MÉTODO DE TRATAMENTO DE UMA DEFORMIDADE TORACOLOMBAR EM UM INDIVÍDUO HUMANO COM ACONDROPLASIA

Abstract

The present invention relates to methods for the treatment of a spinal deformity, such as thoracolumbar deformity in a subject in need of said treatment, said method comprising the step of administering a therapeutically effective amount of an inhibitor of FGFR3 signaling, or an NPR-B agonist and / or an NPR-C agonist to said subject.

Description

[001] The present invention relates to methods for treating a spinal deformity, such as thoracolumbar deformity, in an individual in need of such treatment. The method comprises the step of administering a therapeutically effective amount of an FGFR3 signaling inhibitor, or an NPR-B agonist and / or an NPR-C agonist, to said individual. The invention also provides methods for improving muscle function in an individual in need thereof, particularly for therapeutic use in conditions associated with muscle weakness, muscle condition and / or muscle pain. The methods and uses of the invention are useful in the treatment of, for example, achondroplasia. BACKGROUND OF THE INVENTION

[002] Achondroplasia is the most common form of nonlethal skeletal dysplasia, affecting more than 250,000 people worldwide. Achondroplasia is caused by a pathogenic variant in the gene encoding fibroblast growth factor receptor 3 (FGFR3) and is transmitted as an autosomal dominant trait. FGFR3 is a negative regulator of long bone development and is highly expressed in growth plate chondrocytes.

[003] Infants with achondroplasia typically present with weak muscle tone (hypotonia), resulting in delayed development of motor skills and weak skeletal muscles, contributing to spinal deformities such as kyphosis (Takken et al., Journal of Pediatrics 2017, Vol. 150, pp. 26-30; Patient Guide to Achondroplasia, John Hopkins Dept. Orthopedic Surgery, 2003). Muscle weakness is also a characteristic of achondroplasia in adults (Sims et al., Petition 870250079895, dated 05 / 09 / 2025, p. 11 / 354 2 / 309 J Appl Physiol (1985) March 1, 2018; 124 (3): 696-703; de Vries Am J Med Genet. 2021; 185A: 1023-1032).

[004] Spinal deformities in people with achondroplasia require treatment during childhood and adulthood: infants may need bracing or a cast, and corrective surgery may be necessary during childhood. In adulthood, kyphosis can lead to spinal stenosis, and surgery is often needed to straighten the spine and allow the spinal bones to fuse.

[005] Thoracolumbar deformity in patients with achondroplasia (ACH) is a significant problem that can lead to severe disability, pain, and discomfort (see, for example, Misra et al., Neurosurg Focus 14 (1):Article 4, 2003). Thoracolumbar kyphosis (TLK) is one of the most frequent skeletal manifestations in patients with achondroplasia and can result in back pain, neurological deficits, and urinary disorders, potentially requiring surgical correction (see, for example, Tanaka et al., Medicina 2022, 58, 605).

[006] Thoracolumbar kyphosis (TLK) is prevalent in children with achondroplasia and is associated with delayed motor development, hypotonia, and altered body proportions. In most children with achondroplasia, thoracolumbar kyphosis improves with standing, although, if persistent, it is associated with significant pain and results in surgical intervention later in life (Margalitet et al., J Pediatr Orthop. 2018 Nov / Dec;38(10):491-497). TLK is more prevalent in younger children with achondroplasia, and although thoracolumbar kyphosis decreases with age, this is associated with increased lumbar lordosis and an increased risk of spinal stenosis in adults (Abousamra 2019 Spine Deform. Jan 2019;7(1):163-170).

[007] Thoracolumbar kyphosis is frequently present at birth or observed in the first 6 months in 95% of newborns with ACH (Kopits 1988, Basic Life Sci. 1988;48:189-97). Petition 870250079895, dated 05 / 09 / 2025, p. 12 / 354 3 / 309 In these newborns, the thoracolumbar curvature (TLK) ranges from 15 to 25°, with the apex between T12 and L2 and normal vertebral structures. After the baby begins to sit upright, the curvature increases considerably (typically >60° vs ~5° in healthy children), considered a result of delayed motor development, hypotonia, and altered biomechanics due to increased cranial size, shallow rib cage, and enlarged abdomen. Upon standing, the TLK decreases in most children with ACH, as spinal biomechanics and vertebral body ossification improve, preventing the deformity from becoming "fixed." The incidence decreases in older children to 11% at 10 years of age. Subsequently, the prevalence is greater than 30% in patients over 30 years of age.

[008] Thoracolumbar kyphosis deformity usually occurs or worsens in infancy, when the child begins to sit, and the condition follows a predictable course over time until the child begins to walk. Kyphosis is frequently accompanied by gibbon deformity, vertebral hypoplasia, or apical wedging of the vertebral bodies (typically anterior vertebral wedging), which begins as a result of physiological anterior compression of the vertebral growth areas.

[009] Although spontaneous resolution of postural kyphosis occurs in most children by 3 years of age, kyphosis (TLK angle of approximately > 20°) persists in approximately 30% of children with achondroplasia, and the apical vertebral body (typically L1 or L2) assumes a wedge shape. These gibbus deformities are associated with increased incidence and severity of symptomatic spinal stenosis and more frequent surgical intervention in later life stages (Margalit 2018, J Pediatr Orthop. Nov / Dec 2018;38(10):491-497 & Kopits 1988). In a cohort of patients with ACH, TLK was reported to correlate significantly Petition 870250079895, dated 05 / 09 / 2025, p. 13 / 354 4 / 309 with pain, as assessed by the Visual Analogue Scale (VAS) pain score (r = 0.433, p = 0.021) (Hong 2011, Spine (Phila Pa 1976). August 15, 2011; 36(18): E1233-9). Margalit 2018 reports that apical vertebral translation, apical vertebral wedge percentage for vertebral height, and developmental motor delay are associated with unresolved TLK in achondroplasia.

[0010] Therefore, if left uncorrected, TLK can result in progressive fixed thoracolumbar kyphosis and the formation of a fixed thoracolumbar kyphotic deformity. In adults with achondroplasia, the kyphotic deformity is further exacerbated by spinal stenosis and age-related degenerative hypertrophic changes in the ligaments and facet joints of the spine, leading to neurological complications and pain. The incidence of thoracolumbar kyphosis is closely associated with the development of neurological symptoms and damage (Misra et al., Neurosurg Focus 14 (1):Article 4, 2003).

[0011] Early treatment or prevention of thoracolumbar kyphosis in infants and young children with achondroplasia is therefore important to prevent the development of fixed spinal deformities, which lead to physical deformities, neurological damage, and chronic pain later in life. Untreated pediatric thoracolumbar kyphosis can therefore contribute to thoracolumbar spinal stenosis syndrome and subsequent compression of the spinal cord or cauda equina in adults with achondroplasia.

[0012] Therefore, it is important to monitor infants and children with achondroplasia for spinal deformities, such as thoracolumbar kyphosis, and initiate therapeutic intervention. The C-shaped configuration adopted by the child's spine in the sitting position is best appreciated on plain lateral radiography. Typically, routine lateral and AP radiographs should be obtained at 6-month intervals to assess the degree of thoracolumbar kyphosis until the child reaches, for example, 3 Petition 870250079895, dated 05 / 09 / 2025, page 14 / 354 5 / 309 years of age. Indications for surgical intervention are the progression of kyphosis to an angle greater than or equal to 30° (e.g., T10-L2, T11-L2, or T12-L2 kyphosis angle), the appearance of an anterior vertebral wedge, or vertebral displacement during the observation period.

[0013] Early treatment or prevention of thoracolumbar kyphosis may involve the use of a spinal support (orthosis), such as a thoracolumbar orthosis (TLSO), which can reduce or prevent the progression of thoracolumbar kyphosis. In older children and adults, surgical intervention may be necessary, such as thoracolumbar surgery, for example, anterior and posterior fusion with posterior fixation of the kyphotic segments.

[0014] As reported in the examples herein, in a Phase 2 clinical trial and open-label extension trial, the present inventors found that treatment of children with achondroplasia with a therapeutically effective amount of an NPR-B agonist, such as Navepegritide (compound (1)), results in a statistically significant reduction in thoracolumbar kyphosis, as measured by a decrease in the thoracolumbar kyphosis angle (Cobb angle), as well as in the ACH Z-score and the healthy Z-score. The decrease in thoracolumbar kyphosis was associated with a slight trend toward an increase in lumbar lordosis, which is consistent with the reduction in thoracolumbar kyphosis (e.g., T11-L2 kyphosis angle).

[0015] Thoracolumbar kyphosis is associated with spinal / vertebral bone deformity, which can be corrected more advantageously while the bone epiphyses are open, and therefore the methods and uses of the present invention are advantageous in pediatric patients with achondroplasia, including pediatric patients with non-fixed thoracolumbar kyphosis or fixed thoracolumbar kyphosis. As an example, the methods of the invention can be used to correct, prevent, or reduce the deformity of Petition 870250079895, dated 05 / 09 / 2025, p. 15 / 354 6 / 309 development of spinal vertebral deformity, such as thoracolumbar kyphosis.

[0016] As described herein, thoracolumbar kyphosis may also be associated with muscle weakness and hypotonia, and the present invention may be used in patients with achondroplasia with closed bone epiphyses and in adult patients with achondroplasia. Inhibition of FGFR3 signaling has been a focus for the development of therapeutic interventions for the treatment of achondroplasia. FGFR3 inhibitors may act on the receptor itself or on its downstream signaling pathways in order to inhibit FGFR3 signaling. Suitable examples of FGFR3 inhibitors therefore include tyrosine kinase inhibitors (such as infigratinib, pemigatinib, futibatinib, erdafitinib or TYRA-300), C-type natriuretic peptide (CNP), FGFR3 siRNA and FGFR3 antisense oligonucleotides.

[0017] Infigratinib is a selective FGFR tyrosine kinase inhibitor that has been approved for the treatment of certain types of cancer (Truseltiq) and is in clinical development for height increase in children with achondroplasia (Savarirayan et al., Ther Adv Musculoskelet Dis 2022 Mar 21;14).

[0018] TYRA-300 is a potent oral tyrosine kinase inhibitor selective for FGFR-3, which exhibits activity in the presence of mutations, including the V555 mutation of FGFR3, and which shows selectivity for FGFR3 over FGF1 and other FGFR isoforms. TYRA-300 was developed by Tyra Biosciences.

[0019] FGFR3 signals through several intracellular pathways, including the signal transducer and activator of transcription (STAT) pathway and the mitogen-activated protein kinase (MAPK) pathway, and constitutive activation of FGFR3 is associated with the achondroplasia phenotype. FGFR3 activation is associated with increased phosphorylation of the STAT and MAPK pathways. The MAPK pathway can be regulated by the peptide in Petition 870250079895, dated 05 / 09 / 2025, page 16 / 354 7 / 309 C-type triuretic peptide (CNP). The binding of CNP to its receptor, the natriuretic peptide receptor B (NPR-B), gives rise to the production of cGMP, which activates different signaling mediators, including cyclic nucleotide phosphodiesterases (PDEs), cGMP-gated ion channels (cGICs), and cGMP-dependent protein kinases (cGKI and cGKII). The effect of CNP / NPR-B on FGFR3 is mediated by the activation of cGKII, which inhibits the activation of RAF-1 and, consequently, the activation of MEK1 / 2 and ERK1 / 2 in the MAPK pathway. An example of an FGFR3 inhibitor that acts downstream of FGFR3 includes molecules that activate the NPR-B receptor, since activation of this receptor inhibits downstream FGFR3 signaling, inhibiting the mitogen-activated protein kinase (MAPK) pathway.

[0020] Vosoritide is a variant of C-type natriuretic peptide (CNP) that has been approved for the treatment of achondroplasia in pediatric patients whose bones are still growing and acts directly on the growth plates of bones to promote new bone growth.

[0021] TransCon™ CNP is an investigational long-acting CNP prodrug that is in clinical development for the treatment of achondroplasia in pediatric patients with exposed bone epiphysis (Breinholt et al., Br J Clin Pharmacol. 2022 Nov;88(11):47634772). In a phase 2 clinical trial (ACcomplisH), TransCon™ CNP demonstrated superiority compared to placebo in altering the annualized height-specific SDS for ACH, and a reduction in achondroplasia-related adverse events was reported.

[0022] CNP is a potent regulator of growth plate chondrogenesis, and its binding to natriuretic peptide-binding receptor-2 (NPR-B) on the cell surface of chondrocytes induces intracellular synthesis of cyclic guanosine monophosphate (cGMP) and activates cGMP-dependent signal transduction (Potter et al., Handb Exp Petition 870250079895, dated 05 / 09 / 2025, page 17 / 354 8 / 309 Pharmacol. 2009; (191): 341-366). CNP is indicated in cardiac remodeling and acute myocardial infarction, smooth muscle relaxation, and the treatment of hypertension (Nakagawa and Saito, Biology 2022, 11, 1017). Perez-Ternero et al., PNAS 2022, vol. 119 / 13 e2116470119, reports that C-type natriuretic peptide is a fundamental regulator of metabolic homeostasis. CNP exerts these metabolic regulatory actions by inhibiting sympathetic thermogenic programming via Gi-coupled natriuretic peptide receptor (NPR)-C and reducing the expression of peroxisome proliferator-activated receptor-γ coactivator-1α, while concomitantly boosting adipogenesis via NPR-B / protein kinase-G. Perez-Ternero et al., Front. Mol. Neurosci. 15:991112. doi: 10.3389 / fnmol.2022.991112 reports, from mice with CNP deletion, that CNP plays a role in regulating the blood-brain barrier and modulating locomotor reactivity to novel environments, and notably that CNP deletion in gbCNP- / - mice results in reduced body weight but unchanged muscle mass.

[0023] Another example of an FGFR3 inhibitor that acts on the downstream pathway of FGFR3 itself is the molecule Meclizine, which attenuates the MAPK signaling pathway at the ERK phosphorylation level (see, for example, Kitoh et al 2020. PLoS ONE 15(4): e0229639). (https: / / doi.org / 10.1371 / journal.pone.0229639).

[0024] Mackler et al., 1973 (Arch. Biochem and Biophys 159, 885-888) report that oxidative energy production is reduced in adult achondroplasia (ACH). Domondon et al., Am J Physiol Renal Physiol 2019 317: F1164-F1168, review the regulation of mitochondrial function by natriuretic peptides, highlighting the role of ANP and BNP / NPR-A activation in mitochondria. Miyashita et al., Diabetes 2009 58, 2880-2892, reported that BNP / cGK cascades can promote muscle mitochondrial biogenesis and fat oxidation, in addition to Petition 870250079895, dated 05 / 09 / 2025, page 18 / 354 9 / 309 prevent obesity in BNP-TG mice.

[0025] In contrast, Perez-Ternero et al., PNAS 2022 Vol. 119 Studies No. 13 e2116470119 report that CNP has a preservative function in coordinating metabolic homeostasis, inhibiting sympathetic thermogenic programming via NPR-C, while simultaneously boosting adipogenesis via NPR-B / protein kinase-G, indicating that CNP has an action opposite to the activation of NPR-A ANP / BNP. PGC-1alpha is a key regulator of mitochondrial biogenesis and, as reported in Domondon 2018, PGC-1alpha is upregulated via ANP and BNP. STATEMENT OF INVENTION

[0026] The treatment of achondroplasia has focused on promoting endochondrial bone growth, and treatments have been selected for their ability to improve the annualized growth rate / height of achondroplasia in children. The inventors of the present invention have surprisingly discovered that treating children with achondroplasia with a CNP drug, TransCon CNP (Navepegritide), resulted in improved physical function, as well as a reduction in adverse events related to achondroplasia disease, and correction of spinal deformities such as kyphosis and, particularly, thoracolumbar kyphosis.

[0027] Based on the studies reported below, these improvements in physical function may, at least in part, result from improvements in muscle function, independent of bone growth, or the positive effects observed, for example, in spinal deformities, may be attributed to effects on bone growth, for example, improved vertebral morphology, or the combination of effects on bone growth (such as improved vertebral morphology) and improved physical functioning. Children who received placebo showed impaired physical performance and a much higher incidence of adverse events related to achondroplasia disease. Furthermore, in Petition 870250079895, dated 05 / 09 / 2025, page 19 / 354 In a murine model of achondroplasia, treatment with TransCon CNP was shown to increase pup survival in the first 15 days of life. This finding correlated with a reduced incidence of material infanticide, a phenomenon associated with muscle weakness in pups, and occurred over a time period inconsistent with effects related to bone growth. These findings, that CNP, an inhibitor of FGFR3 signaling (as discussed above, CNP inhibits FGFR3-mediated signaling), is effective in improving physical performance and muscle function independently of enhanced endochondrial bone growth, illustrate that CNP and other FGFR3 inhibition strategies are suitable therapies for improving muscle function, for example, in the treatment of hypotonia and related disorders, in both children and adults.The binding of CNP to the NPR-B receptor may contribute to the mechanism of action, and as such, NPR-B receptor agonists are also considered for this use. The binding of CNP to the NPR-C receptor may contribute to the mechanism of action, and as such, NPR-C receptor agonists are also considered for this use.

[0028] The invention provides a method for treating a spinal deformity in an individual in need of such treatment, said method comprising the step of administering a therapeutically effective amount of an FGFR3 signaling inhibitor, an NPR-B agonist and / or an NPR-C agonist to said individual, thereby treating him or her. See List of Items A for other embodiments relating to methods for treating a spinal deformity.

