 78, line 16 to page 95, line 2, the disclosure of which is incorporated by reference herewith.

[0690] In certain embodiments -Z of formula (la) or (lb) comprises an albumin-binding moiety as disclosed in WO2021 / 055497A1, which is herewith incorporated by reference. Accordingly, in certain embodiments -Z of formula (la) or (lb) is of formula (w)

[0691]

[0692] wherein the dashed line indicates attachment to -L2- or -L1- in formula (la) or (lb).

[0693] In certain embodiments -Z is of formula (w) and -L1- is of formula (III). In certain embodiments -Z is of formula (w) and -L1- is of formula (IV). In certain embodiments -Z is of formula (w) and -L1- is of formula (VI).

[0694] In certain embodiments Z-L2-L'- is of formula (w-a):

[0695]

[0696] wherein the dashed line indicates attachment to -D of formula (la) or (lb).

[0697] In certain embodiments the dashed line in formula (w-a) indicates attachment to a nitrogen of a CNP having the sequence of SEQ ID NO:30. In certain embodiments the dashed line in formula (w-a)Ascendis Pharma Growth Disorders A / S 69 22 December 2025

[0698] CPX75232PC

[0699] indicates attachment to a nitrogen of a CNP having the sequence of SEQ ID NO: 98. In certain embodiments the dashed line in formula (w-a) indicates attachment to a nitrogen of a CNP having the sequence of SEQ ID NO:99. In certain embodiments the dashed line in formula (w-a) indicates attachment to a nitrogen of a CNP having the sequence of SEQ ID NO: 100. Such nitrogen is in certain embodiments the nitrogen of the amine functional group of the side chain of a lysine residue, which may be a lysine residue localized in the ring structure the CNP moiety or may be a lysine localized outside the ring structure. Such nitrogen may also be from the N-terminal amine functional group of the CNP moiety.

[0700] In certain embodiments -Z of formula (la) or (lb) is a hyaluronic acid-based polymer.

[0701] In certain embodiments -Z of formula (la) or (lb) is a polymeric moiety as disclosed in WO 2013 / 024047 Al which is herewith incorporated by reference.

[0702] In certain embodiments -Z of formula (la) or (lb) is a polymeric moiety as disclosed in WO 2013 / 024048 Al which is herewith incorporated by reference.

[0703] In certain embodiments -Z of formula (la) or (lb) is a PEG-based polymer. In certain embodiments -Z is a branched or multi-arm PEG-based polymer.

[0704] In certain embodiments -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. In certain embodiments a branching point is selected from the group consisting of -N<, -CH< and >C<.

[0705] In certain embodiments such branched moiety -Z of formula (la) or (lb) is PEG-based.Ascendis Pharma Growth Disorders A / S 70 22 December 2025

[0706] CPX75232PC

[0707] In certain embodiments 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. In certain embodiments 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. In certain embodiments 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. In certain embodiments 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.

[0708] In certain embodiments -Z comprises a moiety

[0709]

[0710] In certain embodiments -Z comprises an amide bond.

[0711] In certain embodiments -Z of formula (la) or (lb) comprises a moiety of formula (a):Ascendis Pharma Growth Disorders A / S 71 22 December 2025

[0712] CPX75232PC

[0713] " "

[0714]

[0715] wherein

[0716] the dashed line indicates attachment to -L2- or to the remainder of -Z;

[0717] BPais a branching point selected from the group consisting of -N< -CR< and >C<;

[0718] -R is -H or Ci-6 alkyl;

[0719] a is 0 if BPais -N< or -CR< and a is 1 if BPais >C<;

[0720] -Sa-, -Sa’-, -Sa- and -Sa- are independently of each other absent 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 -R1, 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(R2)-, -S(O)2N(R2)-, -S(O)N(R2)-, -S(O)2-, -S(O)-, -N(R2)S(O)2N(R2a)-, -S-, -N(R2)-, -OC(OR2)(R2a)-, -N(R2)C(O)N(R2a)- and -OC(O)N(R2)-;

[0721] 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; wherein each -T- is independently optionally substituted with one or more -R1, which are the same or different;

[0722] each -R1is independently selected from the group consisting of halogen, -CN, oxo (=0), -C00R3, -OR3, -C(0)R3, -C(O)N(R3R3a), -S(O)2N(R3R3a), -S(O)N(R3R3a), -S(O)2R3, -S(O)R3, -N(R3)S(O)2N(R3aR3b), -SR3, -N(R3R3a), -NO2, -0C(0)R3, -N(R3)C(O)R3a, -N(R3)S(O)2R3a, -N(R3)S(O)R3a, -N(R3)C(O)OR3a, -N(R3)C(O)N(R3aR3b), -OC(O)N(R3R3a) and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;

[0723] each -R2, -R2a, -R3, -R3aand -R3bis independently selected from the group consisting of -H and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and

[0724] -Pa, -Paand -Paare independently a polymeric moiety.Ascendis Pharma Growth Disorders A / S 72 22 December 2025

[0725] CPX75232PC

[0726] Optionally the moiety of formula (a) is substituted with one or more substituents. In certain embodiments the moiety of formula (a) is not substituted with one or more substituents.

[0727] In certain embodiments BPaof formula (a) is -N< In certain embodiments BPaof formula (a) is -CR< In certain embodiments -R is -H.

[0728] Accordingly, in certain embodiments a of formula (a) is 0.

[0729] In certain embodiments BPaof formula (a) is >C<

[0730] In certain embodiments -Sa- of formula (a) is absent.

[0731] In certain embodiments -Sa- 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(R4)-, -S(O)2N(R4)-, -S(O)N(R4)-, -S(O)2-, -S(O)-, -N(R4)S(O)2N(R4a)-, -S-, -N(R4)-, -OC(OR4)(R4a)-, -N(R4)C(O)N(R4a)- and -OC(O)N(R4)-; wherein -R4and -R4aare independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. In certain embodiments -Sa- of formula (a) is selected from the group consisting of methyl, ethyl, propyl and butyl, which are optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)- and -C(O)N(R4)-.

[0732] In certain embodiments -Sa- of formula (a) is absent.

[0733] In certain embodiments -Sa- 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(R4)-, -S(O)2N(R4)-, -S(O)N(R4)-, -S(O)2-, -S(O)-, -N(R4)S(O)2N(R4a)-, -S-, -N(R4)-, -OC(OR4)(R4a)-, -N(R4)C(O)N(R4a)- and -OC(O)N(R4)-; wherein -R4and -R4aare independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. In certain embodiments -Sa- of formula (a) is selected from the group consisting of methyl, ethyl, propyl andAscendis Pharma Growth Disorders A / S 73 22 December 2025

[0734] CPX75232PC

[0735] butyl, which are optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)- and -C(O)N(R4)-.

[0736] In certain embodiments -Sa- of formula (a) is absent.

[0737] In certain embodiments -Sa- 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(R4)-, -S(O)2N(R4)-, -S(O)N(R4)-,-S(O)2-, -S(O)-, -N(R4)S(O)2N(R4a)-, -S-, -N(R4)-, -OC(OR4)(R4a)-, -N(R4)C(O)N(R4a)- and -OC(O)N(R4)-; wherein -R4and -R4aare independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. In certain embodiments -Sa- of formula (a) is selected from the group consisting of methyl, ethyl, propyl and butyl, which are optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)- and -C(O)N(R4)-.

[0738] In certain embodiments -Sa- of formula (a) is absent.

[0739] In certain embodiments -Sa- 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(R4)-, -S(O)2N(R4)-, -S(O)N(R4)-,-S(O)2-, -S(O)-, -N(R4)S(O)2N(R4a)-, -S-, -N(R4)-, -OC(OR4)(R4a)-, -N(R4)C(O)N(R4a)- and -OC(O)N(R4)-; wherein -R4and -R4aare independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. In certain embodiments -Sa- of formula (a) is selected from the group consisting of methyl, ethyl, propyl and butyl, which are optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)- and -C(O)N(R4)-.

[0740] In certain embodiments -Pa, -Paand -Paof formula (a) independently comprise a polymer selected from the group consisting of poly(2-methacryloyloxyethyl phosphorylcholine), 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),Ascendis Pharma Growth Disorders A / S 74 22 December 2025

[0741] CPX75232PC

[0742] poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(hydroxymethacrylates), poly(hydroxypropylmethacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyloxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(ortho esters), poly(oxazolines), polypropylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinylmethylethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, xylans, and copolymers thereof.