[0029] The invention provides an FGFR3 signaling inhibitor, an NPR-B agonist and / or an NPR-C agonist for use in the treatment of a spinal deformity, such as a deformity Petition 870250079895, dated 05 / 09 / 2025, page 20 / 354 11 / 309 thoracolumbar deformity in a human individual, such as an individual with achondroplasia. See List of Items B for examples of the use of an FGFR3 signaling inhibitor, an NPR-B agonist, and / or an NPR-C agonist for use in the treatment of a spinal deformity, and List of Items A for therapeutic methods in which an FGFR3 signaling inhibitor, an NPR-B agonist, and / or an NPR-C agonist may be used.

[0030] The invention provides an FGFR3 signaling inhibitor, an NPR-B agonist and / or an NPR-C agonist for use in the treatment of thoracolumbar kyphosis in a human subject, such as a human subject with achondroplasia.

[0031] The invention provides an NPR-B agonist and / or an agonist NPR-C for use in the treatment of a spinal deformity, such as a thoracolumbar deformity in a human individual, such as a human individual who has achondroplasia.

[0032] The invention provides an NPR-B agonist and / or an agonist NPR-C for use in the treatment of thoracolumbar kyphosis in a human subject, such as a human subject with achondroplasia.

[0033] The invention provides C-type natriuretic peptide (CNP), such as Navepegritide or Vosoritide, for use in the treatment of a spinal deformity, such as a thoracolumbar deformity in a human individual, such as a human individual who has achondroplasia.

[0034] The invention provides C-type natriuretic peptide (CNP), such as Navepegritide or Vosoritide, for use in the treatment of thoracolumbar kyphosis in a human subject, such as a human subject with achondroplasia.

[0035] The invention provides C-type natriuretic peptide (CNP), such as Navepegritide or Vosoritide, for use in the treatment of achondroplasia, wherein the use results in the treatment of thoracolumbar kyphosis in Petition 870250079895, dated 05 / 09 / 2025, page 21 / 354 12 / 309 an individual with achondroplasia.

[0036] The invention provides a method for treating a spinal deformity in an individual in need of such treatment, wherein said method comprises the step of administering a therapeutically effective amount of an NPR-B agonist and / or an NPR-C agonist to said individual and thereby treating the individual.

[0037] The invention provides a method for treating kyphosis, such as thoracic kyphosis or thoracolumbar kyphosis, in an individual in need of said treatment, wherein said method comprises the step of administering a therapeutically effective amount of an FGFR3 signaling inhibitor, an NPR-B agonist and / or an NPR-C agonist to said individual and thus treating the individual.

[0038] In some modalities, the spinal deformity is non-fixed thoracolumbar kyphosis.

[0039] The method for treating a spinal deformity may optionally comprise a measurement or diagnostic step of the spinal deformity before and optionally during and / or after said treatment. The measurement and / or diagnosis may be performed during routine patient monitoring and at regular intervals, routinely, over a treatment period of at least about 6 months or at least about 1 year, and may be performed, for example, every 3 months, or approximately every 6 months, or approximately every 9 months, or approximately annually, during said treatment or treatment period. In some embodiments, the medical uses of the invention are directed to patients who have undergone one or more of the measurement steps mentioned herein.

[0040] In some modalities, spinal deformity Petition 870250079895, dated 05 / 09 / 2025, page 22 / 354 13 / 309 bral is or includes a vertebral morphology deformity, such as gibbus deformity, where treatment results in an improvement in vertebral morphology, for example, a reduction in the apical wedge, for example, of the L1 and / or L2 vertebrae.

[0041] In some modalities, the measurement(s) of spinal deformity is / are or includes vertebral morphometry, such as point morphometry of one or more vertebrae, such as a thoracic and / or lumbar vertebra.

[0042] In some modalities, the measurements comprise vertebral morphometry of the L1 and / or L2 vertebrae, optionally using radiographs of the L1 and / or L2 vertebrae, wherein the aforementioned treatment optionally results in a decrease in the PH / MW ratio of the L1 and / or L2 vertebrae.

[0043] In some modalities, the measurement(s) of spinal deformity is / are or includes the measurement of the spinal curvature angle, such as the Cobb angle measurement, such as the Cobb angle of scoliosis, the Cobb angle of kyphosis, the Cobb angle of thoracolumbar kyphosis, or the lumbar Cobb angle.

[0044] In some modalities, the measurement(s) of spinal deformity is / are or includes the measurement of thoracolumbar kyphosis (TLK), such as the Cobb angle of thoracolumbar kyphosis, optionally measured between vertebrae T10 - L2 or T11 - L2 or T12 - L2.

[0045] In some modalities, a Cobb angle of thoracolumbar kyphosis greater than about 20°, or greater than about 25°, or greater than about 30° is indicative of an individual in need of treatment for thoracolumbar kyphosis (TLK).

[0046] In some modalities, treatment results in a reduction or normalization of the Cobb angle of thoracolumbar kyphosis, such as a reduction or normalization of at least 3°, as by Petition 870250079895, dated 05 / 09 / 2025, p. 23 / 354 14 / 309 minus approximately 3° over a treatment period of at least 6 months or at least 12 months. In some modalities, treatment results in a reduction or normalization of the Cobb angle of thoracolumbar kyphosis, such as a reduction or normalization of at least 4°, or at least approximately 4° over a treatment period of at least 6 months or at least 12 months. In some modalities, treatment results in a reduction or normalization of the Cobb angle of thoracolumbar kyphosis, such as a reduction or normalization of the Cobb angle of thoracolumbar kyphosis of at least 5°, or at least approximately 5° over a treatment period of at least approximately 6 months, or at least approximately 12 months.

[0047] In some modalities, the measurement(s) or monitoring is / are or includes a measurement of a spinal deformity, taken from a spinal radiograph, such as a lateral radiograph taken of the individual.

[0048] In some modalities, the aforementioned measurement(s) or monitoring is / are or includes radiography of the spine taken of the individual standing, sitting or lying on their back, or an image or radiograph taken of the individual standing, sitting or lying on their back.

[0049] In some modalities, where before and / or during the treatment period, the individual is a child (a pediatric individual), such as a child aged 0 to 18 years, such as a child aged 0 to 14 years, such as a child under 12 years of age, such as under 10 years of age or under 8 years of age or under 6 years of age, such as a child under 5 years of age.

[0050] In some modalities, before and during treatment or the treatment period, the individual has an open bone epiphysis. Petition 870250079895, dated 05 / 09 / 2025, p. 24 / 354 15 / 309

[0051] In some modalities, before and / or during the treatment period, the individual has a closed bone epiphysis.

[0052] In some categories, the individual must be at least 18 years old, as well as at least 25 years old, and at least 30 years old.

[0053] In some embodiments, the treatment method according to the present invention is performed or initiated in an infant or child aged 0 to 2 years, such as 0 to 12 months, 0 to 3 months, or 0 to 6 months who has been diagnosed with achondroplasia.

[0054] In some modalities, the individual has been diagnosed with achondroplasia. In some modalities, the individual has been diagnosed with a spinal deformity, such as thoracolumbar kyphosis and / or apical vertebral translation or wedging (also called apical wedging) (see, for example, Margalitet et al., J Pediatr Orthop. 2018 Nov / Dec;38(10):491-497, which is incorporated here by reference). In some modalities, the individual has been diagnosed with a developmental delay, such as motor developmental delay. In some modalities, a motor developmental delay may be identified or diagnosed by the inability to sit or walk independently, for example, at 14 or 30 months of age, respectively. In some modalities, the individual presents with a cranial or skull deformity, such as hydrocephalus, presence of ventriculoperitoneal shunt, and foramen magnum decompression.

[0055] In some modalities, the aforementioned treatment is a prophylactic treatment. Prophylactic treatment can be used to prevent the development of a spinal deformity.

[0056] In some modalities, the treatment is corrective, for example, it reduces the severity of the spinal deformity or prevents it. Petition 870250079895, dated 05 / 09 / 2025, page 25 / 354 16 / 309 reduces the progression of spinal deformity.

[0057] It is understood that, when treatment is carried out in an individual with achondroplasia, initiating treatment during infancy or early childhood may be preferable to provide more effective corrective or preventive / prophylactic treatment.

[0058] Once the spinal deformity becomes fixed, such as when the bony epiphyses are closed, for example, in an adult individual, therapeutic benefit can be provided, for example, due to improved muscle function and posture.

[0059] In some embodiments, the therapeutic method or use of the invention further comprises the use of a spinal support or spinal brace, such as a thoracolumbosacral orthosis (TLSO), before, during or after said treatment / treatment period.

[0060] In some embodiments, the therapeutic method of the invention further comprises surgical correction or intervention of the spinal deformity, such as thoracolumbar surgery or spinal fusion surgery, before, during or after said treatment / treatment period.

[0061] In some embodiments, the medical uses of the invention are directed to patients receiving one or more of the treatments mentioned above (including, optionally, spinal support or surgical intervention).

[0062] The invention provides a method for improving muscle function in an individual suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of an FGFR3 signaling inhibitor to said individual.

[0063] The invention provides a method for improving muscle function in an individual suffering from a disease or condition in which muscle function is impaired, the method comprising Petition 870250079895, dated 05 / 09 / 2025, page 26 / 354 17 / 309 administer a therapeutically effective amount of an NPR-B agonist to the individual in question.

[0064] The invention provides a method for improving muscle function in an individual suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of an NPR-C agonist to said individual.

[0065] The invention provides a method for improving muscle function in an individual suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of an FGFR3 signaling inhibitor, an NPR-B agonist or an NPR-C agonist to said individual.

[0066] The invention provides a method for improving muscle function in an individual suffering from a disease or condition in which muscle function is impaired, comprising the method administering a therapeutically effective amount of a C-type natriuretic peptide (CNP) to said individual. In certain embodiments, the NPR-B or CNP agonist is vosoritide (SEQ ID NO: 30).

[0067] The invention provides a method for improving muscle function in an individual suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of a C-type natriuretic peptide (CNP) to said individual, wherein the CNP is administered as a CNP conjugate and / or as a CNP prodrug; or a pharmaceutically acceptable salt thereof.

[0068] The invention provides a method for improving muscle function in an individual suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of a peptide Petition 870250079895, dated 05 / 09 / 2025, page 27 / 354 18 / 309 C-type natriuretic amide (CNP) to said individual, wherein CNP is administered as a CNP conjugate and / or as a CNP prodrug; or a pharmaceutically acceptable salt thereof; said method comprises administering successive doses of a therapeutically effective amount of the CNP conjugate and / or CNP prodrug to the individual, wherein the prolonged exposure of free CNP in the patient's blood plasma between successive doses of the therapeutically effective amount of the CNP conjugate and / or CNP prodrug is at least about 1 pmol / L. In certain embodiments, successive doses are administered, for example, daily, weekly, biweekly or monthly. In certain embodiments, the time interval between successive doses is at least about 24 hours, as well as at least about one week.In certain embodiments, the CNP conjugate or CNP prodrug is a compound of formula (IIf'), formula (IIf), compound (1) or a pharmaceutically acceptable salt thereof.

[0069] The invention provides a method for improving muscle function in an individual suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of a C-type natriuretic peptide (CNP) to said individual, wherein the CNP is administered as a CNP conjugate and / or as a CNP prodrug; or a pharmaceutically acceptable salt thereof, wherein the CNP conjugate or CNP prodrug is a compound of formula (IIf'), formula (IIf), compound (1) or a pharmaceutically acceptable salt thereof.

[0070] In certain modalities, the individual is a human being. In certain modalities, the individual is a human being under 18 years of age. In certain modalities, the individual is a human being at least 18 years of age. In certain modalities, the individual is a human being. Petition 870250079895, dated 05 / 09 / 2025, p. 28 / 354 19 / 309 duo has a closed bony epiphysis.

[0071] The invention provides a method for improving muscle function in an individual suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of a C-type natriuretic peptide (CNP) to said individual, wherein said method comprises an infusion, such as an intravenous or subcutaneous infusion, of CNP to the individual, wherein said infusion results in prolonged exposure to CNP (free CNP) in the patient's blood plasma for a period of at least about 1 hour at at least 1 pmol / L. In certain embodiments, prolonged exposure to CNP (free CNP) in the patient's blood plasma for a period of at least about 2 hours, such as at least about 4 hours, such as at least about 6 hours.

[0072] The invention provides a method for improving muscle function in an individual suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of an FGFR3 signaling inhibitor to said individual, wherein the FGFR3 signaling inhibitor (an FGFR3 antagonist) is an FGFR3 tyrosine kinase inhibitor, such as an FGFR3 tyrosine kinase inhibitor selected from the group consisting of infigratinib, pemigatinib, futibatinib, erdafitinib and TYRA-300.

[0073] The invention provides a method (as a therapeutic method) for improving muscle function in an individual.

[0074] The invention provides a method (as a therapeutic method) for improving skeletal muscle function in an individual.

[0075] The invention provides a method (as a therapeutic method) for improving muscle strength and / or improving muscle endurance in an individual (e.g., skeletal muscle strength). Petition 870250079895, dated 05 / 09 / 2025, page 29 / 354 20 / 309 and / or skeletal muscle endurance).

[0076] The invention provides a method (as a therapeutic method) for improving muscle tone in an individual (e.g., skeletal muscle tone).

[0077] In each case, the method comprises administering an effective amount of an FGFR3 signaling inhibitor or an effective amount of an NPR-C agonist or an effective amount of an NPR-B agonist to the individual in question. In certain embodiments, the method comprises administering an effective amount of an NPR-B / NPR-C agonist (e.g., a CNP).

[0078] The individual may suffer from a disease or disorder that causes impairment of muscle function (e.g., strength, endurance, and / or muscle tone). The disease or disorder may cause impairment of skeletal muscle function.

[0079] Optionally, FGFR3 signaling inhibitors or NPR-B agonists or NPR-C agonists, or CNP, as a CNP conjugate or CNP prodrug or pharmaceutically acceptable salt thereof, may be used in combination with a growth hormone, such as human growth hormone.

[0080] The invention provides an inhibitor of FGFR3 signaling or NPR-B agonists or an NPR-C agonist for use in a method of improving muscle function in an individual, optionally when the individual suffers from a disease or disorder that causes impairment in muscle function.

[0081] The invention provides an inhibitor of FGFR3 signaling or NPR-B agonists or an NPR-C agonist for use in a method of improving skeletal muscle function in an individual, optionally where the individual suffers from a disease or disorder that causes impairment in skeletal muscle function.

[0082] In certain modalities, the individual has a congenital disease. Petition 870250079895, dated 05 / 09 / 2025, page 30 / 354 21 / 309 droplasica, such as a disease selected from the group consisting of achondroplasia, hypochondroplasia, and thanatophoric dysplasia. The individual is preferably a human being. The individual may be under 18 years of age or at least 18 years of age. The individual may have closed bone epiphysis.

[0083] In certain modalities, the FGFR3 signaling inhibitor is an FGFR3 antagonist or an NPR-B agonist.

[0084] In certain embodiments, NPR-C agonists may be used in the methods or uses of the invention.

[0085] FGFR3 antagonists may include a fibroblast growth factor receptor (FGFR) 3 tyrosine kinase inhibitor, an anti-FGFR3 antibody, an anti-FGFR3 antisense oligonucleotide, or an anti-FGFR3 siRNA. A suitable NPR-B agonist is a C-type natriuretic peptide, or its conjugate or prodrug. A suitable NPR-C agonist is a C-type natriuretic peptide, or its conjugate or prodrug.

[0086] Examples of FGFR3 antagonists include fibroblast growth factor receptor (FGFR) 3 tyrosine kinase inhibitors, such as infigratinib, pemigatinib, futibatinib, erdafitinib, or TYRA-300. Document WO2022147246A1 describes such FGFR3 antagonists, which is incorporated herein by reference in its entirety.

[0087] The invention provides a method for improving muscle function (e.g., skeletal muscle function) in an individual suffering from a disease or condition in which muscle function (e.g., skeletal muscle function) is impaired, said method comprising administering a therapeutically effective amount of a CNP.

[0088] The invention provides a method for improving muscle function (e.g., skeletal muscle function) in an individual. Petition 870250079895, dated 05 / 09 / 2025, page 31 / 354 22 / 309 duo suffering from a disease or condition in which muscle function (e.g., skeletal muscle function) is impaired, the said method comprising the administration of a therapeutically effective amount of vosoritide.

[0089] In certain forms, the CNP comprises or consists of SEQ ID NO: 24. In certain embodiments, CNP comprises or consists of a peptide selected from the group consisting of SEQ ID NO: 30, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105 and SEQ ID NO: 90. In some embodiments, CNP is a CNP conjugate or a pharmaceutically acceptable salt thereof, comprising a CNP selected from the group consisting of SEQ ID NO: 30, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105 and SEQ ID NO:90.

[0090] Improvement in muscle function may include, for example, a) increased muscle strength (e.g., skeletal muscle), b) increased muscle tone (e.g., skeletal muscle), c) increased muscle endurance (e.g., skeletal muscle), d) increased muscle mass (e.g., skeletal muscle), e) decreased muscle fatigue (e.g., skeletal muscle), f) increased cardiovascular endurance, g) increased cardiovascular fitness, h) decreased exercise intolerance, i) increased exercise capacity, j) decreased exercise-induced fatigue, or k) increased hypertension.