[0743] In certain embodiments -Pa, -Paand -Paof 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.

[0744] In certain embodiments -Pa, -Paand -Paof formula (a) have a molecular weight of about 5 kDa. In certain embodiments -Pa, -Paand -Paof formula (a) have a molecular weight of about 7.5 kDa. In certain embodiments -Pa, -Paand -Paof formula (a) have a molecular weight of about 10 kDa. In certain embodiments -Pa, -Paand -Paof formula (a) have a molecular weight of about 12.5 kDa. In certain embodiments -Pa, -Paand -Paof formula (a) have a molecular weight of about 15 kDa. In certain embodiments -Pa, -Paand -Paof formula (a) have a molecular weight of about 20 kDa.

[0745] In certain embodiments -Pa, -Paand -Paof formula (a) independently comprise a PEG-based moiety. In certain embodiments -Pa, -Paand -Paof formula (a) independently comprise a PEG-based moiety comprising at least 20% PEG, in certain embodiments comprising at least 30% PEG, in certain embodiments comprising at least 40% PEG, in certain embodiments comprising at least 50% PEG, in certain embodiments comprising at least 60% PEG, in certain embodiments comprisingAscendis Pharma Growth Disorders A / S 75 22 December 2025

[0746] CPX75232PC

[0747] at least 70% PEG, in certain embodiments comprising at least 80% PEG and in certain embodiments comprising at least 90% PEG.

[0748] In certain embodiments -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).

[0749] In certain embodiments -Z comprises a moiety of formula (b):

[0750]

[0751] wherein

[0752] the dashed line indicates attachment to -L2- or to the remainder of -Z;

[0753] bl is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8;

[0754] b2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8;

[0755] 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

[0756] 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.

[0757] Optionally the moiety of formula (b) is substituted with one or more substituents. In certain embodiments the moiety of formula (b) is not substituted with one or more substituents.

[0758] 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. In certain embodiments b3 and b4 of formula (b) are the same integer.Ascendis Pharma Growth Disorders A / S 76 22 December 2025

[0759] CPX75232PC

[0760] In certain embodiments bl of formula (b) is selected from the group consisting of 0, 1, 2, 3 and 4. In certain embodiments bl of formula (b) is selected from the group consisting of 1, 2 and 3. In certain embodiments bl of formula (b) is 2.

[0761] In certain embodiments b2 of formula (b) is selected from the group consisting of 1, 2, 3, 4 and 5. In certain embodiments b2 of formula (b) is selected from the group consisting of 2, 3 and 4. In certain embodiments b2 of formula (b) is 3.

[0762] In certain embodiments bl of formula (b) is 2, b2 of formula (b) is 3 and b3 and b4 range from 400 to 500 or are both about 450. In certain embodiments bl of formula (b) is 2, b2 of formula (b) is 3 and b3 and b4 range from 200 to 250 or are both about 225.

[0763] In certain embodiments -Z comprises one moiety of formula (b). In certain embodiments -Z comprises two moieties of formula (b). In certain embodiments -Z comprises three moieties of formula (b). In certain embodiments -Z comprises four moieties of formula (b). In certain embodiments -Z comprises five moieties of formula (b). In certain embodiments -Z comprises six moieties of formula (b).

[0764] In certain embodiments -Z comprises a moiety of formula (c):

[0765]

[0766] (c), wherein

[0767] the dashed line indicates attachment to -L2- or to the remainder of -Z;

[0768] cl and c2 are independently an integer ranging from and including 150 to 500; in certain embodiments ranging from and including 200 to 460.

[0769] Optionally the moiety of formula (c) is substituted with one or more substituents. In certain embodiments the moiety of formula (c) is not substituted with one or more substituents.Ascendis Pharma Growth Disorders A / S 77 22 December 2025

[0770] CPX75232PC

[0771] In certain embodiments cl and c2 of formula (c) range from and include 200 to 250 and in certain embodiments are about 225. In certain embodiments cl and c2 of formula (c) range from and include 400 to 500 and in certain embodiments cl and c2 of formula (c) are about 450. In certain embodiments both cl and c2 of formula (c) are the same integer.

[0772] In certain embodiments -Z comprises one moiety of formula (c). In certain embodiments -Z comprises two moieties of formula (c). In certain embodiments -Z comprises three moieties of formula (c). In certain embodiments -Z comprises four moieties of formula (c). In certain embodiments -Z comprises five moieties of formula (c). In certain embodiments -Z comprises six moieties of formula (c).

[0773] In certain embodiments the moiety -Z is a branched PEG-based polymer comprising at least 10% PEG, has three branching points and four PEG-based polymer arms and has a molecular weight of about 40 kDa. Accordingly, each of the four PEG-based polymer arms has a molecular weight of about 10 kDa. In certain embodiments each of the three branching points is -CH<

[0774] In certain embodiments the moiety -Z is of formula (f):

[0775]

[0776] wherein

[0777] the dashed line indicates attachment to -L2-;

[0778] BPfis a branching point selected from the group consisting of -N<, -CR< and >C<;

[0779] -R is selected from the group consisting of -H and Ci-6 alkyl;

[0780] f is 0 if BPfis -N< or -CR< and f is 1 if BPfis >C<;

[0781] -Sf-, -Sf-, -Sf- and -Sf- are independently either a chemical bond or are independently selected from the group consisting of C1-50 alkyl, C2-50 alkenyl and C2-50 alkynyl; wherein C1-50 alkyl, C2-50 alkenyl and C2-50 alkynyl are optionally substituted with one or more -R1, 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-,Ascendis Pharma Growth Disorders A / S 78 22 December 2025

[0782] CPX75232PC

[0783] -O-, -C(O)-, -C(O)N(R2)-, -S(O)2N(R2)-, -S(O)N(R2)-, -S(O)2-, -S(O)-, -N(R2)S(O)2N(R2a)-, -S-, -N(R2)-, -OC(OR2)(R2a)-, -N(R2)C(O)N(R2a)- and -OC(O)N(R2)-;

[0784] each -T- is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopoly cyclyl and 8- to 30-membered heteropoly cyclyl; wherein each -T- is independently optionally substituted with one or more -R1, which are the same or different;

[0785] each -R1is independently selected from the group consisting of halogen, -CN, oxo (=0), -C00R3, -OR3, -C(O)R3, -C(O)N(R3R3a), -S(O)2N(R3R3a), -S(O)N(R3R3a), -S(O)2R3, -S(O)R3, -N(R3)S(O)2N(R3aR3b), -SR3, -N(R3R3a), -NO2, -OC(O)R3, -N(R3)C(O)R3a, -N(R3)S(O)2R3a, -N(R3)S(O)R3a, -N(R3)C(O)OR3a, -N(R3)C(O)N(R3aR3b), -OC(O)N(R3R3a) and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;

[0786] each -R2, -R2a, -R3, -R3aand -R3bis independently selected from the group consisting of -H and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;

[0787] and

[0788] -Za, -Zaand -Zaare independently

[0789] "

[0790]

[0791] "

[0792] wherein

[0793] BPa, -Sa-, -Sa-Sa”-, -Sa-Pa, -Pa, -Paand a are used as defined for formula (a).

[0794] Optionally the moiety of formula (f) is substituted with one or more substituents. In certain embodiments the moiety of formula (f) is not substituted with one or more substituents.

[0795] Specific embodiments for BPa, -Sa-, -Sa-Sa”-, -Sa-Pa, -Paand -Paof formula (f) are as defined above for formula (a).Ascendis Pharma Growth Disorders A / S 79 22 December 2025

[0796] CPX75232PC

[0797] In certain embodiments BPfof formula (f) is -CR< and r is 0. In certain embodiments -R is -H. In certain embodiments -Sf- of formula (f) is absent.

[0798] In certain embodiments -Za, -Zaand -Zaof formula (f) have the same structure. In certain embodiments -Za, -Zaand -Zaof formula (f) are of formula (b).

[0799] In certain embodiments bl, b2, b3 and b4 are as described for formula (b).

[0800] In certain embodiments -Sf- of formula (f) is absent, BPaof formula (f) is -CR< with -R being -H. In certain embodiments -Sf- of formula (f) is absent, BPaof formula (f) is -CR< with -R being -H and -Za, -Zaand -Zaof formula (f) are of formula (b).

[0801] In certain embodiments -Z is of formula (g):

[0802]

[0803] wherein

[0804] the dashed line indicates attachment to -L2-;

[0805] -Sg-, -Sg- and -Sg- 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 -R1, 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(R2)-, -S(O)2N(R2)-, -S(O)N(R2)-, -S(O)2-, -S(O)-, -N(R2)S(O)2N(R2a)-, -S-, -N(R2)-, -OC(OR2)(R2a)-, -N(R2)C(O)N(R2a)- and -OC(O)N(R2)-;

[0806] 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-memberedAscendis Pharma Growth Disorders A / S 80 22 December 2025

[0807] CPX75232PC

[0808] heterobicyclyl, 8- to 30-membered carbopoly cyclyl and 8- to 30-membered heteropoly cyclyl; wherein each -T- is independently optionally substituted with one or more -R1, which are the same or different;

[0809] each -R1is independently selected from the group consisting of halogen, -CN, oxo (=0), -COOR3, -OR3, -C(O)R3, -C(O)N(R3R3a), -S(O)2N(R3R3a), -S(O)N(R3R3a), -S(O)2R3, -S(O)R3, -N(R3)S(O)2N(R3aR3b), -SR3, -N(R3R3a), -NO2, -OC(O)R3, -N(R3)C(O)R3a, -N(R3)S(O)2R3a, -N(R3)S(O)R3a, -N(R3)C(O)OR3a, -N(R3)C(O)N(R3aR3b), -OC(O)N(R3R3a) and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;

[0810] each -R2, -R2a, -R3, -R3aand -R3bis independently selected from the group consisting of -H, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;

[0811] and

[0812] -Zaand -Zaare independently

[0813] "

[0814]

[0815] "

[0816] wherein

[0817] BPa, -Sa-, -Sa-Sa”-, -Sa-Pa, -Pa, -Paand a are used as defined for formula (a).

[0818] Optionally the moiety of formula (g) is substituted with one or more substituents. In certain embodiments the moiety of formula (g) is not substituted with one or more substituents.

[0819] Specific embodiments for BPa, -Sa-, -Sa-, -Sa-Sa-Pa, -Paand -Paof formula (g) are as defined above for formula (a).

[0820] In certain embodiments -Sg- 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 -R1, which is the same or different, whereinAscendis Pharma Growth Disorders A / S 81 22 December 2025

[0821] CPX75232PC

[0822] -R1is selected from the group consisting of halogen, oxo (=0), -COOR3, -OR3, -C(O)R3, -C(O)N(R3R3a), -S(O)2N(R3R3a), -S(O)N(R3R3a), -S(O)2R3, -S(O)R3, -N(R3)S(O)2N(R3aR3b), -SR3, -N(R3R3a), -NO2, -OC(O)R3, -N(R3)C(O)R3a, -N(R3)S(O)2R3a, -N(R3)S(O)R3a, -N(R3)C(O)OR3a, -N(R3)C(O)N(R3aR3b), -OC(O)N(R3R3a) and Ci-6 alkyl, wherein Ci-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and

[0823] -R3, -R3aand -R3bare independently selected from -H, methyl, ethyl, propyl and butyl.

[0824] In certain embodiments -Sg- of formula (g) is selected from Ci-6 alkyl.

[0825] In certain embodiments -Sg- 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 -R1, which is the same or different, wherein

[0826] -R1is selected from the group consisting of halogen, oxo (=0), -COOR3, -OR3, -C(O)R3, -C(O)N(R3R3a), -S(O)2N(R3R3a), -S(O)N(R3R3a), -S(O)2R3, -S(O)R3, -N(R3)S(O)2N(R3aR3b), -SR3, -N(R3R3a), -NO2, -OC(O)R3, -N(R3)C(O)R3a, -N(R3)S(O)2R3a, -N(R3)S(O)R3a, -N(R3)C(O)OR3a, -N(R3)C(O)N(R3aR3b), -OC(O)N(R3R3a) and Ci-6 alkyl, wherein Ci-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and

[0827] -R3, -R3aand -R3bare independently selected from -H, methyl, ethyl, propyl and butyl.

[0828] In certain embodiments -Sg- of formula (g) is Ci-6 alkyl.

[0829] In certain embodiments -Sg- 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 -R1, which is the same or different, wherein

[0830] -R1is selected from the group consisting of halogen, oxo (=0), -COOR3, -OR3, -C(O)R3, -C(O)N(R3R3a), -S(O)2N(R3R3a), -S(O)N(R3R3a), -S(O)2R3, -S(O)R3, -N(R3)S(O)2N(R3aR3b), -SR3, -N(R3R3a), -NO2, -OC(O)R3, -N(R3)C(O)R3a, -N(R3)S(O)2R3a, -N(R3)S(O)R3a, -N(R3)C(O)OR3a, -N(R3)C(O)N(R3aR3b), -OC(O)N(R3R3a), and Ci-6 alkyl, wherein Ci-6 alkyl is optionally substituted with one or more halogen, which are the same or different; andAscendis Pharma Growth Disorders A / S 82 22 December 2025

[0831] CPX75232PC

[0832] -R3, -R3aand -R3bare independently selected from -H, methyl, ethyl, propyl and butyl.

[0833] In certain embodiments -Sg- of formula (g) is Ci-6 alkyl.

[0834] In certain embodiments -Zaand -Zaof formula (g) have the same structure. In certain embodiments -Zaand -Zaof formula (g) are of formula (b).

[0835] Specific embodiments for BPa, -Sa-, -Sa-, -Sa

[0836]

[0837] -Sa-Pa, -Paand -Paof formula (g-i) are as defined above for formula (a).

[0838] Specific embodiments for -Sg-, -Sg- and -Sg- of formula (g-i) are as defined for formula (g).

[0839] In certain embodiments -Zaand -Zaof formula (g-i) have the same structure. In certain embodiments -Zaand -Zaof formula (g-i) are of formula (b). Specific embodiments for bl, b2, b3 and b4 are as described for formula (b).

[0840] In certain embodiments -Z is of formula (h):

[0841]

[0842] wherein

[0843] the dashed line indicates attachment to -L2-; and

[0844] each -Zcis a moietyAscendis Pharma Growth Disorders A / S 22 December 2025

[0845] CPX75232PC

[0846]

[0847] wherein

[0848] each cl is independently an integer ranging from about 200 to 250.

[0849] Optionally the moiety of formula (h) is substituted with one or more substituents. In certain embodiments the moiety of formula (h) is not substituted with one or more substituents.

[0850] In certain embodiments both cl of formula (h) are the same. In certain embodiments both cl of formula (h) are about 225.

[0851] In certain embodiments the moiety -Z is of formula (h-i):

[0852]

[0853] (h-i),

[0854] wherein

[0855] the dashed line indicates attachment to -L2-; and

[0856] each -Zcis a moietyAscendis Pharma Growth Disorders A / S 22 December 2025

[0857] CPX75232PC

[0858]

[0859] each cl is independently an integer ranging from 200 to 250.

[0860] Optionally the moiety of formula (h-i) is substituted with one or more substituents. In certain embodiments the moiety of formula (h-i) is not substituted with one or more substituents.

[0861] In certain embodiments both cl of formula (h-i) are the same. In certain embodiments both cl of formula (h-i) are about 225.

[0862] In certain embodiments the CNP conjugate is of formula (Ilf):

[0863]

[0864] wherein

[0865] the unmarked dashed line indicates attachment to a nitrogen of -D; and

[0866] the dashed line marked with the asterisk indicates attachment to -Z having the structureAscendis Pharma Growth Disorders A / S 85 22 December 2025

[0867] CPX75232PC

[0868]

[0869] wherein

[0870] each cl is an integer independently ranging from 200 to 250.

[0871] In certain embodiments the CNP conjugate is of formula (Ilf ’):

[0872]

[0873] wherein

[0874] the unmarked dashed line indicates attachment to a nitrogen of -D; and

[0875] the dashed line marked with the asterisk indicates attachment to -Z having the structureAscendis Pharma Growth Disorders A / S 86 22 December 2025

[0876] CPX75232PC

[0877]

[0878] wherein

[0879] each cl is an integer independently ranging from 200 to 250.

[0880] In certain embodiments the CNP conjugate is of formula (Ilf’):

[0881]

[0882] wherein

[0883] the unmarked dashed line indicates attachment to a nitrogen of -D; and

[0884] the dashed line marked with the asterisk indicates attachment to -Z having the structureAscendis Pharma Growth Disorders A / S 87 22 December 2025

[0885] CPX75232PC

[0886]

[0887] wherein

[0888] each cl is independently an integer ranging from 200 to 250.