[0091] Administration of the effective amount of FGFR3 signaling inhibitor, or the effective amount of NPR-B agonist, or the effective amount of NPR-C agonist may result in increased muscle mass (e.g., skeletal muscle) and / or skeletal muscle / fat ratio in the individual. Petition 870250079895, dated 05 / 09 / 2025, page 32 / 354 23 / 309

[0092] Administration of the effective amount of FGFR3 signaling inhibitor, or the effective amount of NPR-B agonist, or the effective amount of NPR-C agonist may result in increased treatment or prevention of musculoskeletal pain in the individual, improved posture or reduction of abnormal spinal curvature, improvement of kyphosis, such as thoracolumbar kyphosis (TLK), lordosis, such as lumbar lordosis, spinal stenosis or scoliosis, improvement of sleep apnea, obstructive sleep apnea, otitis media, or reduction of obesity. These improvements may arise as a result of improvements in muscle function (e.g., skeletal muscle function). Thus, the treatment, prevention, or improvement of any of the above-mentioned conditions is preferably achieved through improved muscle function (e.g., skeletal muscle function).

[0093] In certain embodiments, CNP is administered as a prodrug. In certain embodiments, the CNP prodrug provides prolonged exposure to the active CNP peptide after administration to the individual.

[0094] The prodrug is optionally a compound of formula (IIf ') or formula (IIf) or compound (1), or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, where the individual is an adult human being (i.e., at least 18 years of age), the individual may have been treated with an FGFR3 signaling inhibitor, or an NPR-B agonist (e.g., CNP) or an NPR-C agonist before the age of 18. The invention, therefore, provides a therapeutic treatment that is initiated before the age of 18 and continued until after the age of 18.

[0096] Administration of an FGFR3 signaling inhibitor, or NPR-B agonist, or NPR-C agonist may lead to one or more increases in muscle function, selected from the group consisting Petition 870250079895, dated 05 / 09 / 2025, page 33 / 354 24 / 309 in: a) increased skeletal muscle strength, b) increased skeletal muscle tone, c) increased skeletal muscle endurance, d) increased skeletal muscle mass, e) decreased skeletal muscle fatigue, f) increased cardiovascular endurance, g) increased cardiovascular fitness, h) decreased exercise intolerance, i) increased exercise capacity, j) decreased exercise-induced fatigue, and k) decreased hypotonia.

[0097] As such, the method may alternatively be described as a method of increasing skeletal muscle strength in an individual (optionally where the individual suffers from a disease or condition in which muscle and skeletal function is impaired), the method comprising administering an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said individual.

[0098] The method may also be described as a method for increasing skeletal muscle tone in an individual (optionally where the individual suffers from a disease or condition in which muscle function, for example, skeletal muscle, is impaired), the method comprising administering an effective amount of an FGFR3 signaling inhibitor or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said individual.

[0099] The method can also be described as a method for increasing skeletal muscle endurance in an individual (opci Petition 870250079895, dated 05 / 09 / 2025, page 34 / 354 25 / 309 generally in which the individual suffers from a disease or condition in which muscle function, for example, of skeletal muscle, is impaired), the method comprising administering an effective amount of an FGFR3 signaling inhibitor or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said individual.

[00100] The method may also be described as a method for increasing skeletal muscle mass in an individual (optionally where the individual suffers from a disease or condition in which muscle function, for example, skeletal muscle function, is impaired), the method comprising administering an effective amount of an FGFR3 signaling inhibitor or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said individual.

[00101] The method may also be described as a method for reducing skeletal muscle fatigue in an individual (optionally where the individual suffers from a disease or condition in which muscle function, for example, skeletal muscle, is impaired), the method comprising administering an effective amount of an FGFR3 signaling inhibitor or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said individual.

[00102] The method may also be described as a method for increasing cardiovascular endurance in an individual (optionally where the individual suffers from a disease or condition in which muscle and skeletal function is impaired), the method comprising administering an effective amount of an FGFR3 signaling inhibitor or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said individual.

[00103] The method can also be described as a method for Petition 870250079895, dated 05 / 09 / 2025, page 35 / 354 26 / 309 to increase cardiovascular fitness in an individual (optionally where the individual suffers from a disease or condition in which muscle and skeletal function is impaired), the method comprising administering an effective amount of an FGFR3 signaling inhibitor or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said individual.

[00104] The method may also be described as a method for reducing exercise intolerance in an individual (optionally where the individual suffers from a disease or condition in which muscle function, for example, skeletal muscle function, is impaired), the method comprising administering an effective amount of an FGFR3 signaling inhibitor or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said individual.

[00105] The method may also be described as a method for increasing exercise capacity in an individual (optionally where the individual suffers from a disease or condition in which muscle function, for example, skeletal muscle function, is impaired), the method comprising administering an effective amount of an FGFR3 signaling inhibitor or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said individual.

[00106] The method may also be described as a method for reducing exercise-induced fatigue in an individual (optionally where the individual suffers from a disease or condition in which muscle function, for example, skeletal muscle function, is impaired), the method comprising administering an effective amount of an FGFR3 signaling inhibitor or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said individual. Petition 870250079895, dated 05 / 09 / 2025, page 36 / 354 27 / 309

[00107] The method may also be described as a method of reducing hypotonia in an individual (optionally where the individual suffers from a disease or condition in which muscle function, for example, skeletal muscle function, is impaired), the method comprising administering an effective amount of an FGFR3 signaling inhibitor or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said individual.

[00108] Administration of an FGFR3 signaling inhibitor or an effective amount of an NPR-B agonist or an NPR-C agonist may result in an increase in the individual's skeletal muscle / fat ratio and the method may alternatively be framed as a method of increasing the skeletal muscle / fat ratio in an individual (optionally where the individual suffers from a disease or condition in which muscle function, for example, skeletal muscle, is impaired), the method comprising administering an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said individual.

[00109] Administration of an FGFR3 signaling inhibitor or an effective amount of an NPR-B agonist or an NPR-C agonist may result in a decrease in hypotonia in the individual and therefore the method may be framed as a method for decreasing hypotonia in an individual (optionally when the individual suffers from a disease or condition in which muscle function, for example, skeletal muscle function, is impaired), the method comprising administering an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist. Petition 870250079895, dated 05 / 09 / 2025, page 37 / 354 28 / 309 NPR-C applied to the individual in question. The method, therefore, can be described as a method for treating hypotonia in the individual.

[00110] The administration of an FGFR3 signaling inhibitor or an effective amount of an NPR-B agonist or an NPR-C agonist may result in a decrease in musculoskeletal pain in the individual and the method may therefore be framed as a method of treatment, prevention or reduction of decreasing musculoskeletal pain in an individual (optionally where the individual suffers from a disease or condition in which muscle function, for example, skeletal muscle function, is impaired), the method comprising administering an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said individual.

[00111] The method also gives rise to an improvement in posture, an improvement in an abnormal curvature of the spine and the method may therefore be framed as a method for improving posture or for treating an abnormal curvature of the spine in an individual (optionally where the individual is suffering from a disease or condition in which muscle function, for example, skeletal muscle, is impaired), the method comprising administering an effective amount of an FGFR3 signaling inhibitor or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said individual.The method may result in an improvement in kyphosis, such as thoracolumbar kyphosis (TLK), lordosis, such as lumbar lordosis, or scoliosis and, as such, may be defined as a method of treating one or more of these conditions in an individual (optionally where the individual suffers from a disease or condition in which muscle function, for example, skeletal muscle, is impaired), the method comprising administering a... Petition 870250079895, dated 05 / 09 / 2025, page 38 / 354 29 / 309 effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to the individual in question.

[00112] The method may result in an improvement in sleep apnea, snoring, obstructive sleep apnea, and otitis media and, as such, may be defined as a method for treating one or more of these conditions in an individual (optionally, when the individual suffers from a disease or condition in which muscle function, for example, skeletal muscle function, is impaired). The method comprises administering an effective amount of an FGFR3 signaling inhibitor or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to the individual in question. A reduction in the frequency of occurrence, incidence, and / or severity of sleep apnea, snoring, obstructive sleep apnea, and otitis media may occur.

[00113] The method may give rise to a reduction in obesity and, as such, may be defined as a method of reducing obesity in an individual (optionally where the individual suffers from a disease or condition in which muscle and skeletal function is impaired), the method comprising administering an effective amount of an FGFR3 signaling inhibitor or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said individual.

[00114] The present invention provides a method for treating kyphosis in a patient in need of such treatment, comprising administering an effective amount of CNP, CNP conjugate or pharmaceutically acceptable salt thereof, or unit dosage form, to the patient, thereby treating the kyphosis. Kyphosis is an abnormal outward curvature of the upper spine, which produces a rounding of the upper back, Petition 870250079895, dated 05 / 09 / 2025, p. 39 / 354 30 / 309, sometimes called "hunchback." It can occur in isolation or be present with scoliosis. In some forms, kyphosis is postural kyphosis. In some forms, kyphosis is thoracic kyphosis or thoracolumbar kyphosis.

[00115] The invention provides a method for treating thoracolumbar kyphosis in an individual in need of such treatment, wherein said method comprises administering an effective amount of an NPR-B agonist, a CNP, a CNP conjugate or a pharmaceutically acceptable salt thereof or unit dosage form to the individual, thereby treating the thoracolumbar kyphosis.

[00116] The invention provides a method for treating thoracolumbar kyphosis in an individual in need of such treatment, comprising administering an effective amount of an NPR-B agonist, a CNP, a CNP conjugate or a pharmaceutically acceptable salt thereof, or unit dosage form, to the individual, thereby treating thoracolumbar kyphosis, wherein the individual is under 18 years of age, such as under 14 years of age, such as under 12 years of age, such as under 10 years of age, such as under 8 years of age, such as up to six years of age or up to five years of age. In some embodiments, the individual is at least 5 years of age.

[00117] In certain modalities, the patient was diagnosed with bone dysplasia or bone disorder, as a selected disorder from the group consisting of achondroplasia, hypochondroplasia, short stature, Noonan syndrome, and SHOX deficiency.

[00118] The present invention also provides a method for treating foramen magnum stenosis in a patient in need of such treatment, comprising administering an effective amount of CNP, CNP conjugate or pharmaceutically acceptable salt thereof, or unit dosage form, to the patient, tra Petition 870250079895, dated 05 / 09 / 2025, page 40 / 354 31 / 309 thus causing stenosis of the foramen magnum. In some cases, the patient presents with achondroplasia.

[00119] The present invention also provides a method for treating otitis media or ear infection in a patient or for reducing the incidence of ear infection in a patient in need of such treatment, said method comprising administering a therapeutically effective amount of a CNP, CNP conjugate or pharmaceutically acceptable salt thereof, or unit dosage form, to the patient, thereby treating the otitis media or ear infection or reducing the incidence of ear infection. In some embodiments, the patient has achondroplasia.

[00120] The present invention also provides a method for treating sleep apnea syndrome in a patient in need of such treatment, comprising administering a therapeutically effective amount of a CNP, CNP conjugate or pharmaceutically acceptable salt thereof, or unit dosage form, to the patient. By way of example, the treatment may reduce the incidence or severity of sleep apnea. In some embodiments, the patient has achondroplasia.

[00121] The present invention also provides a method for reducing the frequency of adverse events related to achondroplasia in a patient diagnosed with achondroplasia, said method comprising administering a therapeutically effective amount of a CNP, CNP conjugate or pharmaceutically acceptable salt thereof or unit dosage form, wherein optionally the patient may be a pediatric patient and / or a patient with open bone epiphysis.

[00122] The invention provides a method for improving or increasing an individual's emotional well-being, said method comprising administering an effective amount of an NPR-B agonist to Petition 870250079895, dated 05 / 09 / 2025, page 41 / 354 32 / 309 individual, and may optionally include the step of monitoring the individual's emotional well-being, for example, before, during and / or after a treatment period, such as using the ACEM Emotional Well-being Index.

[00123] The invention provides a method for improving or enhancing an individual's daily living function, said method comprising administering an effective amount of an NPR-B agonist to the individual, and optionally may include the step of monitoring the individual's daily living function, for example, before, during and / or after a treatment period, such as using ACEM, the daily living function index.

[00124] In any of the methods described above, the individual may have a chondrodysplasia disease, such as a disease selected from the group consisting of achondroplasia, hypochondroplasia, and thanatophoric dysplasia.

[00125] In the methods described above, the individual may present with achondroplasia. In some modalities, the individual does not present with achondroplasia.

[00126] In any of the methods described above, the individual may have achondroplasia, the individual being a human being at least 18 years of age, or a human being whose bone epiphysis is closed.

[00127] To the extent that a method is mentioned herein, the invention also provides an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist for use in that method and use of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist in the manufacture of a drug for use in that method.

[00128] In certain modalities, the CNP is in the form of one of Petition 870250079895, dated 05 / 09 / 2025, page 42 / 354 33 / 309 unitary sample comprising a CNP conjugate or a pharmaceutically acceptable salt thereof.

[00129] In certain embodiments, the unit dosage form of CNP comprises a therapeutically effective amount of a CNP conjugate or pharmaceutically acceptable salt thereof, in which a CNP moiety is reversibly conjugated to a polymeric moiety. BRIEF DESCRIPTION OF THE FIGURES

[00130] Figure 1: Percentage of survival (percentage of survival observed) of Fgfr3Y367C / + pups during the study period (16 days), comparing groups treated with compound (1) at 5.6 mg / kg / day (solid line), compound (1) at 1.2 mg / kg every three days (dashed line) or vehicle only (dotted line).

[00131] Figure 2: Change in pedicle width (calibrated) after 52 weeks of treatment (cohorts 3 and 4), compared to placebo, as detailed in Example 14. The data illustrate a trend toward increased pedicle width in the treatment compared to placebo (PLA).

[00132] Figure 3: The change in mean hand length after 52 weeks of treatment (Cohorts 3 and 4) compared to placebo (PLA), as detailed in Example 15. The results indicate a clear dose-dependent increasing trend in hand length during treatment.

[00133] Figure 4: Measurement of thoracolumbar kyphosis from lateral panels AC shows the median value ± 5-95 percentiles in box plots. Panel A shows a statistically significant decrease in the degree of thoracolumbar kyphosis after 52 weeks of treatment with compound 1, which is further illustrated by a corresponding statistically significant decrease in the achondroplasia-related Z-score (ACH) (Panel B) and a statistically significant decrease Petition 870250079895, dated 05 / 09 / 2025, page 43 / 354 34 / 309 significant in the healthy Z-score (Panel C). Panel D illustrates how the change in degree was measured from lateral radiographs of individuals with lumbar lordosis and thoracic kyphosis (TLK).

[00134] Figure 5: 10-point morphometry diagram taken from a cross-section of a vertebral column (L1, radiograph). PH = Posterior height, MH = Mean height (MH is measured at 50% of the inferior width), AH = Anterior height, MW = Mean width. LW = Inferior width. In the case of wedge-shaped vertebral deformity (typically L1 or L2), commonly observed in achondroplasia, a decrease in the PH / MW ratio is indicative of a normalization of vertebral morphology (e.g., reduction of the apical wedge).

[00135] Figure 6 A and B: An illustration of the reduction in spinal deformity in an individual from cohort 4 at baseline (6A, individual aged 5.3 years) and after 52 weeks (6B, aged 6.3 years) of treatment with compound (1) 100 pg / kg / week.

[00136] Figure 7 A and B: Close-up of lateral radiographs of the individual shown in Figures 6A and B, illustrating the normalization of the L1 vertebra after 52 weeks of treatment, which corresponds to the reduction of thoracolumbar kyphosis (TLK). Figure 7A is the initial radiograph, Figure 7B is the radiograph after 52 weeks of treatment. DEFINITIONS

[00137] As used herein, the term “about” in combination with a numerical value is used to indicate a range that varies from and includes the numerical value plus and minus not more than 10% of said numerical value, in certain embodiments not more than 8% of said numerical value, in certain embodiments not more than 5% of said numerical value, and in certain embodiments not more than 2% of said numerical value. For example, the phrase “about 200” is used to mean a range that varies from and includes 200 + / - 10%, that Petition 870250079895, dated 05 / 09 / 2025, p. 44 / 354 35 / 309 is, ranging from and including 180 to 220; in certain modalities, 200 + / - 8%, ranging from and including 184 to 216; in certain modalities, ranging from and including 200 + / - 5%, that is, ranging from and including 190 to 210; and in certain modalities 200 + / - 2%, that is, ranging from and including 196 to 204. It is understood that a percentage given as “about 20%” does not mean “20% + / - 10%”, that is, ranging from and including 10 to 30%, but “about 20%” means ranging from and including 18 to 22%, that is, plus and minus 10% of the numerical value which is 20.

[00138] As used herein, the term “antimicrobial” refers to a chemical substance, such as a chemical substance that kills or inhibits the growth of microorganisms, such as bacteria, fungi, yeasts, protozoa, molds, and / or destroys viruses.

[00139] As used herein, the term “buffer” or “buffering agent” refers to a chemical compound that maintains the pH within a desired range. Physiologically tolerated buffers include, for example, sodium phosphate, succinate, histidine, bicarbonate, citrate, acetate, sulfate, nitrate, chloride, and pyruvate. Antacids such as Mg(OH)2 or ZnCOa may also be used.