[0889] In certain embodiments each cl of formula (Ilf), (Ilf) or (Ilf’) is about 225.

[0890] In certain embodiments -D of formula (Ilf), (Ilf) or (Ilf’) is a CNP moiety having the sequence of SEQ ID NO:24, SEQ ID NO:25 or SEQ ID NO:30. In certain embodiments -D of formula (Ilf), (Ilf) or (Ilf’) is a CNP moiety having the sequence of SEQ ID NO:24. In certain embodiments -D of formula (Ilf), (Ilf) or (Ilf’) is a CNP moiety having the sequence of SEQ ID NO:20. In certain embodiments -D of formula (Ilf), (Ilf) or (Ilf’) is a CNP moiety having the sequence of SEQ ID NO:21. In certain embodiments -D of formula (Ilf), (Ilf) or (Ilf’) is a CNP moiety having the sequence of SEQ ID NO:22. In certain embodiments -D of formula (Ilf), (Ilf) or (Ilf’) is a CNP moiety having the sequence of SEQ ID NO:23. In certain embodiments -D of formula (Ilf), (Ilf) or (Ilf’) is a CNP moiety having the sequence of SEQ ID NO:30.Ascendis Pharma Growth Disorders A / S 88 22 December 2025

[0891] CPX75232PC

[0892] In certain embodiments -D of formula (Ilf), (Ilf) or (Ilf’) is a CNP moiety which is attached to -L1- through the nitrogen of the N-terminal amine functional group of CNP. In certain embodiments -D of formula (Ilf), (Ilf) or (Ilf’) is a CNP moiety which is attached to -L1- through a nitrogen provided by the amine functional group of a lysine side chain of the CNP moiety. In certain embodiments 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. Accordingly, in certain embodiments the CNP moiety is connected to -L1- in the CNP conjugate of formula (Ilf), (Ilf) or (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. In certain embodiments the CNP moiety is connected to -L1- in the CNP conjugate of formula (Ilf), (Ilf) or (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. In certain embodiments the CNP moiety is connected to -L1- in the CNP conjugate of formula (Ilf), (Ilf) or (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 -L1- in the CNP conjugate of formula (Ilf), (Ilf) or (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. In certain embodiments the CNP moiety is connected to -L1- in the CNP conjugate of formula (Ilf), (Ilf) or (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. In certain embodiments 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. Accordingly, in certain embodiments the CNP moiety is connected to -L1- in the CNP conjugate of formula (Ilf), (Ilf) or (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.

[0893] In certain embodiments the CNP conjugate is of formula (Ilf), (Ilf) or (Ilf’), wherein -D is a CNP moiety having the sequence of SEQ ID NO:20 and is attached to -L1- through the amine functional group provided by the side chain of the lysine at position 30. In certain embodiments the CNP conjugate is of formula (Ilf), (Ilf) or (Ilf’), wherein -D is a CNP moiety having the sequence of SEQ ID NO:21 and is attached to -L1- through the amine functional group provided by the side chain of the lysine at position 29. In certain embodiments the CNP conjugate is of formula (Ilf), (Ilf) or (Ilf’), wherein -D is a CNP moiety having the sequence of SEQ ID NO:22 and is attached to -L1- throughAscendis Pharma Growth Disorders A / S 89 22 December 2025

[0894] CPX75232PC

[0895] the amine functional group provided by the side chain of the lysine at position 28. In certain embodiments the CNP conjugate is of formula (Ilf), (Ilf) or (Ilf’), wherein -D is a CNP moiety having the sequence of SEQ ID NO:23 and is attached to -L1- through the amine functional group provided by the side chain of the lysine at position 27. In certain embodiments the CNP conjugate is of formula (Ilf), (Ilf) or (Ilf’), wherein -D is a CNP moiety having the sequence of SEQ ID NO:30 and is attached to -L1- through the amine functional group provided by the side chain of the lysine at position 27.

[0896] It is understood that the positions of the cysteines and lysines mentioned herein 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.

[0897] In certain embodiments the CNP conjugate is of formula (Ilf), (Ilf) or (Ilf’), wherein -D is a CNP moiety having the sequence of SEQ ID NO:24 and is attached to -L1- through the amine functional group provided by the side chain of the lysine at position 26.

[0898] The CNP conjugate of formula (Ilf’), in which -D is a CNP moiety having the sequence of SEQ ID NO:24, which is attached to -L1- through the amine functional group provided by the side chain of the lysine at position 26, is also known as navepegritide.

[0899] In certain embodiments the CNP conjugate is BMN-333, which is (4R,10S,16S,19S,22S,28S,31S,34S,37S,40S,43S,49S,52R)-52-(2-((S)-2-((S)-2-((S)-2-(2-((S)-2-((S)-2-((S)-2-((S)-2-(2-((S)-2-((S)-2-((S)-2-((S)-2-((S)-2-((S)-2-((S)-l-(L-prolylglycyl-L-glutaminyl-L-glutamyl-L-histidyl)pyrrolidine-2-carboxamido)-4-amino-4-oxobutanami-do)propanamido)-5-guanidinopentanamido)-6-aminohexanamido)-3-(4-hydroxyphenyl)pro-panamido)-6-aminohexanamido)acetamido)propanamido)-4-amino-4-oxobutanamido)-6-aminohexanamido)-6-aminohexanamido)acetamido)-4-methylpentanamido)-3-hydroxypro-panamido)-6-aminohexanamido)acetamido)-49-benzyl-28-((S)-sec-butyl)-34-(carboxymethyl)-40-((S)-33,51-dicarboxy-8-(2-hydroxyethyl)-6, 12,21,30,35-pentaoxo-14,17,23,26-tetraoxa-Ascendis Pharma Growth Disorders A / S 90 22 December 2025

[0900] CPX75232PC

[0901] 5,8, ll,20,29,34-hexaazahenpentacontyl)-31-(3-guanidinopropyl)-16,22-bis(hydroxymethyl)- 10,37,43-triisobutyl-19-(2-(methylthio)ethyl)-6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51-hexadecaoxo-l,2-dithia-5, 8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-hexadecaazacyclotripentacontane-4carboxylic acid.

[0902] BMN-333 has the following structure

[0903]

[0904] wherein

[0905] the dashed line indicates attachment to the nitrogen of the amine functional group of the side chain of the lysine at position 27 of SEQ ID NO:30, i.e., of the lysine marked with the asterisk in the following sequence PGQEHPNARKYKGANKKGLSKGCFGLK*LDRIGSMSGLGC (SEQ ID NO: 30).

[0906] The pharmaceutical composition comprising the CNP or CNP conjugate may be a dry or a liquid pharmaceutical composition. In certain embodiments the pharmaceutical composition is a dry pharmaceutical composition. In certain embodiments the pharmaceutical composition is a liquid pharmaceutical composition. In certain embodiments the pharmaceutical composition has a pH ranging from pH 4 to pH 6. In certain embodiments the pharmaceutical composition has a pH ranging from pH 4.5 to pH 5.5. In certain embodiments the pharmaceutical composition has a pH of about 5.

[0907] The CNP or CNP conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such CNP or CNP conjugate may be administered in a dose ranging from 50 pg CNP / kg to 150 pg CNP / kg, wherein the kg refers to the weight of the patient. In certain embodiments the CNP or CNP conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such CNP or CNP conjugate is administered in a dose ranging from 75 pg CNP / kg to 125 pg CNP / kg. In certain embodiments the CNP or CNP conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such CNP or CNP conjugate is administered in a dose of about 100 pg CNP / kg.Ascendis Pharma Growth Disorders A / S 91 22 December 2025

[0908] CPX75232PC

[0909] The weight of a patient may range from 2 kg to 90 kg or from 4 kg to 70 kg or from 5 kg to 60 kg.

[0910] In certain embodiments the CNP or CNP conjugate may be provided in three different strengths, i.e., in containers that contain three different concentrations of the CNP or CNP conjugate. In certain embodiments the CNP or CNP conjugate may be provided in four different strengths. In certain embodiments the CNP or CNP conjugate may be provided in five different strengths. In certain embodiments the CNP or CNP conjugate may be provided in six different strengths.

[0911] In certain embodiments the CNP conjugate of formula (Ilf), (Ilf’) or (Ilf”) is provided in three different strengths, which comprise 1.3 mg CNP / container, 2.8 mg CNP / container and 5.5 mg CNP / container.