[00140] As used herein, the term “CNP” refers to all CNP polypeptides, in certain embodiments, of mammalian species, such as human and mammalian species, in particular human and murine species, as well as their variants, analogs, orthologs, homologs, derivatives and fragments thereof, which are characterized by regulating the growth, proliferation and differentiation of chondrocytes of the cartilaginous growth plate. Human pre-pro-CNP, comprising 126 amino acids, is subsequently cleaved to produce CNP-53 and CNP-22. The term “CNP” also includes all variants, analogs, orthologs, homologs, derivatives and fragments thereof of CNP. The variants, analogs, orthologs, homologs, derivatives and fragments thereof of CNP, as described in the docu Petition 870250079895, dated 05 / 09 / 2025, page 45 / 354 36 / 309 ments WO 2009 / 067639 A2 and WO 2010 / 135541 A2 are incorporated herein by reference. CNP peptides and pharmaceutical compositions comprising CNP peptides are described in WO2009 / 067639, WO2010 / 135541, WO2017 / 020034, WO2017 / 100400, WO2021055497, WO2021 / 030411, WO2023 / 283657 and WO2022 / 115563, all incorporated by reference. Exemplary CNP peptides are provided and include vosoritide. Regardless of the CNP portion length, the wild-type CNP annular portion sequence is FGLKLDRIGSMSGLG (SEQ ID NO: 96).

[00141] As used herein, the term “C1-4 alkyl” alone or in combination means a straight or branched chain alkyl moiety having from 1 to 4 carbon atoms. If present at the end of a molecule, examples of straight or branched chain 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 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 atom of a C1-4 alkyl carbon can optionally be substituted as defined above. Optionally, a C1-4 alkyl group can be interrupted by one or more moieties as defined below.

[00142] As used herein, the term “C1-6 alkyl” alone or in combination means a linear or branched chain alkyl moiety having from 1 to 6 carbon atoms. If present at the end of a molecule, examples of linear or branched chain C1-6 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl. When two portions of a molecule are linked by the C1-6 alkyl group, then examples of such C1-6 alkyl groups are CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)- and -C(CH3)2-. Petition 870250079895, dated 05 / 09 / 2025, p. 46 / 354 37 / 309 Each hydrogen atom of a C1-6 carbon may optionally be replaced by a substituent as defined above. Optionally, a C1-6 alkyl group may be interrupted by one or more moieties as defined below.

[00143] Consequently, “C1-10 alkyl”, “C1-20 alkyl” or “C1-50 alkyl” means an alkyl chain having from 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, C1-20 alkyl or C1-50 alkyl may be interrupted by one or more moieties as defined below.

[00144] As used herein, the term “C2-6 alkenyl” alone or in combination means a linear or branched chain hydrocarbon moiety comprising at least one carbon-carbon double bond having from 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-CH3 and -CH=CH-CH=CH2. When two moieties of a molecule are linked by the C2-6 alkenyl group, then an example of such a 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 below.

[00145] Consequently, the term “C2-10 alkenyl”, “C2-20 alkenyl” or “C2-50 alkenyl” alone or in combination means a linear or branched chain hydrocarbon moiety comprising at least one carbon-carbon double bond having from 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 Petition 870250079895, dated 05 / 09 / 2025, p. 47 / 354 38 / 309 te, an alkenyl C2-10, alkenyl C2-20 or alkenyl C2-50 may be interrupted by one or more moieties as defined below.

[00146] As used herein, the term “C2-6 alkynyl” alone or in combination means a linear or branched chain hydrocarbon moiety comprising at least one carbon-carbon triple bond having from 2 to 6 carbon atoms. If present at the end of a molecule, examples are -C^CH, -CH2-C^CH, -CH2-CH2-C^CH 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 bonds may occur. Optionally, a C2-6 alkynyl may be interrupted by one or more moieties as defined below.

[00147] Consequently, as used herein, the term “C2-10 alkynyl”, “C2-20 alkynyl” and “C2-50 alkynyl” alone or in combination means a linear or branched chain hydrocarbon moiety comprising at least one carbon-carbon triple bond having from 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 bonds may occur. Optionally, a C2-10 alkynyl, C2-20 alkynyl or C2-50 alkynyl group may be interrupted by one or more moieties as defined below.

[00148] As mentioned above, a C1-4 alkyl, C1-6 alkyl, C110 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 that are, in certain embodiments, selected from the group Petition 870250079895, dated 05 / 09 / 2025, p. 48 / 354 39 / 309 which consists of , . . 4n^, , , R s . II , , —NCN^, e RR where the dashed lines indicate connection to the rest of the portion or reagent; and -R and -Ra are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, penyl and hexyl.

[00149] As used herein, the term “C3-10 cycloalkyl” means a cyclic alkyl chain having from 3 to 10 carbon atoms, which may be saturated or unsaturated, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl. Each hydrogen atom of a C3-10 cycloalkyl carbon may be replaced by a substituent as defined above. The term “C3-10 cycloalkyl” also includes bridging bicycles such as norbornane or norbornene.

[00150] As used herein, the term “8- to 30-membered carbopolycyclyl” or “8- to 30-membered carbopolycycle” means a cyclic portion of two or more rings with 8 to 30 ring atoms, wherein two adjacent rings share at least one ring atom and which may contain up to the maximum number of double bonds (aromatic or non-aromatic ring that is wholly, partially or unsaturated). In certain embodiments, an 8- to 30-membered carbopolycyclyl means a cyclic portion of two, three, four or five rings. Petition 870250079895, dated 05 / 09 / 2025, p. 49 / 354 40 / 309

[00151] As used herein, the term “3- to 10-membered heterocycline” 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 that is fully, partially or unsaturated) in which 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 in which the ring is linked to the rest of the molecule by means of a carbon or nitrogen atom.Examples of 3- to 10-membered heterocycles include, but are not limited to, aziridine, oxirane, thiirane, azirine, oxirene, thyyrene, azetidine, oxetane, thiethane, 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, diazepam, azepine, and homopiperazine. Each hydrogen atom of a 3- to 10-membered heterocyclic group or 3- to 10-membered heterocyclic group can be replaced by a substituent as defined below.

[00152] As used herein, the term “8- to 11-membered heterobicycle” or “8- to 11-membered heterobicycle” means a heterocyclic portion of two rings with 8 to 11 ring atoms, in which at least one ring atom is shared by both rings and which may contain up to the maximum number of double bonds (aromatic or non-aromatic ring that is wholly, partially or unsaturated) in which at least one ring atom up to 6 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur. Petition 870250079895, dated 05 / 09 / 2025, p. 50 / 354 41 / 309 (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-) and in which the ring is linked to the rest of the molecule by means of a carbon or nitrogen atom. Examples of 8- to 11-membered heterobicycles are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine and pteridine. The term 8- to 11-membered heterobicycle also includes two-ring spiro structures, such as 1,4-dioxa-8azaspiro[4.5]decane, or bridging heterocycles, such as 8-azabicyclo[3.2.1]octane. Each hydrogen atom of an 8- to 11-membered heterobicycle or of an 8- to 11-membered heterobicycle carbon can be replaced by a substituent as defined below.

[00153] Similarly, the term “8- to 30-membered heteropolycycle” or “8- to 30-membered heteropolycycle” means a heterocyclic portion of more than two rings with 8 to 30 ring atoms, in certain embodiments of three, four or five rings, in which two neighboring rings share at least one ring atom and which may contain up to the maximum number of double bonds (aromatic or non-aromatic ring that is totally, partially or unsaturated), in which at least one ring atom up to 10 ring atoms are replaced by a heteroatom selected from the sulfur group (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-) and in which the ring is linked to the rest of a molecule by means of a carbon or nitrogen atom.

[00154] The phrase “the Rx / Ry pair is linked together with the atom to which they are attached to form a C3-10 cycloalkyl or a 3- to 10-membered heterocycline” is understood to relate to a portion of the structure: Petition 870250079895, dated 05 / 09 / 2025, p. 51 / 354 42 / 309 RX / Ry means that Rx and Ry form the following structure: J where R is a 3- to 10-membered C3-10 cycloalkyl or heterocycline.

[00155] It is also understood that the sentence “the Rx / Ryé pair bonded together with the atoms to which they are bonded to form a ring A” relates to a portion of the structure: XV R Ry means that Rxe Ry form the following structure:

[00156] As used herein, the term “polypeptide variant of "CNP" refers to a polypeptide of the same species that differs from a reference CNP polypeptide. Generally, the differences are limited so that the amino acid sequence of the reference and variant are generally quite similar and, in many regions, identical. In certain embodiments, CNP polypeptide variants are at least 70%, 80%, 90%, or 95% identical to a reference CNP polypeptide. For a polypeptide to have an amino acid sequence that is at least, for example, 95% "identical" to a reference amino acid sequence, it is understood that the amino acid sequence of the polypeptide in question is identical to the reference sequence, except that the sequence of the polypeptide in question may include up to Petition 870250079895, dated 05 / 09 / 2025, p. 52 / 354 43 / 309 five amino acid changes for every 100 amino acids of the reference amino acid sequence. These changes from the reference sequence may occur at the amino (N-terminal) or carboxy-terminal (C-terminal) positions of the reference amino acid sequence or anywhere between these terminal positions, interspersed individually between residues in the reference sequence or in one or more contiguous groups within the reference sequence. The reference sequence may be a complete amino acid sequence of the reference sequence or any specified fragment as described. Such CNP polypeptide variants may be naturally occurring variants, such as naturally occurring allelic variants encoded by one of several alternative forms of a CNP occupying a given locus on a chromosome or organism, or isoforms encoded by naturally occurring splicing variants originating from a single primary transcript.Alternatively, a CNP polypeptide variant may be a variant that is not known to occur naturally and that can be produced by mutagens using techniques known in the art. It is known in the art that one or more amino acids can be deleted from the N-terminus or C-terminus of a bioactive peptide or protein without substantial loss of biological function. These N- and / or C-terminal deletions are also covered by the term CNP polypeptide variant.

[00157] As used herein, the term “dose” or “unit dose” refers to the predetermined amount of a drug, such as CNP, administered at one time to produce a given 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.

[00158] As used herein, the term “pharmaceutical form” refers to the physical form comprising the active pharmaceutical ingredient in Petition 870250079895, dated 05 / 09 / 2025, page 53 / 354 44 / 309 combination with selected additional ingredients or excipients intended to be administered to sites of action in the body via various drug administration routes. It also refers to the physical form in which a precise mixture of active pharmaceutical ingredients and excipients is presented to aid administration and delivery to sites of action, achieve a rapid onset of action, and improve bioavailability. As used herein, the term “unit pharmaceutical form” refers to a pharmaceutical form configured for a single administration to a patient. For example, a unit pharmaceutical form might be a single vial or container containing an amount of drug suitable for a single administration.

[00159] As used herein, the term “dosing regimen” refers to the combination of the dose and frequency with which a drug is administered. Dosing regimens may also include a route of administration (e.g., subcutaneous) and / or the duration of administration (e.g., until the patient reaches 18 years of age or until epiphyseal closure). Administration of a dosing regimen may maintain a steady-state serum CNP concentration, in which peaks, troughs, and area under the curve, over a defined range, remain within defined fluctuation margins and / or the ratio of peaks to troughs does not exceed a defined limit.

[00160] As used herein, the term “drug” refers to a substance used in the treatment, cure, prevention, or diagnosis of a disease or used to improve physical or mental well-being. If a drug, such as CNP, is conjugated to another moiety, the portion of the resulting product that originates from the drug is called the “drug moiety.”

[00161] As used herein, the term “excipient” refers to compounds administered together with the drug or medicinal conjugate. Petition 870250079895, dated 05 / 09 / 2025, p. 54 / 354 45 / 309 menthol, for example, buffering agents, isotonicity modifiers, preservatives, stabilizers, anti-adsorption agents, oxidation protection agents, or other auxiliary agents. However, in some cases, an excipient may have dual or triple functions. The term "excipient" may also refer to a diluent, adjuvant, or vehicle with which the drug or drug conjugate is administered. Such a pharmaceutical excipient may be a sterile liquid, such as water, and oils, including those of petroleum, animal, vegetable, or synthetic origin, including, but not limited to, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is a preferred excipient when the pharmaceutical formulation is administered orally. Saline and aqueous dextrose are preferred excipients when the pharmaceutical formulation is administered intravenously or subcutaneously.Saline solutions and aqueous solutions of dextrose and glycerol 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, skimmed milk powder, glycerol, propylene glycol, water, ethanol, and the like. The pharmaceutical formulation may also contain small amounts of humectants or emulsifiers, pH buffering agents such as acetate, succinate, Tris (tris(hydroxymethyl)aminomethane), carbonate, phosphate, HEPES (4-(2-hydroxyethyl)-1-piperazinoethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), or it may contain detergents such as Tween®, poloxamers, poloxamines, CHAPS, Igepal®, or amino acids such as glycine, lysine or histidine.These pharmaceutical formulations can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, and the like. The pharmaceutical formulation can... Petition 870250079895, dated 05 / 09 / 2025, page 55 / 354 46 / 309 can be formulated as a suppository, with traditional binders and excipients such as triglycerides. The oral formulation may include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc., of pharmaceutical grade. Such formulations will contain a therapeutically effective amount of the drug or portion of the drug, together with an adequate amount of excipient, so as to provide the form for administration appropriate to the patient. The formulation must be suitable for the route of administration.

[00162] As used herein, the term “formulation” or “pharmaceutical formulation” refers to a formulation containing one or more CNP conjugates and one or more excipients, as well as any product resulting, directly or indirectly, from the combination, complexation or aggregation of any two or more ingredients of the composition, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Consequently, the pharmaceutical formulations of the present invention encompass any formulation or composition made by mixing one or more CNP conjugates and a pharmaceutically acceptable excipient, such as a buffering agent and a bulking agent.

[00163] As used herein, the term “free form” of a drug refers to the drug in its unmodified, fully active pharmacological form, for example, after being released from the CNP conjugate or from a pharmaceutically acceptable salt thereof.

[00164] As used herein, the term “functional group” means a group of atoms that can react with other groups of atoms. Functional groups include, but are not limited to, the following groups: carboxylic acid (-(C=O)OH), primary or secondary amine (-NH2, —NH—), maleimide, thiol (-SH), sulfonic acid (-(O=S=O)OH), carbonate, carbamate (-O(C=O)N<), hydroxyl (-OH), aldehyde ( Petition 870250079895, dated 05 / 09 / 2025, page 56 / 354 47 / 309 (C=O)H), ketones (-(C=O)-), hydrazine (>NN<), isocyanate, isothiocyanate, phosphoric acid (-O(P=O)OHOH), phosphonic acid (-O(P=O)OHH), haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, disulfide, sulfonamides, sulfuric acid, vinyl sulfone, vinyl ketone, diazoalkanes, oxiranes and aziridines.

[00165] As used herein, the term “halogen” means fluorine, chlorine, bromine, or iodine. Generally, halogen is preferred to be fluorine or chlorine.

[00166] As used herein, the term “interrupted” means that a portion is inserted between two carbon atoms or – if the insertion is at one end of the portion – between a carbon or heteroatom and a hydrogen atom, in certain embodiments between a carbon and a hydrogen atom.

[00167] As used herein, the term “isotonicity agent” refers to a compound that minimizes pain, irritation, and tissue damage that may result from cellular damage due to osmotic pressure differences between the injected solution and the plasma.

[00168] As used herein, the term “portion” means a part of a molecule that lacks one or more atoms compared to the corresponding reagent. If, for example, a reagent of formula -“H”, a drug portion, such as a CNP portion, is released from a conjugate such as a drug, such as CNP.

[00169] It is understood that if the chemical sequence or structure of a group of atoms is given, indicating which group of atoms is attached to two moieties or interrupts a moiety, said chemical sequence or structure may be attached to the two moieties in any orientation, unless explicitly stated otherwise. For example, a moiety “-C(O)N(R1)-” may be attached to two moieties or interrupt a moiety as “-C(O)N(R1)-” or as “-N(R1)C(O)-”. Similarly, a moiety: Petition 870250079895, dated 05 / 09 / 2025, p. 57 / 354 48 / 309 It can be linked to two portions or it can interrupt a portion, such as: or how

[00170] If the CNP portion comprises one or more acidic or basic groups, the unit dosage form also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular pharmaceutically usable salts thereof. Thus, CNP portions comprising one or more acidic groups may be present and used, for example, as alkali metal salts, alkaline earth metal salts, or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as, for example, ethylamine, ethanolamine, triethanolamine, or amino acids, and other salts or amines known to those skilled in the art. CNP portions comprising one or more basic groups, i.e., groups that can be protonated, may be present and used in the form of their addition salts with inorganic or organic acids.Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, ptoluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, and others. Petition 870250079895, dated 05 / 09 / 2025, page 58 / 354 49 / 309 of 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 those skilled in the art. To those skilled in the art, other methods are known for converting the basic group into a cation, such as the alkylation of an amine group, resulting in a positively charged ammonium group and an appropriate counterion of the salt. If the CNP portions comprise both acidic and basic groups, the pharmaceutical formulations according to the present invention also include, in addition to the salt forms mentioned, internal salts or betaines (zwitterions).The respective salts can be obtained by usual methods known to those skilled in the art, such as, for example, by contacting these conjugates with an organic or inorganic acid or base in a solvent or dispersant, or by anionic or cationic exchange with other salts. The unit dosage form according to the present invention also includes all salts of the CNP conjugates which, due to low physiological compatibility, are not directly suitable for use in pharmaceutical products, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[00171] As used herein, the term “patient” refers to an individual eligible for treatment or prophylaxis in accordance with the invention, particularly a human individual.

[00172] As used herein, the term “pharmaceutically acceptable” means a substance that does not cause harm when administered to a patient and, preferably, means approved by a regulatory agency such as the EMA (Europe) and / or the FDA (USA) and / or any other national regulatory agency for use in animals, preferably for use in humans. Petition 870250079895, dated 05 / 09 / 2025, p. 59 / 354 50 / 309

[00173] As used herein, the term “physiological conditions” refers to an aqueous buffer at pH 7.4 and 37 °C.

[00174] The term “polypeptide,” as used herein, refers to a chain of at least 2 and up to 50 monomeric amino acids linked by peptide (amide) bonds. For drugs and CNP amino acids only, sequences with more than 50 amino acids will also be called “polypeptide” for simplification.

[00175] As used herein, the term “preservative” refers to a chemical substance that has antimicrobial effects and prevents chemical degradation.

[00176] As used herein, the term “protein” refers to a chain of more than 50 amino acid monomer moieties linked by peptide bonds, in which, preferably, no more than 12,000 amino acid monomer moieties are linked by peptide bonds, such as no more than 10,000 amino acid monomer moieties, no more than 8,000 amino acid monomer moieties, no more than 5,000 amino acid monomer moieties, or no more than 2,000 amino acid monomer moieties.

[00177] As used herein, the term “polymer” means a molecule comprising repeating structural units, i.e., monomers, connected by chemical bonds in a linear, circular, branched, cross-linked or dendrimeric fashion, 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, for example, a molecular weight of at least 1 kDa, a molecular weight of at least 2 kDa, a molecular weight of at least 3 kDa or a molecular weight of at least 5 kDa. If the polymer is soluble, in certain Petition 870250079895, dated 05 / 09 / 2025, page 60 / 354 51 / 309 modalities it will have a molecular weight of at most 1000 kDa, as at most 750 kDa, as at most 500 kDa, as at most 300 kDa, as at most 200 kDa, as at most 100 kDa.

[00178] It is also understood that a protein or polypeptide is a polymer in which amino acids are repeating structural units, although the side chains of each amino acid may be different.

[00179] As used herein, the term “polymeric” or “polymeric portion” means a reagent or portion comprising one or more polymers or polymeric portions. A reagent or polymeric portion may optionally also comprise one or more other portions, which are, in certain embodiments, selected from the group consisting of: • C1-50 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 • Selected linkages from the group comprising <>, s, \ · , ^N^, s > , \\· , where dashed lines indicate linkage to the remainder of the portion or reagent, and - R and Rasão selected independently of each other from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and he Petition 870250079895, dated 05 / 09 / 2025, p. 61 / 354 52 / 309 xila.

[00180] A 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 a molecular weight distribution. Consequently, the molecular weight ranges, molecular weights, ranges of number of monomers in a polymer and number of monomers in a polymer, as used herein, refer to the number-average molecular weight and the number-average number of monomers, that is, the arithmetic mean of the molecular weight of the polymer or polymer portion and the arithmetic mean of the number of monomers of the polymer or polymer portion.

[00181] Thus, in a polymeric portion comprising “x” monomeric units, any integer given for “x” therefore corresponds to the arithmetic mean of the numbers of monomers. Any interval of integers given for “x” provides the range of integers in which the arithmetic mean of the numbers of monomers lies. An integer for “x” given as “about x” means that the arithmetic mean of the numbers of monomers lies in a range of integers of x + / - 10%, in certain embodiments, in a range of integers of x + / - 8%, in certain embodiments, in a range of integers of x + / - 5%, and in certain embodiments, in a range of integers of x + / - 2%.

[00182] As used herein, the term “PEG-based” in relation to a moiety or reagent means that the moiety or reagent comprises PEG. In certain embodiments, a PEG-based moiety or reagent comprises at least 10% (w / w) PEG, such as at least 20% (w / w) PEG, such as at least 30% (w / w) PEG, such as at least 40% (w / w) PEG, such as at least 50% (w / w), such as at least 60% (w / w) PEG, such as at least 70% (w / w) PEG, such as at least 80% (w / w) PEG, such as by Petition 870250079895, dated 05 / 09 / 2025, p. 62 / 354 53 / 309 less than 90% (w / w) of PEG, such as at least 95% (w / w) of PEG. The remaining weight percentage of the PEG-based portion or reagent are other portions selected from the following portions and linkages: • C1-50 alkyl, C2-50 alkenyl, C2-50 alkynyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterocyclyl, phenyl, naphthyl, indenyl, indanyl and tetralinyl; and • selected connections from the group comprising IIIIII '1I1 1I o , 8 , \ . , \: , -88, \ \ · , R where dashed lines indicate connection to the rest of the portion or reagent, and - R and Rasão selected independently of each other from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[00183] As used herein, the term “PEG-based comprising at least % of X of PEG” in relation to a moiety or reagent means that said moiety or reagent comprises at least the remaining weight percent of the PEG-based moiety or reagent. Other moieties in certain embodiments are selected from the following moieties and linkages: • C1-50 alkyl, C2-50 alkenyl, C2-50 alkynyl, C3-10 cycloalkyl, 3 to 10 membered heterocyclyl, 8 to 11 membered heterobicyclyl, Petition 870250079895, dated 05 / 09 / 2025, p. 63 / 354 54 / 309 phenyl, naphthyl, indenyl, indanyl and tetralinyl; and • selected connections from the group comprising - , s > , \\· , and where dashed lines indicate connection to the rest of the portion or reagent, and - R and Rasão selected independently of each other from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[00184] As used herein, the term “based on hyaluronic acid comprising at least % of X hyaluronic acid” is used appropriately.

[00185] As used herein, the term “prodrug” refers to a drug moiety, such as a CNP moiety, reversibly and covalently conjugated to a polymeric moiety, such as -Z, via a reversible linker moiety. A prodrug releases the reversibly and covalently linked drug moiety in the corresponding drug form. In other words, a prodrug is a conjugate comprising a drug moiety, such as a CNP moiety, which is covalently and reversibly conjugated to a polymeric moiety via a reversible linker moiety, where the covalent and reversible conjugation of the polymeric moiety to the reversible linker moiety occurs directly or via a spacer. Such prodrugs Petition 870250079895, dated 05 / 09 / 2025, p. 64 / 354 55 / 309 drugs or conjugates release the previously conjugated drug portion in the form of a free drug.

[00186] As used herein, the term “random spiral” refers to a peptide or protein that adopts / possesses / forms, in certain embodiments, a conformation that substantially needs a defined secondary and tertiary structure, as determined by circular dichroism spectroscopy performed in aqueous buffer at room temperature and pH 7.4. In certain embodiments, the room temperature is about 20 °C, i.e., between 18 °C and 22 °C, while in certain embodiments the room temperature is 20 °C.

[00187] As used herein, the term “reversible bond” refers to a bond that is cleavable, in the absence of enzymes, under physiological conditions (aqueous buffer at pH 7.4, 37 °C), with a half-life ranging from one hour to six months, as from one hour to four months, as from one hour to three months, from one hour to two months, or from one hour to one month. Consequently, a stable bond is a bond with a half-life under physiological conditions (aqueous buffer at pH 7.4, 37 °C) greater than six months.

[00188] As used herein, the term “reagent” means a chemical compound comprising at least one functional group for reaction with the functional group of another chemical compound or drug. A drug comprising a functional group (such as a primary or secondary amine or a hydroxyl functional group) is also understood to be a reagent.

[00189] As used herein, the term “reversible linker fragment” refers to a covalent conjugate to a drug, such as a CNP group, via a reversible linkage, and also to a polymeric group, such as -Z, wherein the covalent conjugation with said polymeric group is direct or via a spacer group, such as L2. In certain embodiments, the linkage between -Z and Petition 870250079895, dated 05 / 09 / 2025, p. 65 / 354 56 / 309 - L2 is a stable bond. A conjugate comprising a reversible bonding group can be called a reversible conjugate.

[00190] As used herein, the term “spacer” or “spacer portion” refers to a portion suitable for connecting two portions. Suitable spacers may be selected from the group consisting of C1-50 alkyl, C2-50 alkenyl or C2-50 alkynyl, where C1-50 alkyl, C2-50 alkenyl or C2-50 alkynyl is optionally interrupted by one or more groups selected from -NH-, -N(C1-4 alkyl)-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)N(C1-4 alkyl)-, -OC(O)-, -S(O)-, -S(O)2-, 4- to 7-membered heterocyclyl, phenyl and naphthyl.

[00191] As used herein, the term “substituted” means that one or more -H atoms of a molecule or portion are replaced by a different atom or group of atoms, which are called “substituents”.

[00192] In certain embodiments, one or more such substituents are, independently of each other, selected from the group consisting of halogens, -CN, -COORx1, -ORx1, -C(O)Rx1, -C(O)N(Rx1Rx1a), -S(O)2N(Rx1Rx1a), -S(O)N(Rx1Rx1a), -S(O)2Rx1, -S(O)Rx1, - N(Rx1)S(O)2N(Rx1aRx1b), -SRx1, -N(Rx1Rx1a), -NO2, -OC(O)Rx1, - N(Rx1)C(O)Rx1a, -N(Rx1)S(O)2Rx1a, -N(Rx1)S(O)Rx1a, -N(Rx1)C(O)ORx1a, -N(Rx1)C(O)N(Rx1aRx1b), -OC(O)N(Rx1Rx1a), -T0, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T0, C1-50 alkyl, C2-50 alkenyl, and C250 alkynyl are optionally substituted with one or more -Rx2 groups, 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 -T0-, -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)-; -Rx1, -Rx1a, -Rx1bsion, independently of each other, selected from the group consisting of -H, Petition 870250079895, dated 05 / 09 / 2025, p. 66 / 354 57 / 309 - T0, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T0, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Rx2 groups, 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 -T0-, 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)-; each T0 is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 6- to 11-membered heterobicyclyl; wherein each T0 is independently, optionally, substituted with one or more -Rx2, which are the same or different; Each -Rx2 is independently selected from the group consisting of halogen, -CN, oxo (=O), -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 halogens, which are the same or different; each -Rx3, -Rx3a, -Rx4, -Rx4a, -Rx4b is independently selected from the group consisting of -H and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogens, which are the same or different.

[00193] In certain embodiments, one or more substituents are independently selected from the halogen group, -CN, -COORx1, -ORx1, -C(O)Rx1, -C(O)N(Rx1Rx1a), -S(O)2N(Rx1Rx1a), -S(O)N(Rx1Rx1a), -S(O)2Rx1, -S(O)Rx1, - N(Rx1)S(O)2N(Rx1aRx1b), -SRx1, -N(Rx1Rx1a), -NO2, -OC(O)Rx1, Petition 870250079895, dated 05 / 09 / 2025, p. 67 / 354 58 / 309 - N(Rx1)C(O)Rx1a, -N(Rx1)S(O)2Rx1a, -N(Rx1)S(O)Rx1a, -N(Rx1)C(O)ORx1a, -N(Rx1)C(O)N(Rx1aRx1b), -OC(O)N(Rx1Rx1a), -T0, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl; wherein -T0, C1-10 alkyl, C2-10 alkenyl, and C210 alkynyl are optionally substituted with one or more -Rx2 groups, which are the same or different, and wherein C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl groups are optionally interrupted by one or more groups selected from the group consisting of -T0-, -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)-; Each -Rx1, -Rx1a, -Rx1b, -Rx3, -Rx3a is independently selected from the group consisting of -H, halogen, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; each T0 is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 6- to 11-membered heterobicyclyl; wherein each T0 is independently, optionally, substituted with one or more -Rx2, which are the same or different; Each -Rx2 is independently selected from the group consisting of halogen, -CN, oxo (=O), -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 halogens, which are the same or different; Each -Rx4, -Rx4a, -Rx4b is independently selected from the group consisting of -H, halogen, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

[00194] In certain modalities, one or more substitutes are, in Petition 870250079895, dated 05 / 09 / 2025, p. 68 / 354 59 / 309 dependent on each other, selected from the group consisting of halogen, -CN, -COORx1, -ORx1, -C(O)Rx1, -C(O)N(Rx1Rx1a), -S(O)2N(Rx1Rx1a), -S(O)N(Rx1Rx1a), -S(O)2Rx1, -S(O)Rx1, -N(Rx1)S(O)2N(Rx1aRx1b), -SRx1, -N(Rx1Rx1a), -NO2, -OC(O)Rx1, -N(Rx1)C(O)Rx1a, -N(Rx1)S(O)2Rx1a, -N(Rx1)S(O)Rx1a, -N(Rx1)C(O)ORx1a, -N(Rx1)C(O)N(Rx1aRx1b), -OC(O)N(Rx1Rx1a), -T0, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; wherein -T0, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more -Rx2 groups, 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 -T0-, -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)-; Each -Rx1, -Rx1a, -Rx1b, -Rx2, -Rx3, -Rx3a is independently selected from the group consisting of -H, halogen, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; Each T0 is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 6- to 11-membered heterobicyclyl; wherein each T0 is independently, optionally, substituted with one or more -Rx2, which are the same or different.

[00195] In certain embodiments, a maximum of 6 -H atoms of an optionally substituted molecule are independently replaced by a substituent, for example, 5 H atoms are independently replaced by a substituent, 4 H atoms are independently replaced by a substituent, 3 H atoms are independently replaced by a substituent, 2 H atoms are independently replaced by a substituent, or 1 H atom is replaced by a substituent.

[00196] As used herein, the term “therapeutically quantity” Petition 870250079895, dated 05 / 09 / 2025, p. 69 / 354 "60 / 309 effective" means a quantity sufficient to cure, alleviate, or partially interrupt the clinical manifestations of a given disease and its complications. The effective quantities for each purpose will depend on the severity of the disease or injury, as well as the weight and general condition of the individual. It is understood that determining an appropriate dosage can be achieved through routine experimentation, constructing a matrix of values ​​and testing different points on the matrix, which is within the common skills of a trained physician. In the context of this invention, therapeutically effective quantity refers to dosages that aim to achieve a therapeutic effect for an extended period of time, i.e., for at least one day, as well as for two days, as well as for three days, as well as for four days, as well as for five days, as well as for six days, as well as for one week or as well as for two weeks.

[00197] As used, the term “traceless ligand” means a reversible ligand that, after cleavage, releases the drug in its free form.

[00198] As used herein, the term “water-soluble” with reference to a polymeric moiety means that when such a polymeric moiety is part of the CNP conjugate, at least 1 g of the CNP conjugate comprising such a water-soluble polymeric moiety can be dissolved in one liter of water at 20°C to form a homogeneous solution.

[00199] In general, the term “to comprehend” or “comprising” also encompasses “to consist of” or “consisting of”.

[00200] The amino acid sequences of CNP polypeptides can be varied without significant effect on the structure or function of the peptide. Such mutants include deletions, insertions, inversions, repeats, and substitutions selected according to general rules known in the art, so as to have little effect on activity. For example, guidelines on how to perform amino acid substitutions Petition 870250079895, dated 05 / 09 / 2025, page 70 / 354 61 / 309 of the phenotypically silent are provided in Bowie et al. (1990), Science 247:1306-1310, which is incorporated here by reference in its entirety, in which the authors indicate that there are two main approaches to studying amino acid sequence tolerance to change.

[00201] As used herein, the term “CNP analog” refers to CNPs from different and unrelated organisms that perform the same functions in each organism, but which did not originate from a common ancestral structure to the ancestors of the organisms. Instead, analogous CNPs arose separately and subsequently evolved to perform the same or similar functions. In other words, CNP analog polypeptides are polypeptides with quite different amino acid sequences that perform the same biological activity, that is, they regulate the growth, proliferation, and differentiation of chondrocytes in the cartilaginous growth plate.

[00202] As used herein, the term “CNP ortholog” refers to the CNP within two different species whose sequences are related to each other through a common homologous CNP in an ancestral species, but which have evolved to become different from each other.

[00203] As used herein, the term “CNP homolog” refers to CNPs from different organisms that perform the same functions in each organism and that originate from an ancestral structure that the ancestors of the organisms had in common. In other words, CNP homologous polypeptides are polypeptides with very similar amino acid sequences that perform the same biological activity, that is, they regulate the growth, proliferation, and differentiation of chondrocytes in the cartilaginous growth plate. In certain embodiments, CNP polypeptide homologs Petition 870250079895, dated 05 / 09 / 2025, p. 71 / 354 62 / 309 can be defined as polypeptides that exhibit at least 40%, 50%, 60%, 70%, 80%, 90%, or 95% identity with a reference CNP polypeptide. DETAILED DESCRIPTION OF THE INVENTION

[00204] The invention relates to a method for improving muscle function, such as skeletal muscle function, in an individual suffering from a disease or condition in which muscle function is impaired, the method comprising administering an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said individual. FGFR3 signaling inhibitors

[00205] The FGFR3 signaling pathway is well understood and involves the MAPK and STET pathways. In non-pathological states, the receptor is activated by ligand binding (e.g., FGF1, FGF2, or FGF9) and receptor dimerization, which brings the tyrosine kinase domains of each member of the receptor dimer pair closer together, allowing them to cross-phosphorylate on the tyrosines in their activation loops. This activates the kinases, which then bind to adaptor proteins and phosphorylate cytoplasmic substrates, triggering downstream signaling cascades that control cell growth and differentiation. Certain pathological states are associated with constitutive FGFR3 activation, and in these states, receptor dimerization and phosphorylation can occur without ligand binding.