[0912] In certain embodiment the CNP conjugate of formula (Ilf), (Ilf’) or (Ilf”) is provided as a lyophilized pharmaceutical composition, which is reconstituted prior to administration. After reconstitution the concentration of CNP in the form of the CNP conjugate of formula (Ilf), (Ilf’) or (Ilf”) is in certain embodiments 2.2 mg / mL. Such reconstituted pharmaceutical composition may comprise 2.2 mg / mL CNP in the form of the CNP conjugate of formula (Ilf), (Ilf’) or (Ilf”), 1.18 mg / mL succinic acid, 85 mg / ml trehalose dihydrate and water for injection. Such reconstituted pharmaceutical composition may have a pH of about 5. Such reconstituted pharmaceutical composition may also comprise tromethamine and hydrochloric acid as needed to adjust the pH.

[0913] In certain embodiments the reconstituted pharmaceutical composition has a concentration of the CNP in the form the CNP conjugate of formula (Ilf), (Ilf) or (Ilf”) of 4.6 mg / mL. In certain embodiments such reconstituted pharmaceutical composition may comprise 4.6 mg / mL CNP in the form of the CNP conjugate of formula (Ilf), (Ilf’) or (Ilf”), 1.18 mg / mL succinic acid, 77 mg / mL trehalose dihydrate and water for injection. Such reconstituted pharmaceutical composition may have a pH of about 5. Such reconstituted pharmaceutical composition may also comprise tromethamine and hydrochloric acid as needed to adjust the pH.

[0914] In certain embodiments the reconstituted pharmaceutical composition has a concentration of the CNP in the form the CNP conjugate of formula (Ilf), (Ilf) or (Ilf”) of 5.5 mg / mL. In certain embodiments such reconstituted pharmaceutical composition may comprise 5.5 mg / mL CNP in the form of the CNPAscendis Pharma Growth Disorders A / S 92 22 December 2025

[0915] CPX75232PC

[0916] conjugate of formula (Ilf), (Ilf’) or (Ilf”), 1.18 mg / mL succinic acid, 73 mg / mL trehalose dihydrate and water for injection. Such reconstituted pharmaceutical composition may have a pH of about 5. Such reconstituted pharmaceutical composition may also comprise tromethamine and hydrochloric acid as needed to adjust the pH.

[0917] The reconstituted pharmaceutical composition comprising the CNP conjugate of formula (Ilf), (Ilf’) or (Ilf”) is administered once weekly by subcutaneous injection.

[0918] In certain embodiments the CNP is vosoritide, i.e., the CNP of SEQ ID NO:30, which is marketed as VOXZOGO®, and is provided in three different strengths, which comprise 0.4 mg CNP / vial, 0.56 mg CNP / vial and 1.2 mg CNP / vial. Each vial comprises vosoritide together with inactive ingredients as a lyophilized powder.

[0919] The 0.4 mg strength of VOXZOGO® is provided in a vial that also contains 0.14 mg / vial citric acid monohydrate, 7.5 mg / vial mannitol, 0.36 mg / vial methionine, 0.025 mg / vial polysorbate 80, 0.54 mg / vial sodium citrate dihydrate and 29.01 mg / vial trehalose dihydrate. After reconstitution with 0.5 mL sterile water for injection, the resulting concentration of vosoritide is 0.4 mg / 0.5 mL and the nominal deliverable volume is 0.4 mL.

[0920] The 0.56 mg strength of VOXZOGO® is provided in a vial that also contains 0.20 mg / vial citric acid monohydrate, 10.50 mg / vial mannitol, 0.51 mg / vial methionine, 0.035 mg / vial polysorbate 80, 0.76 mg / vial sodium citrate dihydrate and 40.61 mg / vial trehalose dihydrate. After reconstitution with 0.7 mL sterile water for injection, the resulting concentration of vosoritide is 0.56 mg / 0.7 mL and the nominal deliverable volume is 0.6 mL.

[0921] The 1.2 mg strength of VOXZOGO® is provided in a vial that also contains 0.17 mg / vial citric acid monohydrate, 9 mg / vial mannitol, 0.44 mg / vial methionine, 0.030 mg / vial polysorbate 80, 0.65 mg / vial sodium citrate dihydrate and 34.81 mg / vial trehalose dihydrate. After reconstitution with 0.6 mL sterile water for injection, the resulting concentration of vosoritide is 1.2 mg / 0.6 mL and the nominal deliverable volume is 0.5 mL.

[0922] VOXZOGO® is administered once daily via subcutaneous injection.Ascendis Pharma Growth Disorders A / S 93 22 December 2025

[0923] CPX75232PC

[0924] In certain embodiments the CNP or CNP conjugate is administered in a co-treatment with one or more further drugs. Such one or more further drug may be selected from the group consisting of growth hormone, human anti-FGFR3 antibodies, soluble forms of human fibroblast growth factor receptor 3, tyrosine kinase inhibitors, statins, antihistamines, CNP agonists, IGF-1, ANP, BNP, inhibitors of peptidases and proteases and inhibitors of NPR-C.

[0925] Such one or more further drug may be administered simultaneously, separately or by sequential administration.

[0926] In certain embodiments the one or more further drug is a growth hormone, such as a human growth hormone. Human growth hormone has the sequence of SEQ ID NO: 106:

[0927] FPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSFLQNPQTSLCFSESIPT PSNREETQQKSNLELLRISLLLIQSWLEPVQFLRSVFANSLVYGASDSNVYDLLKDLEEGIQ TLMGRLEDGSPRTGQIFKQTYSKFDTNSHNDDALLKNYGLLYCFRKDMDKVETFLRIVQC RSVEGSCGF

[0928] In certain embodiments the one or more further drug is a conjugate comprising human growth hormone, such as lonapegsomatropin.

[0929] Examples

[0930] Materials and Methods

[0931] Example 1: Synthesis of navepegritide

[0932] Navepegritide was synthesized as described in WO2017 / 118693 for conjugate 1 li. Navepegritide has the following structure:

[0933]

[0934] (Ilf’),

[0935] whereinAscendis Pharma Growth Disorders A / S 94 22 December 2025

[0936] CPX75232PC

[0937] the unmarked dashed line indicates attachment to the nitrogen of the amine functional group of the lysine side chain at position 26 of CNP-38 (SEQ ID NO:24); and

[0938] the dashed line marked with the asterisk indicates attachment to the structure

[0939]

[0940] wherein

[0941] each cl is independently an integer ranging from 200 to 250.

[0942] Each one of the four PEG arms of navepegritide has a molecular weight of about 10 kDa.

[0943] Example 2:

[0944] Navepegritide phase 2b trial design (Regulatory Agency Identifier Number: NCT05598320)

[0945] Data was obtained from a Phase 2b, multicenter, double-blind (DB), randomized, placebo-controlled trial evaluating efficacy, safety and pharmacokinetic properties of 100 pg / kg once weekly navepegritide or placebo administered subcutaneously (SC) to children with achondroplasia aged 2 to 11 years followed by an open-label extension (OLE) period of 52 weeks. The DB period was a 52-Ascendis Pharma Growth Disorders A / S 95 22 December 2025

[0946] CPX75232PC

[0947] week, randomized, placebo-controlled treatment period evaluating 100 pg / kg / week navepegritide or placebo (randomization ratio 2:1). Trial participants were stratified by age and sex at the time of randomization (3 strata: aged <5years, aged >5 years and female, aged >5 years and male. The DB period was preceded by a 5-week screening period.

[0948] A total of 84 participants were randomized in the trial, of which 57 received navepegritide and 27 received placebo. The vast majority (97.6%) of participants completed 52 weeks of treatment in the DB period and entered the OLE period. Two participants, both in the navepegritide group, discontinued treatment and withdrew from the trial due to withdrawal by parent / guardian.

[0949] X-ray analysis of lower extremity curvature

[0950] One exploratory objective of the trial was the evaluation of the treatment impact of navepegritide on growth and morphology of dysplastic bone.

[0951] X-ray data of the lower extremity (anterior to posterior standing lower extremity X-ray) was collected. X-ray data were calibrated to adjust for the distance from the participant to the X-ray detector. Endpoints based on linear measurements are reported as calibrated values while those based on angular measurements or length ratios are reported as uncalibrated values.

[0952] For endpoints with a target of zero, such as for lower extremity curvature, changes from baseline were calculated as the difference between the absolute values at baseline and week 52. Negative absolute changes reflect a lessening of deformity, while positive absolute changes reflect worsening. Z-scores for tibia-femoral angle (TFA) and mechanical axis deviation (MAD) were calculated relative to an average-stature population using the reference data in Sabharwal et al. (J Pediatr Orthop 2008.