[00206] Inhibition of FGFR3 signaling can occur by reducing or preventing the activity of the signaling cascade at any point in the cascade. For example, FGFR3 antagonists can bind to the receptor itself to reduce or prevent the binding of the activating ligand, and such molecules can be defined as direct FGFR3 antagonists. Examples include anti-FGFR3 antibodies, for example. Petition 870250079895, dated 05 / 09 / 2025, page 72 / 354 63 / 309 example, monoclonal antibodies against FGFR3. Suitable examples are described in WO2022 / 040560, which describes anti-FGFR3 monoclonal antibodies and their use in the treatment of achondroplasia, and is incorporated herein by reference in its entirety. Similarly, documents WO2018 / 145120 and WO2020 / 180898, both incorporated herein by reference in their entirety, disclose anti-FGFR3 monoclonal antibodies and their use in treatment. Vofatamab (B701) is a clinically developed fibroblast growth factor receptor 3-specific monoclonal antibody.

[00207] FGFR3 signaling inhibitors can also act in preventing FGFR3 signaling by preventing or reducing ligand binding to FGFR3. FGFR3 ligand decoy molecules have been developed for this purpose, providing an alternative molecule to which the ligand can bind, reducing or inhibiting signaling through the FGFR3 molecule. An example of a molecule that has been used to prevent excessive intracellular signaling through FGFR3 and alleviate the symptoms of achondroplasia is a soluble form of human FGFR3 (sFGFR3). This form has been shown to act as a decoy receptor and prevent FGF binding to FGFR3. Soluble FGFR3 / sFGFR3 polypeptide decoys are described in documents WO2016 / 110786, WO2022 / 106976 and WO2018 / 007597, all incorporated herein by reference in their entirety. Recifercept is a soluble FGFR3 decoy in clinical development for the treatment of achondroplasia in children (Gonçalves et al., PLoS One. 2020; 15(12): e0244368).

[00208] FGFR3 signaling inhibitors can also act to reduce or prevent FGFR3 signaling by acting (e.g., binding to or inhibiting activity) on the intracellular portion of the FGFR3 molecule itself, for example, by inhibiting or reducing phosphorylation of the molecule. Tyrosine kinase inhibitors, such as infigratinib or Petition 870250079895, dated 05 / 09 / 2025, page 73 / 354 64 / 309 TYR 300, as selective FGFR3 tyrosine kinase inhibitors, can be used for this purpose. WO 2022 / 187443 describes selective FGFR3 tyrosine kinase inhibitors (tyrosine kinase inhibitors) for use in the treatment of achondroplasia and other disorders and is incorporated herein by reference in its entirety. LY3866288, also known as LOXO-435 (also known as LOX-24350), is an FGFR3 inhibitor in clinical development.

[00209] Alternative inhibitors of FGFR3 signaling can perform this function by acting on (e.g., binding to or preventing the activity of) molecules that are downstream of the receptor in one or more of its signaling pathways. Such inhibitors of the FGFR3 signaling pathway can act to reduce or prevent the activity of the MAPK signaling pathway or the STAT signaling pathway downstream of FGFR3. Examples of targets for FGFR3 signaling inhibitors in the MAPK pathway are the proteins ras, raf, mek, and erk. CNP thus acts as an inhibitor of the FGFR3 signaling pathway; activation of the CNP's NPR-B receptor gives rise to cGMP production and PKG activation, which inhibits raf kinase. CNP and other NPR-B agonists can therefore also be inhibitors of FGFR3 signaling. FGFR3 signaling inhibitors can therefore act directly or indirectly on one or more of the FGFR3s themselves, ras, raf, mek and erk, or STAT.

[00210] Similarly, preventing or reducing the expression of the FGFR3 protein itself is another possible way to inhibit FGFR3 signaling. An inhibitor of FGFR3 signaling can therefore act to reduce or decrease the amount of FGFR3 protein in the cell. Examples of suitable strategies include antisense molecules and siRNA, for example, targeting the FGFR3 protein itself. In these cases, the amount of FGFR3 in the cell in question may be less than 90, 80, 70, 60, 50, 40, 30, 20 or 10% of the amount of FGFR3 in the Petition 870250079895, dated 05 / 09 / 2025, page 74 / 354 65 / 309 cell in the absence of the siRNA molecule or the antisense molecule, or before administration of the siRNA molecule or the antisense molecule.

[00211] Suitable examples of FGFR3 signaling inhibitors therefore include antibodies to FGFR3 (e.g., antagonist antibodies to FGFR3), tyrosine kinase inhibitors (such as infigratinib, pemigatinib, futibatinib, erdafitinib, or TYRA300), molecules that prevent or reduce FGFR3 ligand binding, molecules that inhibit FGFR3 signaling by activating the NPR-B receptor (e.g., C-type natriuretic peptide (CNP) and variants thereof), FGFR3 siRNAs, and FGFR3 antisense oligonucleotides.

[00212] In certain embodiments, the fibroblast growth factor receptor 3 (FGFR3) antagonist is infigratinib, which has the structure below, or a pharmaceutically acceptable salt thereof:

[00213] Infigratinib has been approved for the treatment of certain types of cancer and is currently in clinical development for the treatment of achondroplasia in children aged 3 to 11 years, who receive up to 0.25 mg / kg of infigratinib daily in tablet form. High-dose infigratinib, used in cancer treatment, is associated with side effects that may include muscle weakness and muscle cramps. Therefore, it may be desirable to limit the daily dose, in the context of the present invention, to about 3 mg / kg or less, such as about 0.25 mg / kg or less.

[00214] Other FGFR3 signaling inhibitors include pemigatinib, futibatinib, erdafitinib, or TYRA-300. FGFR3 signaling inhibitors, including TYRA-300, are described in the documents. Petition 870250079895, dated 05 / 09 / 2025, page 75 / 354 66 / 309 WO2023 / 279041, WO2021 / 138392, WO2022 / 147246 and WO2021 / 138391, all incorporated herein by reference in their entirety.

[00215] FGFR3 signaling inhibitors can be identified and characterized by standard methods, such as those described, for example, in WO2023 / 279041, WO2021 / 138392, WO2022 / 147246 and WO2021 / 138391. CNP PHARMACEUTICALS

[00216] In an advantageous embodiment, C-type natriuretic peptide (CNP) drugs are used. As discussed above, CNP in vivo binds to NPR-B to exert its effect on the FGFR3 signaling pathway and therefore can also be described as an NPR-B agonist. Other NPR-B agonists can also be used according to the invention, including small molecule NPR-B receptor agonists.

[00217] CNP drugs are molecules that include a CNP peptide, as defined above. CNP drugs and CNP peptides are preferably administered in a form in which they are NPR-B agonists, as defined above, or in a form that gives rise to the production of NPR-B agonists in vivo (e.g., as a result of in vivo processing that releases a CNP peptide that is an NPR-B agonist in vivo).

[00218] By way of example, the drug CNP may be administered in the form of a CNP peptide, or a CNP peptide conjugate, or a CNP prodrug. The methods of the invention may also employ NPR-C ligands; CNP is an example of an NPR-C ligand. FGFR3 Inhibition Assay

[00219] Guagnana et al., J. Med. Chem. 2011, 54, 7066-7083, incorporated herein by reference in its entirety, provides a radiometric kinase assay that can be used to identify an inhibitor Petition 870250079895, dated 05 / 09 / 2025, page 76 / 354 67 / 309 FGFR3 tyrosine kinase pain: The enzymatic activity of the kinase measures the phosphorylation of a synthetic substrate by the purified GST fusion FGFR3-K650E kinase domain in the presence of radiolabeled ATP. Also described in Guagnana et al. are the BaF3 Cell Line Proliferation Assays and the FGFR1-4 Cellular Autophosphorylation Assay, which can also be used to identify FGFR3 inhibitors. An NPR-B activity assay can be used to identify NPR-B agonists.

[00220] Functional CNP peptides and free CNP released from the CNP prodrug and other NPR-B agonists can be identified using an NPR-B assay, such as the NPR-B assay reported in Breinholt et al., 2019 J Pharmacol Exp Ther 370:459-471, which is incorporated herein by reference in its entirety.

[00221] The activity of CNP to induce an intracellular cyclic guanosine monophosphate (cGMP) response can be determined in NIH3T3 cells. These cells express NPR-B on the cell surface (Abbey and Potter, 2003 Endocrinology, Volume 144, Issue 1, January 1, 2003, Pages 240-246), and stimulation of this receptor with CNP leads to intracellular production of the secondary messenger cGMP. In summary, NIH3T3 cells are cultured in F-12 medium of Dulbecco's modified Eagle medium with 5% FBS and 5 mM glutamine at 37°C and 5% CO2. For each assay, cells are resuspended in stimulation buffer (Dulbecco's PBS with 0.5 mM 3-isobutyl-1-methylxanthine), seeded in a 96-well plate (5 x 10⁴ / well), and incubated in duplicate with CNP at different concentrations.After a 30-minute incubation at 37 °C and 5% CO2, the cells are lysed in the provided lysis buffer, and the cGMP level is measured using a commercially available cGMP assay based on fluorescence energy transfer resolution. Petition 870250079895, dated 05 / 09 / 2025, page 77 / 354 68 / 309 time (cGMP kit, catalog 62GM2PEB; Cisbio, Codolet, France). Activity is determined using a four-parameter logistic curve fitting and by parallel line analysis of the sample compared to CNP-38 (SEQ ID NO:24 (CNP-38): LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, where the cysteines at positions 22 and 38 are connected via a disulfide bridge) as a reference standard (PLA 2.0 software; Stegmann Systems, Rodgau, Germany).

[00222] In certain embodiments, the NPR-B agonist (e.g., C-type natriuretic peptide) has at least about 25% of the NPR-B activity (activity to elicit an intracellular cGMP response in an NIH3T3 cell assay) of a CNP-38 reference standard, such as at least about 50%, 75%, 80%, 85%, 90% of the activity of the CNP-38 reference standard in the NPR-B activity assay as described above.

[00223] It is understood that, for CNP prodrugs, the activity of the prodrug in the CNP assay will need to be evaluated based on the CNP released (free CNP) from the prodrug. An NPR-C affinity and agonist assay that can be used to identify NPR-C agonists.

[00224] Functional CNP peptides and free CNP released from the CNP prodrug and other NPR-C ligands can be identified using an NPR-C affinity assay, such as the NPR-C affinity assay reported in Breinholt et al., 2019 J Pharmacol Exp Ther 370:459-471.

[00225] This C-type natriuretic peptide affinity assay uses a HEK293 cell line that stably overexpresses human C-type natriuretic peptide. This C-type natriuretic peptide affinity assay can be used to evaluate the relative C-type natriuretic peptide affinity of a CNP or other C-type natriuretic peptide compared to a CNP-38 standard. In certain embodiments, C-type natriuretic peptide possesses at least about 25% of the affinity. Petition 870250079895, dated 05 / 09 / 2025, page 78 / 354 69 / 309 affinity for NPR-C of the CNP-38 reference standard, such as at least about 50% affinity of the CNP-38 reference standard, such as at least about 75% affinity for NPR-C of the CNP-38 reference standard, in the NPR-C affinity assay.

[00226] Zhou and Murthy, Am J Physiol Cell Physiol 284: C1255C1261, 2003, which is incorporated herein by reference in its entirety, reports the G protein activating activity of NPRC and provides an assay for the identification of receptor-activated G protein assays by [35S]GTPyS binding, and an assay for PLCbeta activity, both of which can be used to identify NPR-C ligands with NPR-C agonist activity (NPR-C agonists: for example, a standard to be used in the evaluation of NPR-C agonists in an NPR-C activity assay is cANP4-23). ​​Zhou and Murthery also describe an ANP [125I] binding assay, which can be used to identify NPR-C ligands. Exemplary CNPs (including CNP peptides)

[00227] The natural human CNP-22 (SEQ ID NO:1) has the following sequence: GLSKGCFGLKLDRIGSMSGLGC, in which the cysteines at positions 6 and 22 are connected via a disulfide bridge.

[00228] In certain forms, the term “CNP” also refers to the following peptide sequences: SEQ ID NO:2 (CNP-53): DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:3 (G-CNP-53): GDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:4 (M-CNP-53): Petition 870250079895, dated 05 / 09 / 2025, page 79 / 354 70 / 309 MDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:5 (P-CNP-53): PDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:6 (CNP-53 M48N): DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC; SEQ ID NO:7 (CNP-53 Δ15-31): DLRVDTKSRAAWARGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:8 (CNP-52): LRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:9 (CNP-51): RVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:10 (CNP-50): VDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:11 (CNP-49): DTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:12 (CNP-48): TKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:13 (CNP-47): KSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:14 (CNP-46): SRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIPetição 870250079895, de 05 / 09 / 2025, pág. 80 / 354 71 / 309 GSMSGLGC; SEQ ID NO:15 (CNP-45): RAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:16 (CNP-44): AAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:17 (CNP-44 Δ14-22): AAWARLLQEHPNAGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:18 (CNP-44 Δ15-22): AAWARLLQEHPNARGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:19 (CNP-43): AWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:20 (CNP-42): WARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:21 (CNP-41): ARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:22 (CNP-40): RLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:23 (CNP-39): LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:24 (CNP-38): LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, in which the cysteines at positions 22 and 38 are connected via a disulfide bridge; SEQ ID NO:25 (CNP-37): Petition 870250079895, dated 05 / 09 / 2025, page 81 / 354 72 / 309 QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:26 (CNP-37 Q1pQ, where pQ = pyroglutamate): pQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:27 (G-CNP-37): GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:28 (P-CNP-37): PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:29 (M-CNP-37): MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:30 (PG-CNP-37) (Vosoritida peptide sequence): PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:31 (MG-CNP-37): MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:32 (CNP-37 M32N): QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC; SEQ ID NO:33 (G-CNP-37 M32N): GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC; SEQ ID NO:34 (G-CNP-37 K14Q): GQEHPNARKYKGANQKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:35 (G-CNP-37 K14P): GQEHPNARKYKGANPKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:36 (G-CNP-37 K14Q, Δ15): GQEHPNARKYKGANQGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:37 (G-CNP-37 K14Q, K15Q): GQEHPNARKYKGANQQGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:38 (CNP-36): Petition 870250079895, dated 05 / 09 / 2025, page 82 / 354 73 / 309 EHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:39 (CNP-35): HPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:40 (CNP-34): PNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:41 (CNP-33): NARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:42 (CNP-32): ARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:43 (CNP-31): RKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:44 (CNP-30): KYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:45 (CNP-29): YKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:46 (CNP-28): KGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:47 (GHKSEVAHRF-CNP-28): GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:48 (CNP-27): GANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:49 (CNP-27 K4Q, K5Q): GANQQGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:50 (CNP-27 K4R, K5R): GANRRGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:51 (CNP-27 K4P, K5R): GANPRGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:52 (CNP-27 K4S, K5S): GANSSGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:53 (CNP-27 K4P, K5R): Petition 870250079895, dated 05 / 09 / 2025, page 83 / 354 74 / 309 GANGANPRGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO:54 (CNP-27 K4R, K5R, K9R): GANRRGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO:55 (CNP-27 K4R, K5R, K9R, M22N): GANRRGLSRGCFGLKLDRIGSNSGLGC; SEQ ID NO:56 (P-CNP-27 K4R, K5R, K9R): PGANRRGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO:57 (M-CNP-27 K4R, K5R, K9R): MGANRRGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO:58 (fragment of HSA-CNP-27): GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLG; SEQ ID NO:59 (fragment of HSA-CNP-27 M22N): GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSNSGLGC; SEQ ID NO:60 (M-HSA-CNP-27 fragment): MGHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:61 (P-HSA-CNP-27 fragment): PGHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:62 (CNP-26): ANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:63 (CNP-25): NKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:64 (CNP-24): KKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:65 (CNP-23): KGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:66 (R-CNP-22): RGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:67 (ER-CNP-22): Petition 870250079895, dated 05 / 09 / 2025, page 84 / 354 75 / 309 ERGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:68 (R-CNP-22 K4R): RGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO:69 (ER-CNP-22 4KR): ERGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO:70 (RR-CNP-22): RRGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO:71 (fragment of HRGP-CNP-22): GHHSHEQHPHGANQQGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:72 (fragment of HRGP-CNP-22): GAHHPHEHDTHGANQQGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:73 (fragment of HRGP-CNP-22): GHHSHEQHPHGANPRGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:74 (fragment of IgG1(Fc)-CNP-22): GQPREPQVYTLPPSGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:75 (fragment of HSA-CNP-22): GQHKDDNPNLPRGANPRGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:76 (fragment of HSA-CNP-22): GERAFKAWAVARLSQGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:77 (fosteocrine inhibitor fragment NPR) C-CNP22): FGIPMDRIGRNPRGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:78 (heparin-binding domain fragment) FGF2-CNP22): GKRTGQYKLGSKTGPGPKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:79 (fragment of IgG1(Fc)-CNP-22 K4R): GQPREPQVYTGANQQGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO:80 (fragment of HSA-CNP-22 K4R): Petition 870250079895, dated 05 / 09 / 2025, page 85 / 354 76 / 309 GVPQVSTSTGANQQGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO:81 (fibronectin-CNP-22 K4R fragment): GQPSSSSQSTGANQQGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO:82 (fibronectin fragment-CNP-22 K4R): GQTHSSGTQSGANQQGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO:83 (fibronectin fragment-CNP-22 K4R): GSTGQWHSESGANQQGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO:84 (zinc finger fragment-CNP-22 K4R): GSSSSSSSSSGANQQGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO:85 (CNP-21): LSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:86 (CNP-20): SKGCFGLKLDRIGSMSGLGC; SEQ ID NO:87 (CNP-19): KGCFGLKLDRIGSMSGLGC; SEQ ID NO:88 (CNP-18): GCFGLKLDRIGSMSGLGC; SEQ ID NO:89 (CNP-17): CFGLKLDRIGSMSGLGC; SEQ ID NO:90 (fragment of BNP-CNP-17- fragment of BNP): SPKMVQGSGCFGLKLDRIGSMSGLGCKVLRRH; SEQ ID NO:91 (CNP-38 L1G): GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:92 (Ac-CNP-37; where Ac= acetyl): AcQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO:93: QEHPNARX1YX2GANX3X4GLSX5GCFGLX6LDRIGSMSGL GC, Petition 870250079895, dated 05 / 09 / 2025, p. 86 / 354 77 / 309 where Xi, X2, X3, X4, X5 and X6 are independently selected from the group consisting of K, R, P, S and Q, on the condition that at least one of Xi, X2, X3, X4, X5 and X6 is selected from the group consisting of R, P, S and Q; in certain embodiments, Xi, X2, X3, X4, X5 and X6 are selected from the group consisting of K and R, on the condition that at least one of Xi, X2, X3, X4, X5 and X6 is R; SEQ ID NO:94: QEHPNARKYKGANX1X2GLSX3GCFGLX4LDRIGSMSGLGC, where Xi, X2, X3 and X4 are independently selected from the group consisting of K, R, P, S and Q, with the condition 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 condition that at least one of Xi, X2, X3 and X4 is R; SEQ ID NO:95: QEHPNARKYKGANXiX2GLSKGCFGLKLDRIGSMSGLGC, where XiX2 are selected from the group consisting of KR, RK, KP, PK, SS, RS, SR, QK, QR, KQ, RQ, RR and QQ.