[0953] 28 (7):740-746).

[0954] Significant improvements in lower extremity curvature were observed with navepegritide compared to placebo, an effect that was associated with a decrease in fibular overgrowth over the 52-week period.

[0955] Tibia-Femoral Angle (TFA):Ascendis Pharma Growth Disorders A / S 96 22 December 2025

[0956] CPX75232PC

[0957] At baseline, observed mean TFA was 6.083 degrees in the navepegritide group and 9.316 degrees in the placebo group, reflecting varus malalignment (positive value) in most participants, as would be expected with achondroplasia.

[0958] At week 52, LS mean absolute change from baseline in TFA was -1.425 degrees (95% CI: -2.227, -0.623) in the navepegritide group versus 0.388 degrees (95% CI: -0.716, 1.493) in the placebo group. The treatment difference (-1.814 degrees [95% CI: -3.162, -0.465]) was significant (p = 0.0094), reflecting a greater decrease in leg bowing in the navepegritide versus placebo group. The reduction in TFA observed during the DB period continued during the OLE period in the navepegritide / navepegritide group, with a mean change from week 52 to week 104 of -0.804 degrees. In the placebo / navepegritide group, a reduction was observed after the switch to navepegritide treatment, with a mean change of -1.704 degrees from week 52 to week 104. From week 0 to week 104, mean changes in TFA of -2.171 degrees in the navepegritide / navepegritide group and -1.493 degrees in the placebo / navepegritide group were observed.

[0959] The LS mean difference in TFA angle of -1.814 degrees was approximately 2 times the inter-rater difference (0.93 degrees) and >3.5 times the mean intra-rater difference (0.47 degrees).

[0960] The impact of navepegritide on TFA was further amplified in those with greater degrees of leg bowing at baseline (baseline TFA >5 degrees) with a treatment difference of -3.99 degrees (95% CI -6.83 to -1.15, p < 0.01, n = 39) at week 52. Greater mean changes were also observed with navepegritide treatment from week 52 to week 104 in this subgroup, with mean changes of -1.839 degrees in the navepegritide / navepegritide group and -3.538 degrees in the placebo / navepegritide group.

[0961] In addition, participants with baseline TFA >5 degrees experienced greater improvements in the Achondroplasia Child Experience Measures - Physical Functioning (ACEM-PF; Am J Med Genet A. (2021), 185(1): 33-45) with navepegritide vs. placebo at week 52. A correlation between changes from baseline in TFA and in ACEM-PF in this subgroup was observed (r = 0.31, p = 0.0617) with significant correlations for the ACEM-PF items ‘walk long distances’ (r = 0.48, p = 0.0029), and ‘sit for long periods of time’ (r = 0.39, p = 0.0202). These correlations were further improved in younger subjects (<8 years at baseline).Ascendis Pharma Growth Disorders A / S 97 22 December 2025

[0962] CPX75232PC

[0963] TFA Z-score:

[0964] At baseline, observed mean TFA Z-score was 5.339 in the navepegritide group and 6.112 in the placebo group, indicating a markedly greater TFA in the participants compared to an average-stature population.

[0965] At week 52, LS mean absolute change from baseline in TFA Z-score was -0-364 (95% CI: -0.790, 0.062) in the navepegritide group versus 1.046 (95% CI: -2.382, -0.438) was significant (p = 0.0057), reflecting a greater decrease in leg bowing in the navepegritide versus placebo group.

[0966] All data is summarized in Table 1.

[0967] Table 1: Analysis of change from baseline in tibia-to-femoral angle and tibia-to-femoral angle Z-score at week 52

[0968]

[0969] Ascendis Pharma Growth Disorders A / S 98 22 December 2025

[0970] CPX75232PC

[0971]

[0972] Mechanical Axis Deviation (MAD):

[0973] At baseline, observed mean MAD was 8.349 mm in the navepegritide group and 12.538 mm in the placebo group, reflecting varus malalignment in most participants (positive value) as expected with achondroplasia.

[0974] At week 52, LS mean absolute change from baseline in MAD was -1.005 mm (95% CI: -1.865, -0.144) in the navepegritide group vs. 1.776 mm (95% CI: 0.031, 3.522) in the placebo group. The treatment difference (-2.781 mm [95% CI: -4.706, -0.856]) was significant (p = 0.0063), reflecting a greater decrease in leg bowing in the navepegritide vs. placebo group.

[0975] The LS mean difference in MAD of -2.781 mm was >2.5 times the inter-rater difference (1.01 mm) and >2.5 times the mean intra-rater difference (0.98 mm).

[0976] MAD Z-score:

[0977] At baseline, observed mean MAD Z-score was 2.441 in the navepegritide group and 2.339 in the placebo group, indicating a greater MAD than in an average-stature population.

[0978] At week 52, LS mean absolute change from baseline in MAD Z-score was -0.356 (95% CI: -0.584, -0.128) in the navepegritide group vs. 0.543 (95% CL -0.186, 1.272) in the placebo group. The treatment difference (-0.899 [95% CI: -1.657, -0.141]) was significant (p = 0.0223) (Table 2), reflecting a greater decrease in leg bowing in the navepegritide vs. placebo group.

[0979] All data is summarized in Table 2.

[0980] Table 2: Analysis of Absolute Change form Baseline in Mechanical Axis Deviation and Mechanical Axis Deviation Z-score at Week 52 (Full Analysis Set)Ascendis Pharma Growth Disorders A / S 99 22 December 2025

[0981] CPX75232PC

[0982]

[0983] Fibula-to-Tibia Ratio

[0984] At baseline, observed mean fibula-to-tibia ratio was 1.064 in the navepegritide group and 1.080 in the placebo group, reflecting fibular overgrowth (fibula length > tibia length) as expected in achondroplasia.

[0985] At week 52, LS mean change from baseline in fibula-to-tibia ratio was 0.001 (95% CI: -0.003, 0.006) in the navepegritide group vs. 0.017 (95% CI: 0.011, 0.024) in the placebo group. The treatment difference (-0.016 [95% CI: -0.024, -0.008]) was significant (p = 0.0001), reflecting a stable fibula-Ascendis Pharma Growth Disorders A / S 100 22 December 2025

[0986] CPX75232PC

[0987] to-tibia ratio in the navepegritide group and a further exacerbation of fibular overgrowth in the placebo group.

[0988] Spinal Canal Dimensions

[0989] In achondroplasia, spinal stenosis is a serious complication which leads to pain, reduced mobility, and increased frequency of surgical intervention. Increased risk of lumbar spinal stenosis in achondroplasia is associated with a reduction in spinal canal parameters, with interpedicular distance (IPD) and pedicle width (PW) decreasing from LI to L5 unlike the average stature population where they increase.

[0990] The spinal canal dimensions were measured in this trial as IPD and PW. Both were numerically improved across L1-L5 with navepegritide compared to placebo, with LS mean differences in IPD of 0.275 mm (95% CI: -0.362, 0.911) and inPW of 0.202 mm (95% CI: -0.085, 0.490).

[0991] Similar numerical increases were observed for the IPD Z-score (0.219 [95% CI: -0.195, 0.633]) and PW Z-score (0.405 [95% CI: -0.044, 0.855]). At an individual vertebral level, the greatest treatment difference with navepegritide compared to placebo in ASND0036 was observed for IPD at LI (0.618 mm [95% CL 0.094, 1.143], p = 0.0222) and for PW at L4 (0.335mm [95% CI: -0.030, 0.700], p = 0.0706).

[0992] The increases in IPD and PW with navepegritide indicate greater expansion of spinal canal size compared to placebo. Preventing or reversing the achondroplasia-related decrease in lumbar spinal canal size with treatment has the potential to reduce the frequency of spinal stenosis in this population.

[0993] Abbreviations:

[0994] CI confidence interval

[0995] LS least squares

[0996] n number of participants in the analysis

[0997] N number of participants in the analysis set

[0998] OLE open label extension

[0999] SD standard deviation

Claims

Ascendis Pharma Growth Disorders A / S 101 22 December 2025CPX75232PCClaims1. A CNP or CNP conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such CNP or CNP conjugate or a pharmaceutically acceptable salt thereof for use in the treatment of a lower extremity deformity in a subject with a skeletal dysplasia and wherein the subject has or is at risk of developing said lower extremity deformity.