[00229] It is understood that the cysteine ​​equivalents at positions 22 and 38 of SEQ ID NO:24 are also connected by means of a disulfide bridge in SEQ ID Nos: 2 to 95.

[00230] It is also recognized by one skilled in the art that the conjugates of the present invention can be prodrugs. [0023i] The unit dose comprised in the unit dosage form of the present invention depends on the patient's actual body weight.

[00232] Vosoritide is approved for daily subcutaneous administration and is administered in doses of approximately 15 pg / kg, although it may be administered in higher doses in infants (e.g., about 30 pg / kg). Vosoritide is currently available Petition 870250079895, dated 05 / 09 / 2025, page 87 / 354 78 / 309 in vials of 0.4 mg, 0.56 mg and 1.2 mg, and the recommended daily dose based on actual body weight (ABC) is as follows. at 11 kg: 0.24 mg SC qDay at 16 kg: 0.28 mg SC qDay at 21 kg: 0.32 mg SC qDay at 32 kg: 0.4 mg SC qDay at 43 kg: 0.5 mg SC qDay at 59 kg: 0.6 mg SC qDay at 89 kg: 0.7 mg SC qDay >90 kg: 0.8 mg SC qDay

[00233] For younger children, a higher dose has been reported to be more effective.

[00234] In certain modalities, the unit dose varies from 50 pg to 7000 pg of CNPJ. In certain modalities, the unit dose varies from 100 pg to 5,000 pg of CNP. In certain modalities, the unit dose varies from 100 pg to 3,000 pg of CNP. In certain modalities, the unit dose varies from 100 pg to 2,000 pg of CNP. In certain modalities, the unit dose varies from 100 pg to 1,000 pg of CNP. In certain modalities, the unit dose varies from 150 pg to 750 pg of CNP. In certain modalities, the unit dose varies from 150 pg to 500 pg of CNP. In certain modalities, the unit dose varies from 150 pg to 350 pg of CNP. In certain embodiments, the unit dose is approximately 700 pg of CNP. In certain embodiments, approximately 600 pg of CNP. In certain embodiments, approximately 500 pg of CNP. In certain embodiments, approximately 400 pg of CNP. In certain embodiments, approximately 300 pg of CNP.

[00235] In certain modalities, the unit dose is 6 pg of CNPJ / kg. In certain modalities, CNPJ / kg. In certain modalities, CNPJ / kg. In certain modalities, the unit dose is 20 pgde, the unit dose is 50 pgde, and the unit dose is 75 pgde. Petition 870250079895, dated 05 / 09 / 2025, p. 88 / 354 79 / 309 CNPJ / kg. In certain modalities, CNPJ / kg. In certain modalities, CNPJ / kg. In certain modalities, CNPJ / kg.

[00236] In certain modalities CNP / kg. In certain modalities, CNPJ / kg. In certain modalities, CNPJ / kg. In certain modalities, CNPJ / kg. In certain modalities, CNPJ / kg. In certain modalities, CNPJ / kg.

[00237] In certain embodiments, the unit dose is 100 pg, the unit dose is 125 pg, the unit dose is 150 pg, the unit dose is 6 pg, the unit dose is 20 pg, the unit dose is 50 pg, the unit dose is 75 pg, the unit dose is 100 pg, the unit dose is 125 pg, the unit dose is 150 pg, the unit dosage form is solid.

[00238] In certain embodiments, such as for the compound of formula (IIf ') or formula (IIf) or compound (1), the unit dose varies from about 12.3 nmol CNP / kg to at least about 37 nmol CNP / kg. In certain embodiments, the unit dose varies from 12.3 nmol CNP / kg to 36.9 nmol CNP / kg. In certain embodiments, the unit dose is at least 24.6 nmol CNP / kg. In certain embodiments, the unit dose varies from about 24.6 nmol CNP / kg. In certain embodiments, the unit dose varies from 24.6 nmol CNP / kg.

[00239] In certain embodiments, such as for the compound of formula (Ilf ') or formula (Ilf) or compound (1), the unit dose varies from about 6 pg CNP / kg to at least about 100 pg CNP / kg. In certain embodiments, the unit dose varies from about 6 pg CNP / kg to about 150 pg CNP / kg.

[00240] In certain embodiments, such as for the compound of formula (IIf ') or formula (IIf) or compound (1), the unit dose comprised in the unit dosage form of the present invention varies from 6 pg of Petition 870250079895, dated 05 / 09 / 2025, p. 89 / 354 80 / 309 CNP / kg at least 100 pg of CNP / kg. In certain embodiments, the unit dose varies from 6 pg of CNP / kg to 150 pg of CNP / kg.

[00241] The single dose is preferably administered weekly.

[00242] For CNP conjugates or CNP prodrugs, such as for the compound of formula (IIf ') or formula (IIf) or compound (1), it is understood that “x” pg of CNP / kg refers to “x” pg of CNP, that is, the portion of CNP contained in the CNP conjugate, per kilogram of the patient’s body weight. Similarly, it is understood that “y” nmol of CNP / kg refers to “y” nmol of CNP, that is, the portion of CNP contained in the CNP conjugate, per kilogram of the patient’s body weight. The Individual / Patient

[00243] In certain modalities, the individual is an adult. Adult humans are 18 years of age or older. In certain modalities, the individual is at least 19 years of age, such as at least 20 or 25 years of age.

[00244] In certain modalities, the individual is a pediatric patient, that is, under 18 years of age, such as under 16 years of age or under 14 years of age, or under 5 years of age. In certain modalities, the individual is a child (for example, under 1 year of age or under 9 or 6 months of age).

[00245] The individual is also called a patient.

[00246] In certain modalities, the patient's body weight varies from approximately 2 kg to approximately 80 kg. In certain modalities, the patient's body weight varies from approximately 4 kg to approximately 60 kg. In certain modalities, the patient's body weight is approximately 5 kg. In certain modalities, the patient's body weight is approximately 9 kg. In certain modalities, the patient's body weight is approximately 10 kg. In certain modalities, the patient's body weight is approximately 11 kg. In certain modalities, the patient's body weight is approximately 12 kg. In certain modalities, the patient's body weight is Petition 870250079895, dated 05 / 09 / 2025, page 90 / 354 81 / 309 approximately 15 kg. In certain modalities, the patient's body weight is approximately 20 kg. In certain modalities, the patient's body weight is approximately (at least) 30 kg. In certain modalities, the patient's body weight is approximately (at least) 40 kg. In certain modalities, the patient's body weight is approximately (at least) 50 kg. In certain modalities, the patient's body weight is approximately (at least) 60 kg. In certain modalities, the patient's body weight is approximately (at least) 70 kg. In certain modalities, the patient's body weight is approximately (at least) 80 kg. Diseases or conditions in which muscle function is impaired

[00247] In certain modalities, the individual suffers from a disease or condition in which muscle function (e.g., skeletal muscle) is impaired. This means that normal muscle function is reduced or absent. The reduction in muscle function can be assessed in relation to threshold levels or by reference to an individual without the disease or condition. The loss or reduction of muscle function may arise as a result of the disease or condition acting directly on the muscle (e.g., a myopathy) or it may be a disease affecting the neuromuscular junction or a disease affecting the nervous system.

[00248] The disease or condition in which muscle function (e.g., skeletal muscle) is impaired may include a chondrodysplasia disease, such as a disease selected from the group consisting of achondroplasia, hypochondroplasia, and thanatophoric dysplasia. In certain forms, the individual presents with achondroplasia.

[00249] In certain modalities, the individual has a Rasopathy.

[00250] In certain modalities, the individual presents with a chondrodysplasia disease, such as a selected disease from the group consisting of achondroplasia, hypochondroplasia, and thanatophoric dysplasia. In certain modalities, the individual presents with achondroplasia. Petition 870250079895, dated 05 / 09 / 2025, page 91 / 354 82 / 309

[00251] In certain modalities, the individual does not present with a chondrodysplasia disease, such as a selected disease from the group consisting of achondroplasia, hypochondroplasia, and thanatophoric dysplasia. In certain modalities, the individual does not present with achondroplasia. In certain modalities, the individual does not present with a chondrodysplasia disease.

[00252] Skeletal muscle is one of the three main types of muscles in the body, the others being cardiac muscle and smooth muscle. Skeletal muscle is that which attaches to bone via tendons. The term “skeletal muscle” can also be used to refer to striated muscle. Administration of an FGFR3 signaling inhibitor or an NPR-B or NPR-C agonist has been shown to result in improved muscle function, particularly skeletal muscle function.

[00253] In certain modalities, the individual presents with a myopathy. Myopathies are a heterogeneous group of disorders that primarily affect skeletal muscle structure, metabolism, or channel function, typically resulting in muscle weakness, stiffness, cramps, and spasms, and may result in or contribute to skeletal deformities such as abnormal curvature of the spine. Myopathies generally manifest with muscle weakness that interferes with activities of daily living. In some modalities, the myopathy or impaired muscle function may be a mitochondrial myopathy, that is, a myopathy caused by a defect in the mitochondria. Myopathy can be hereditary or acquired. Hereditary myopathies can be congenital myopathies, that is, the symptoms of the myopathy begin at birth or in early childhood.

[00254] In certain modalities, the individual has a disease or condition associated with an impairment in neuromuscular function, such as a neuromuscular or neurodegenerative disease. Petition 870250079895, dated 05 / 09 / 2025, p. 92 / 354 83 / 309

[00255] In some modalities, therefore, the methods are performed on an individual with a disease or condition associated with an impairment in neuromuscular function, such as a neuromuscular or neurodegenerative disease.

[00256] The invention also provides a method for treating or preventing a disease or condition associated with impaired neuromuscular function, such as a neuromuscular or neurodegenerative disease. The method comprises administering a therapeutically effective amount of an FGFR3 signaling inhibitor, an NPR-B agonist, or an NPR-C agonist (for example, an NPR-B agonist, such as a C-type natriuretic peptide (such as CNP conjugates)), to an individual suffering from neuromuscular or neurodegenerative diseases. In some embodiments, the neuromuscular or neurodegenerative disease is one in which there is mitochondrial dysfunction.

[00257] Administering an effective amount of FGFR3 signaling inhibitor, NPR-B agonist, or NPR-C agonist (e.g., NPR-B agonist) to an individual with a disease or condition associated with impaired neuromuscular function may result in improved mitochondrial function in the individual. This may, for example, be observed (or monitored) through improved muscle function, such as improved skeletal muscle function or neuromuscular function; or through slowing, delaying, or reducing disease progression, such as a reduced rate of muscle function loss or decline or a reduced rate of neuromuscular function loss or decline (e.g., compared to a baseline or to the individual before or in the absence of treatment). In some modalities, the treatment method may be initiated after diagnosis of the disease or condition associated with impaired neuromuscular function and, optionally Petition 870250079895, dated 05 / 09 / 2025, p. 93 / 354 84 / 309 Finally, before significant or noticeable loss of muscle or neuromuscular function.

[00258] Mitochondrial dysfunction, or mitochondrial dysfunction, is indicated in many neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), ataxias such as Friedreich's ataxia (AFRD), and amyotrophic lateral sclerosis (ALS). Mitochondrial dysfunction can be identified by diagnosing a disease or disorder associated with mitochondrial dysfunction, through genetic testing, i.e., identifying a genetic polymorphism associated with or causing mitochondrial dysfunction, through biochemical analysis of a biopsy of the affected tissue, or through biochemical markers in blood or urine (see, for example, Muraresku et al., Curr Genet Med Rep. Jun 2018; 6(2): 62-72).

[00259] The disease or condition associated with impaired neuromuscular function may include a neuromuscular disorder / neuromuscular diseases (NMDs). Proper NMD disorders and diseases may be associated with mitochondrial impairment and dysfunction (see, for example, Marra et al., Biomolecules 2021, vol. 11 (11); 1633). The methods of the present invention can therefore be used to improve mitochondrial function or retard the decline of mitochondrial function in individuals with a disease or condition associated with impaired neuromuscular function (e.g., an NMD) (e.g., compared to a reference or to the individual before or in the absence of treatment).

[00260] The methods of the present invention can therefore be used to improve muscle function or delay the decline of muscle function in those diseases or conditions associated with impaired neuromuscular function. Examples of neuromuscular diseases include genetically acquired diseases, including muscular dystrophies and myopathies, as well as neuromuscular diseases. Petition 870250079895, dated 05 / 09 / 2025, p. 94 / 354 85 / 309 res. Neuromuscular diseases include neurodegenerative diseases and disorders associated with loss of mitochondrial function and may, for example, be selected from the group consisting of: Motor neuron disease (MND, also known as Amyotrophic Lateral Sclerosis, ALS); Parkinson's disease (PD), Multiple sclerosis (MS, including progressive MS or relapsing-remitting MS); Alzheimer's disease (AD); ataxias, such as Friedreich's ataxia (FAA), and Huntington's disease (HD).

[00261] Parkinson's disease (PD) is associated with mitochondrial dysfunction, and the pathogenesis in PD leads to muscle weakness and fatigue (Borsche et al., J Parkinsons Dis. 2021;11(1):45-60). Timmer et al., J Neurosci. 2007 Jan 17; 27(3): 459-471 indicates aberrant FGFR3 / FGF-2 signaling in animal models of PD. Central and systemic CNP (amino-terminal proCNP) levels are reduced in Parkinson's disease and can be restored by treatment with monoamine oxidase inhibitors (Espiner et al., J Neural Transm (Vienna). April 2014;121(4):371-8; Woodward, Parkinsonism Relat Disord. 2017 Oct;43:15-19). Muscle weakness and fatigue, which can significantly affect gait, are commonly reported by patients with PD. Zheng et al., Sci Transl Med. October 6, 2010; 2(52): 52ra73 report PGC-1a as a therapeutic target in Parkinson's disease.Mitochondrial dysfunction is a central dysfunction in the pathology of Parkinson's Disease (PD), and genes associated with PD, including PGC-1α, are strictly related to mitochondrial integrity (Piccinin, Int. J. Mol. Sci 2001 22(7) 3487). Low PGC1α expression is indicative in PD, and there is a need for therapeutic agents that increase PGC-1α expression and improve mitochondrial function in patients with PD.

[00262] Muscle function can be routinely monitored in patients with PD through physical function tests, such as tests of Petition 870250079895, dated 05 / 09 / 2025, page 95 / 354 86 / 309 sit-to-stand and six-minute walk tests (see, for example, Clael et al., Neurosci J 2918 8507018). Suitable physical function tests used in monitoring patients with PD may include speech, facial expression, rising from a chair, gait, or postural stability (see, for example, Brusse et al., Physical Therapy, Volume 85, Issue 2, February 1, 2005, Pages 134-141). Recently, the FDA approved a PD monitoring application (Rube Labs) for monitoring patients via a smart device (e.g., a smartphone or smartwatch), which can provide all-day monitoring of physical activities such as walking, as well as other PD symptoms such as tremors and dyskinesia. Therefore, it is anticipated that such smart device applications will be used to monitor effective treatment according to the present invention.

[00263] Reduced PGC-1α expression contributes to mitochondrial dysfunction and correlates with neuronal loss in multiple sclerosis (Witte et al., Acta Neuropathol. 2013 Feb;125(2):231-43; Peixoto de Barcelos Biology (Basel) 2019 8(2):37). Rosenkranz et al., eLife A study published in 2021;10:e61798 reports that increased mitochondrial activity in neurons protects against neurodegeneration in a murine model of multiple sclerosis (MS) and proposes that increasing mitochondrial activity in neurons may be a therapeutic strategy for MS. Rajendran et al., Cells 2021, reports on FGF / FGFR signaling in MS and FGFR inhibition as a therapeutic option to reduce inflammation and induce remyelination. Multiple sclerosis causes muscle fatigue, pain, imbalance, and reduced physical activity, which can further contribute to muscle weakness. In fact, muscle fatigue is considered the most common symptom of MS. Monitoring muscle function in MS can be done through self-report questionnaires or by using smart devices that can provide monitoring. Petition 870250079895, dated 05 / 09 / 2025, page 96 / 354 87 / 309 remote fatigue and activity (e.g., Block Front. Neurol. 2022 13 https: / / doi.org / 10.3389 / fneur.2022.878313, Stuart et al., Mult Scler J Exp Transl Clin. 7 Dec 2020;6(4):2055217320975185). Witte et al. report that reduced PGC-1alpha expression is correlated with neuronal loss in MS.