2. The CNP or CNP conjugate for use of claim 1, wherein the lower extremity deformity is lower leg bowing.

3. The CNP or CNP conjugate for use of claim 1 or 2, wherein the lower extremity deformity is due to one or more factors selected from the group consisting of an increased relative length of the fibula compared to the tibia; asymmetric growth of condyles; and increased laxity at the hip and / or knee joints.

4. The CNP or CNP conjugate for use of any one of claims 1 to 3, wherein the skeletal dysplasia is a skeletal dysplasia that results in leg bowing.

5. The CNP or CNP conjugate for use of any one of claims 1 to 4, wherein the skeletal dysplasia is caused by decreased mineralization.

6. The CNP or CNP conjugate for use of claim 5, wherein the skeletal dysplasia that is caused by decreased mineralization is XLH.

7. The CNP or CNP conjugate for use of claim 5, wherein the skeletal dysplasia that is caused by decreased mineralization is HPP.

8. The CNP or CNP conjugate for use of any one of claims 1 to 4, wherein the skeletal dysplasia is achondroplasia.Ascendis Pharma Growth Disorders A / S 102 22 December 2025CPX75232PC9. The CNP or CNP conjugate for use of any one of claims 1 to 8, wherein the subject has lower extremity deformity.

10. The CNP or CNP conjugate for use of any one of claims 1 to 9, wherein the treatment reduces the tibia-to-femoral angle.

11. The CNP or CNP conjugate for use of any one of claims 1 to 10, wherein the treatment reduces the tibia-to-femoral angle Z-score.

12. The CNP or CNP conjugate for use of any one of claims 1 to 11, wherein the treatment reduces the mechanical axis deviation.

13. The CNP or CNP conjugate for use of any one of claims 1 to 12, wherein the treatment reduces the mechanical axis deviation Z-score.

14. The CNP or CNP conjugate for use of any one of claims 1 to 13, wherein the treatment reduces the fibula-to-tibia ratio.

15. The CNP or CNP conjugate for use of any one of claims 1 to 8, wherein the subject is at risk of developing lower extremity deformity.

16. The CNP or CNP conjugate for use of any one of claims 1 to 15, wherein the treatment comprises the step of measuring one or more parameters indicative of the lower extremity deformity.

17. The CNP or CNP conjugate for use of claim 16, wherein the measurement of the one or more parameters is prior to the initiation of the treatment, during and / or after the treatment.

18. The CNP or CNP conjugate for use of claim 16 or 17, wherein the one or more parameters are selected from the group consisting of the tibia-to-femoral angle, the mechanical axis deviation and the fibula-to-tibia ratio.Ascendis Pharma Growth Disorders A / S 103 22 December 2025CPX75232PC19. The CNP or CNP conjugate for use of any one of claims 16 to 18, wherein the parameters are measured by taking X-rays of the lower extremities while standing.

20. The CNP or CNP conjugate for use of any one of claims 1 to 19, wherein the treatment starts upon diagnosis of the skeletal dysplasia.

21. The CNP or CNP conjugate for use of any one of claims 1 to 20, wherein the treatment starts upon birth.

22. The CNP or CNP conjugate for use of any one of claims 1 to 21, wherein the subject is a human subject.

23. The CNP or CNP conjugate for use of any one of claims 1 to 22, wherein the subject is a pediatric subject.

24. The CNP or CNP conjugate for use of any one of claims 1 to 22, wherein the subject is an infant.

25. The CNP or CNP conjugate for use of any one of claims 1 to 22, wherein the subject is a newborn.

26. The CNP or CNP conjugate for use of any one of claims 1 to 25, wherein the treatment lasts until bone epiphyses are closed.

27. The CNP or CNP conjugate for use of any one of claims 1 to 25, wherein the treatment continues beyond the closure of bone epiphyses.

28. The CNP or CNP conjugate for use of any one of claims 1 to 23, wherein the subject is a pediatric subject of less than 8 years of age.

29. The CNP or CNP conjugate for use of any one of claims 1 to 28, wherein the subject has a TFA angle of >5 degrees.Ascendis Pharma Growth Disorders A / S 104 22 December 2025CPX75232PC30. The CNP or CNP conjugate for use of any one of claims 1 to 29, wherein the treatment comprises successive administrations of the CNP or CNP conjugate.

31. The CNP or CNP conjugate for use of any one of claims 1 to 30, wherein the treatment comprises daily administrations of the CNP or CNP conjugate.

32. The CNP or CNP conjugate for use of any one of claims 1 to 30, wherein the treatment comprises weekly administrations of the CNP or CNP conjugate.

33. The CNP or CNP conjugate for use of any one of claims 1 to 32, wherein the CNP or CNP conjugate is administered by subcutaneous injections.

34. The CNP or CNP conjugate for use of any one of claims 1 to 33, wherein the treatment increases gait speed.

35. The CNP or CNP conjugate for use of any one of claims 1 to 34, wherein the treatment increases stride length.

36. The CNP or CNP conjugate for use of any one of claims 1 to 35, wherein the treatment increases cadence.

37. The CNP or CNP conjugate for use of any one of claims 1 to 36, wherein the treatment reduces knee valgus moments.

38. The CNP or CNP conjugate for use of any one of claims 1 to 37, wherein the treatment increases mediolateral static stability.

39. The CNP or CNP conjugate for use of any one of claims 1 to 38, wherein the treatment increases dynamic stability.

40. The CNP or CNP conjugate for use of any one of claims 1 to 39, wherein the treatment increases knee joint stability in the medio-lateral direction.Ascendis Pharma Growth Disorders A / S 105 22 December 2025CPX75232PC41. The CNP or CNP conjugate for use of any one of claims 1 to 40, wherein the CNP is a CNP having a sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID N0:9, 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, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO 53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104 and SEQ ID NO: 105.

42. The CNP or CNP conjugate for use of any one of claims 1 to 41, wherein the CNP is a peptide having the sequence of SEQ ID NO:30.

43. The CNP or CNP conjugate for use of any one of claims 1 to 40, wherein the CNP conjugate is a conjugate of formula (la) or (lb)(la),whereinAscendis Pharma Growth Disorders A / S 106 22 December 2025CPX75232PC-D is a CNP moiety;-L1- is a reversible linker moiety;-L2- is absent or a spacer moiety;-Z is a polymeric moiety or an albumin-binding 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; andy is an integer selected from the group consisting of 2, 3, 4 and 5.

44. The CNP or CNP conjugate for use of claim 43, wherein the CNP conjugate is of formula (la).

45. The CNP or CNP conjugate for use of claim 43 or 44, wherein x is 1.

46. The CNP or CNP conjugate for use of any one of claims 43 to 45, wherein -D has the sequence of SEQ IDNO:24.

47. The CNP or CNP conjugate for use of any one of claims 43 to 45, wherein -D has the sequence of SEQ IDNO:30.

48. The CNP or CNP conjugate for use of any one of claims 43 to 47, wherein -L1- is of formula (II)whereinthe dashed line indicates attachment to a nitrogen, hydroxyl or thiol of -D;-X- is selected from the group consisting of -C(R4R4a)-, -N(R4)-, -O-, -C(R4R4a)-C(R5R5a)-, -C(R5R5a)-C(R4R4a)-, -C(R4R4a)-N(R6)-, -N(R6)-C(R4R4a)-, -C(R4R4a)-O-, -O-C(R4R4a)- and -C(R7R7a)-;>X1=is selected from the group consisting of >C= and >S(O)=;-X2- is selected from the group consisting of -C(R8R8a)- and -C(R8R8a)-C(R9R9a)-;Ascendis Pharma Growth Disorders A / S 107 22 December 2025CPX75232PC=X3is selected from the group consisting of =0, =S and =N-CN;-R1, -Rla, -R2, -R2a, -R4, -R4a, -R5, -R5a, -R6, -R8, -R8a, -R9and -R9aare independently selected from the group consisting of -H and Ci-6 alkyl;-R3and -R3aare independently selected from the group consisting of -H and Ci-6 alkyl, provided that in case one of -R3and -R3aor both are other than -H they are connected to the N atom to which they are attached through an sp3-hybridized carbon atom; -R7is selected from the group consisting of -N(R10R10a) and -NR10-(C=O)-R11; -R7a, -R10, -R10aand -R11are independently of each other selected from the group consisting of -H and Ci-6 alkyl;optionally one or more of the pairs -Rla / -R4a, -Rla / -R5a, -Rla / -R7a, -R4a / -R5aand -R8a / -R9aform a chemical bond;optionally one or more of the pairs -RJ / -Rla, -R2 / -R2a, -R4 / -R4a, -R5 / -R5a, -R8 / -R8aand -R9 / -R9aare 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 -RV-R4, -RV-R5, -RV-R6, -RJ / -R7a, -R4 / -R5, -R4 / -R6, -R8 / -R9and -R2 / -R3are joined together with the atoms to which they are attached to form a ring A;optionally -R3 / -R3aare joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycle;A is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl; andwherein -L1- is substituted with -L2- and wherein -L1- is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (II) is not replaced by -L2- or a substituent.

49. The CNP or CNP conjugate for use of any one of claims 43 to 48, wherein -L2- is absent.

50. The CNP or CNP conjugate for use of any one of claims 43 to 49, wherein -Z is a branched PEG-based moiety.Ascendis Pharma Growth Disorders A / S 108 22 December 2025CPX75232PC51. The CNP or CNP conjugate for use of any one of claims 43 to 50, wherein the CNP conjugate is of formula (Ilf)(Hf),whereinthe unmarked dashed line indicates attachment to a nitrogen of -D; andthe dashed line marked with the asterisk indicates attachment to -Z having the structurewhereineach -Zaiswhereineach cl is an integer independently ranging from 200 to 250.Ascendis Pharma Growth Disorders A / S 109 22 December 2025CPX75232PC52. The CNP or CNP conjugate for use of any one of claims 43 to 51, wherein the CNP conjugate is of formula (Ilf ’)whereinthe unmarked dashed line indicates attachment to a nitrogen of -D; andthe dashed line marked with the asterisk indicates attachment to -Z having the structurewhereineach -Zaiswhereineach cl is an integer independently ranging from 200 to 250.Ascendis Pharma Growth Disorders A / S 110 22 December 2025CPX75232PC53. The CNP or CNP conjugate for use of any one of claim 43 to 52, wherein the CNP conjugate is of formula (Ilf’)whereinthe unmarked dashed line indicates attachment to a nitrogen of -D; andthe dashed line marked with the asterisk indicates attachment to -Z having the structurewhereineach -Zciswhereineach cl is independently an integer ranging from 200 to 250.Ascendis Pharma Growth Disorders A / S 111 22 December 2025CPX75232PC54. The CNP or CNP conjugate for use of any one of claims 51 to 53, wherein -D is CNP having the SEQ ID NO:24 and wherein the dashed line in formula (Ilf), (Ilf ‘) and (Ilf’) indicates attachment to the amine functional group of the side chain of a lysine residue at position 26.

55. A method of treating, preventing or decreasing a lower extremity deformity in a subject suffering from a skeletal dysplasia, the method comprising administering a therapeutically effective amount of a CNP or CNP conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such CNP or CNP conjugate or a pharmaceutically acceptable salt thereof, to said subject.

56. The method of claim 55, wherein the lower extremity deformity is lower leg bowing.

57. The method of claim 55 or 56, wherein the lower extremity deformity is due to one or more factors selected from the group consisting of an increased relative length of the fibula compared to the tibia; asymmetric growth of condyles; and increased laxity at the hip and / or knee joints.

58. The method of any one of claims 55 to 57, wherein the skeletal dysplasia is a skeletal dysplasia that results in leg bowing.

59. The method of any one of claims 55 to 57, wherein the skeletal dysplasia is caused by decreased mineralization.

60. The method of any one of claim 59, wherein the skeletal dysplasia that is caused by decreased mineralization is XLH.

61. The method of claim 59, wherein the skeletal dysplasia that is caused by decreased mineralization is HPP.

62. The method of any one of claims 55 to 58, wherein the skeletal dysplasia is achondroplasia.

63. The method of any one of claims 55 to 62, wherein the subject has lower extremity deformity.Ascendis Pharma Growth Disorders A / S 112 22 December 2025CPX75232PC64. The method of any one of claims 55 to 63, wherein said administration gives rise to a reduced tibia-to-femoral angle.

65. The method of any one of claims 55 to 64, wherein said administration gives rise to a reduced tibia-to-femoral angle Z-score.

66. The method of any one of claims 55 to 65, wherein said administration gives rise to a reduced mechanical axis deviation.

67. The method of any one of claims 55 to 66, wherein said administration gives rise to a reduced mechanical axis deviation Z-score.

68. The method of any one of claims 55 to 67, wherein said administration gives rise to a reduced fibula-to-tibia ratio.

69. The method of any one of claims 55 to 68, wherein the subject is a human subject.

70. The method of any one of claims 55 to 69, wherein the subject is a pediatric subject.

71. The method of any one of claims 55 to 69, wherein the subject is an infant.

72. The method of any one of claims 55 to 69, wherein the subject is a newborn.

73. The method of any one of claims 55 to 72, wherein said administration lasts until bone epiphyses are closed.

74. The method of any one of claims 55 to 72, wherein said administration continues beyond the closure of bone epiphyses.

75. The method of any one of claims 55 to 70, wherein the subject is a pediatric subject of less than 8 years of age.Ascendis Pharma Growth Disorders A / S 113 22 December 2025CPX75232PC76. The method of any one of claims 55 to 75, wherein the subject has a TFA angle of >5 degrees.

77. A method of improving a lower extremity deformity in a subject suffering from a skeletal dysplasia, the method comprising:i) assessing the lower extremity deformity, at least once, in the subject suffering from the skeletal dysplasia, andii) administering a therapeutically effective amount of a CNP or CNP conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such CNP or CNP conjugate or a pharmaceutically acceptable salt thereof, to said subject.

78. The method of claim 77, wherein the assessment of the lower extremity deformity provides a baseline value or determination of the lower extremity deformity, optionally wherein said assessment is carried out within a month before initiating the administering step.

79. The method of claim 77 or 78, wherein the assessment of the lower extremity deformity comprises the step of measuring one or more parameters indicative of said lower extremity deformity.

80. The method of claim 79, wherein the step of measuring the one or more parameters is prior to the initiation of the treatment, during and / or after the treatment.

81. The method of claim 79 or 80, wherein the one or more parameters are selected from the group consisting of tibia-to-femoral angle, mechanical axis deviation and fibula-to-tibia ratio.

82. The method of any one of claims 79 to 81, wherein the one or more parameters are measured by taking X-rays of the lower extremities while standing.

83. The method of any one of claims 77 to 82, wherein the step of administering starts upon diagnosis of the skeletal dysplasia.

84. The method of any one of claims 77 to 83, wherein the step of administering starts upon birth.Ascendis Pharma Growth Disorders A / S 114 22 December 2025CPX75232PC85. The method of any one of claims 77 to 84, wherein the step of administering comprises successive administrations of the therapeutically effective amount CNP or CNP conjugate or pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising such CNP or CNP conjugate or pharmaceutically acceptable salt thereof.

86. The method of any one of claims 77 to 84, wherein the step of administering comprises daily administrations of the therapeutically effective amount CNP or CNP conjugate or pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising such CNP or CNP conjugate or pharmaceutically acceptable salt thereof.

87. The method of any one of claims 77 to 84, wherein the step of administering comprises weekly administrations of the therapeutically effective amount of the CNP or CNP conjugate or pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising such CNP or CNP conjugate or pharmaceutically acceptable salt thereof.

88. The method of claims 77 to 87, wherein the therapeutically effective amount of the CNP or CNP conjugate or pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising such CNP or CNP conjugate or pharmaceutically acceptable salt thereof is administered by subcutaneous injections.

89. The method of any one of claims 77 to 88, wherein said administration gives rise to increased gait speed, in the subject.

90. The method of any one of claims 77 to 88, wherein said administration gives rise to increased stride length, in the subject.

91. The method of any one of claims 77 to 88, wherein said administration gives rise to increased cadence, in the subject.

92. The method of any one of claims 77 to 88, wherein said administration gives rise to reduced knee valgus moments, in the subject.Ascendis Pharma Growth Disorders A / S 115 22 December 2025CPX75232PC93. The method of any one of claims 77 to 88, wherein said administration gives rise to increased mediolateral static stability, in the subject.

94. The method of any one of claims 77 to 88, wherein said administration gives rise to increased dynamic stability, in the subject.

95. The method of any one of claims 77 to 88, wherein said administration gives rise to increased knee joint stability in the medio-lateral direction, in the subject.

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