[00264] Zhao et al., Cells, Jul 2022; 11(13) 2049 report that mitochondrial dysfunction is a key contributing factor in amyotrophic lateral sclerosis (ALS) and that mitochondrial dysfunction is associated with and involved in the pathogenesis of the disease. Zhao et al., Molecular Neurodegeneration 6, article number: 51 (2011) report that PGC1alpha plays a protective role in ALS.

[00265] Impairment of mitochondrial biogenesis mediated by PGC-1α is indicated in the pathology of Alzheimer's disease and precedes mitochondrial dysfunction associated with AD progression (Bhatia, Curr. Neuropharmacol. 2002 20(4): 675-692). Physical functioning is affected in people living with dementia, such as Alzheimer's disease (AD), and can lead to slow reaction time, muscle weakness, poor coordination and impaired balance and, along with cognitive impairment, is a major contributor to events such as falls and fractures. In later stages of dementia, physical ability can be significantly compromised, severely limiting walking, gait and movement (see, for example, Taraldsen et al., BMC Geriatrics volume 21, article number: 670 (2021), which reports the use of physical accelerometer sensors to monitor daily physical activity in patients with dementia).

[00266] Several changes in muscle function may arise as a result of administration of the FGFR3 signaling inhibitor or the NPR-B agonist or the NPR-C agonist.

[00267] For example, there may be an improvement in muscle strength. Muscle strength is the maximum capacity to exert force for a short period of time. Petition 870250079895, dated 05 / 09 / 2025, p. 97 / 354 88 / 309 time period. This can be assessed, for example, using the Oxford Scale, which involves testing key muscles of the upper and lower extremities against the examiner's resistance and rating the patient's strength on a scale of 0 to 5 accordingly (Naqvi U. Muscle strength grading. InStatPearls [Internet] May 29, 2019. StatPearls Publishing. Available at: https: / / www.ncbi.nlm.nih.gov / books / NBK436008 / ): • 0 No muscle activation • 1 Trace of muscle activation, such as a contraction, without reaching full range of motion • 2 Muscle activation with gravity eliminated, reaching full range of motion • 3 Muscle activation against gravity, full range of motion • 4 Muscle activation against some resistance, full range of motion • 5 Muscle activation against all resistance from the examiner, full range of motion

[00268] Commonly tested muscles include the shoulder abductors, elbow flexors, elbow extensors, wrist extensors, finger flexors, intrinsic hand muscles, hip flexors, knee extensors, dorsiflexors, extensor hallucis longus, and plantar flexors. These muscle groups are commonly chosen so that important spinal nerve roots can be systematically assessed; for example, testing the strength of the elbow flexors, elbow extensors, wrist extensors, finger flexors, and intrinsic hand muscles allows for a methodical assessment of the nerve roots from C5 to T1. Alternatively, or additionally, distal strength can be measured semi-quantitatively with a handgrip ergometer (or with an inflated blood pressure cuff, tightened by the patient) to record grip strength, or dynamometry, which is a measurement Petition 870250079895, dated 05 / 09 / 2025, page 98 / 354 89 / 309 is the most accurate measurement of the force a muscle can exert and can allow differences in strength to be recorded over time. An increase in muscle strength, therefore, can be observed as an increase in the Oxford score, or an increase in distal strength, as assessed by a handgrip ergometer (or with a blood pressure cuff inflated and tightened by the patient) to record grip strength, or dynamometry.

[00269] For example, there may be an improvement in muscle tone. Muscle tone is also called residual muscle tension or tone and is the continuous, passive partial contraction of muscles, or the muscle's resistance to passive stretching during the resting state. It helps maintain posture and decreases during REM sleep. It is different from muscle strength. Muscle tone is regulated by the activity of motor neurons and can be affected by several factors, including age, disease, and nerve damage (hypotonia). Hypotonia refers to decreased muscle tone at rest and decreased resistance to passive movement. Hypotonia is rarely seen in isolation without some degree of weakness. Hypotonia (low muscle tone) describes reduced muscle stiffness that does not effectively support upright posture against gravity or does not produce adequate force during contraction; as a result, hypotonic muscles are typically more compliant than stiff.Hypotonia is observed, for example, in individuals with various conditions such as Down syndrome, muscular dystrophy, cerebral palsy, Prader-Willi syndrome, myotonic dystrophy, Marfan syndrome, and Tay-Sachs disease. Hypotonia is generally assessed by medical observation, and an improvement in hypotonia will result in increased resting muscle tone and resistance to passive movement, as evaluated by a medical professional.

[00270] For example, there may be an improvement in muscle endurance. Petition 870250079895, dated 05 / 09 / 2025, page 99 / 354 90 / 309 Muscle endurance (or muscular stamina). This is the ability of a muscle or group of muscles to resist fatigue during repetitive muscle contractions against an external force. This is usually assessed observationally, for example, by performing a repetitive exercise over a period of time, for example, counting the number of push-ups a patient can perform in a given period, for example, 60 seconds, or determining how long an individual takes to perform a given number of repetitions of an exercise. An improvement in muscular endurance would manifest as an improvement in the number of repetitive exercises in the given time period or a reduction in the amount of time required to perform a given number of repetitions of the exercise.

[00271] For example, there may be an improvement in muscle mass. Muscle mass is the amount of muscle in an individual's body, including skeletal muscles, smooth muscles, and cardiac muscles. In preferred modalities, there is an improvement in skeletal muscle mass. Muscle mass can be measured, for example, by performing dual-energy X-ray absorptiometry, a computed tomography scan, or a magnetic resonance imaging scan. Muscle mass can be increased by the methods of the invention, and an increase in muscle mass can also give rise to an increase in the muscle-to-fat ratio (e.g., skeletal muscle-to-fat ratio). Fat mass can be measured using DEXA and Bioelectrical Impedance Analysis (BIA). Additionally or alternatively, there may also be an increase in one or more of the following: muscle volume, muscle density, and muscle length of the individual.

[00272] For example, there may be a decrease in muscle fatigue. Muscle fatigue is used to describe the decline in force produced by a muscle or group of muscles during contractions. Petition 870250079895, dated 05 / 09 / 2025, page 100 / 354 91 / 309 competitive against an external force. An example of a test to measure muscle fatigue is the Biering-Sorenson test, which has been used to assess fatigue of the trunk extensor muscle group and is also used as a test for back pain. The test, as described by Sorenson (Biering-Sorensen F. Physical measurements as risk indicators for low-back trouble over a one-year period. Spine. 1984;9:106-119), is “to measure how many seconds the individual is able to maintain the upper body unsupported (from the upper edge of the iliac crest) horizontally, while placed in prone position with the buttocks and legs fixed to the couch by three wide canvas straps and the arms crossed over the chest. A decrease in muscle fatigue would manifest in an improvement in the amount of time the individual is able to remain in the required position.

[00273] For example, there may be an increase in cardiovascular endurance, which is the ability of an individual's heart and lungs to supply their body with oxygen. This can also be defined as the ability to perform moderate to high intensity exercise (at a percentage of VO2 max) for an extended period. Cardiovascular endurance can be measured by standard techniques, including measuring VO2 max by indirect calorimetry. VO2 max is the maximum amount of oxygen an individual can utilize during intense or maximal exercise and is typically measured by determining the volume and gas concentrations of inhaled and exhaled air while a person performs maximal and graded exercise on a treadmill or cycle ergometer. VO2 max.Oxygen consumption can be expressed in terms of liters of oxygen consumed per minute (l / min), or the values ​​can be normalized for differences in body size and expressed in milliliters of oxygen consumed per kilogram of body weight per minute (ml / kg / min). An increase in cardiovascular endurance can therefore be observed as one. Petition 870250079895, dated 05 / 09 / 2025, page 101 / 354 92 / 309 increase in VO2 max (l / min), or (ml / kg / min) using this assay.

[00274] For example, there may be an increase in cardiovascular fitness. Cardiovascular fitness is the body's maximum capacity to absorb oxygen. This is also measured as VO2 max (L O2 / min). An increase in cardiovascular fitness may also be observed as an increase in VO2 max (l / min), or (ml / kg / min).

[00275] For example, there may be a decrease in exercise intolerance. Exercise intolerance is the body's reduced ability to perform activities involving strenuous movement and can result in the inability or decreased ability to perform physical exercise at a normal level or duration. Objective tests for exercise intolerance include moderate activity, for example, climbing stairs, a six-minute walk, a brisk walking test, a cardiac stress test, and the cardiopulmonary exercise test (CPET). In the six-minute walk test, the goal is to see how far a person can walk, with approximately 600 meters being a reasonable result for an average person without exercise intolerance. A decrease in exercise intolerance may therefore be observed as an increase in the distance a person can walk in the six-minute test.

[00276] For example, there may be an increase in exercise capacity, which is the maximum amount of physical exertion a patient can sustain. This can be assessed by maximal exercise tests (e.g., ESTs, which are symptom-limited tests performed with a 12-lead ECG used to diagnose exercise-induced myocardial ischemia, arrhythmias, or an abnormal blood pressure response, or a cardiopulmonary exercise test), submaximal exercise tests, six-minute walk tests, and incremental walking tests, with the appropriate test being selected depending on the individual's physical condition. An increase in Petition 870250079895, dated 05 / 09 / 2025, page 102 / 354 93 / 309 exercise capacity can therefore be observed as an increase in the score obtained in any of these assessments.

[00277] For example, there may be a decrease in exercise-induced fatigue (EF), which is a reduction in maximum voluntary muscle strength resulting from intense and prolonged exercise. In general, this is measured by observing the state of fatigue after intense and prolonged exercise.

[00278] Many of the improvements in muscle function are based on observation by a medical professional and are not quantified; however, the increase or improvement can be observed by the medical professional based on standard tests for that muscle function that are used in the field. Any increases or improvements that can be quantified may be an increase or improvement in performance, as determined by a score or value that is at least 1, 2, 3, 5, 10, 15, 20, 25, 30, 35% improved (whether the actual value increases or decreases, depending on the nature of the test) relative to that value without or before administration of the FGFR3 signaling inhibitor or NPR-B agonist or NPR-C agonist, for example, after at least 1, 2, 3, 4, 5, 6, 12, 18, 24, 36 months of administration of the FGFR3 signaling inhibitor or NPR-B agonist or NPR-C agonist.Optionally, biochemical assays on muscle biopsies or for muscle metabolism products released into body fluids can be used in these methods and may yield quantitative results.

[00279] As noted above, an improvement in muscle function can be defined as an improvement relative to muscle function without or before the administration of an FGFR3 signaling inhibitor or NPR-B agonist or NPR-C agonist. In certain modalities, therefore, an individual treated with an FGFR3 signaling inhibitor or NPR-B agonist or NPR-C agonist still Petition 870250079895, dated 05 / 09 / 2025, page 103 / 354 94 / 309 may exhibit an overall decline in muscle function (e.g., over time), but this decline in muscle function may, in these modalities, be less than the decline that would have occurred in the absence of treatment. In such alternative modalities, an improvement in muscle function may manifest as a reduction in the decline of muscle function (e.g., compared to the decline in muscle function in the absence of treatment). This is particularly the case for conditions referred to as a disease or condition associated with an impairment of neuromuscular function, such as a neuromuscular or neurodegenerative disease. This may mean that an individual takes longer to reach a given level of muscle function than would be expected based on their diagnosis.In other words: the progression of the disease (for example, in terms of muscle function) is slowed, for example, so that it takes at least 1, 2, 3, 6 months or at least 1, 2 or 3 years longer to reach a certain point in the progression of the disease than in the absence of treatment.

[00280] There may also be improvement in musculoskeletal pain in the individual. Musculoskeletal pain is defined as acute or chronic pain affecting bones, muscles, ligaments, tendons, and even nerves. Pain can include a number of different pain syndromes, ranging from local pain to neuropathic pain. Musculoskeletal pain is predominantly somatic in nature. The most prevalent forms of musculoskeletal pain are chronic low back pain and neck pain.

[00281] Musculoskeletal pain, for example, can be pain in the musculoskeletal system, including joints, ligaments, muscles, nerves, or tendons. In some modalities, musculoskeletal pain can be chronic pain, typically pain that persists for more than 12 weeks. In some modalities, musculoskeletal pain Petition 870250079895, dated 05 / 09 / 2025, page 104 / 354 95 / 309 Musculoskeletal pain can be muscle pain, such as musculoskeletal pain, such as chronic musculoskeletal pain. In some modalities, musculoskeletal pain may be associated with abnormal curvature of the spine. In some modalities, the pain may not be associated with arthritis, such as osteoarthritis. In some modalities, musculoskeletal pain may be myalgia. In some modalities, musculoskeletal pain may be associated with or caused by muscle cramps or spasms. Musculoskeletal pain can be diagnosed or monitored, for example, through patient-reported pain (see, for example, Nielsen and Arendt-Nielsen, Curr Pain Headache Rep. 2003 Dec;7(6):443-51); magnetic resonance imaging or computed tomography; electromyography, for example, to measure electrical activity in nerves and muscles.

[00282] There may also be an improvement in posture or a reduction in abnormal spinal curvature. Poor or inadequate posture refers to postural dysfunction and can be defined as when an individual's spine is positioned in unnatural positions where curves are emphasized. Complications of poor posture include back pain, spinal dysfunction, joint degeneration, hunched shoulders, and a protruding belly. The improvements associated with posture and spinal curvature after administration of an FGFR3 signaling inhibitor, or NPR-B agonist, or NPR-C agonist, may result from improvements in muscle function, as described above.This is consistent with observations in Example 1 that treatment with the test compound (1) had an impact on survival after only 15 days of treatment, a period consistent with historical effects on muscle survival, and the increased incidence of maternal infanticide has been described in murine models with muscle weakness as an important phenotypic trait (e.g., Sullivan 2014). Petition 870250079895, dated 05 / 09 / 2025, page 105 / 354 96 / 309

[00283] Improvement may be in kyphosis, lordosis, or scoliosis, or in spinal stenosis, which may, for example, arise from any of the above spinal deformities. Kyphosis is an exaggerated forward rounding of the upper spine. Lordosis is an exaggerated inward curvature of the spine. Scoliosis is an abnormal lateral curvature of the spine. Spinal stenosis may, for example, arise from any of the above spinal deformities and is a narrowing of the spinal canal in the spine. Optionally, improvement in kyphosis, lordosis, spinal stenosis, or scoliosis occurs through improved muscle function. These spinal abnormalities may occur in chondrodysplastic disease, and preferably, the individual with kyphosis, lordosis, spinal stenosis, or scoliosis has a chondrodysplastic disease, such as a selected disease from the group consisting of achondroplasia, hypochondroplasia, and thanatophoric dysplasia.

[00284] Abnormal spinal curvature can, for example, be monitored by physical examination or by an imaging method (e.g., X-ray, spinal radiography, computed tomography, or magnetic resonance imaging). Signs of abnormal spinal curvature may include, for example, uneven shoulders, head not centered above the pelvis, one or both hips elevated or abnormally high, irregular waist, and thin body. Spinal curvature can, for example, be measured by the Cobb method.

[00285] Improvements in spinal deformities, such as kyphosis (including thoracic kyphosis and thoracolumbar kyphosis) and lordosis (such as lumbar lordosis), can be measured or monitored by point morphometry of the vertebra. Point morphometry before and during treatment, or after treatment, can be used to detect changes in the shape of the vertebral body. As an example, spinal deformities in achondroplasia can lead to vertebral deformation and kyphosis (such as thoracolumbar kyphosis). Kyphosis, such as thoracolumbar kyphosis Petition 870250079895, dated 05 / 09 / 2025, p. 106 / 354 97 / 309 bar, can also be caused or aggravated by muscle weakness / hypotonia. As illustrated here, in the treatment of children with open bone epiphysis, the present invention can be used to prevent or correct bone deformity of the spine, including, for example, vertebral morphology (e.g., reduction of the apical wedge, for example, of the L1 and / or L2 vertebrae). In children and adults, the benefits in improving physical functioning, such as improved muscle function / reduced hypotonia, are also therapeutically beneficial. Other modalities related to the treatment of abnormal curvature of the spine.

[00286] In some embodiments, the invention relates to the treatment of a spinal deformity in an individual with a chondrodysplastic disease, such as the achondroplasia described herein. Spinal deformities in chondrodysplasias, such as achondroplasia, can lead to pain and disability. Congenital narrowing of the spinal canal is common in achondroplasia and is associated with neurological symptoms that worsen with age and can cause sudden premature death, potentially requiring corrective surgery or repeated corrective surgeries throughout the patient's life.

[00287] Spinal deformity may include an abnormal curvature of the spine that can be corrected, at least partially, by strengthening the back muscles, appropriately through the therapeutic uses described or claimed. Spinal deformity may be an abnormal morphology of the spinal pedicle or spinal stenosis, typical of achondroplasia, which may be further aggravated by an abnormal curvature of the spine. Abnormal morphology of the spinal pedicle may be a reduction in interpedicular distance or pedicle width. Interpedicular narrowing and thickened pedicles are common in achondroplasia, and the resulting spinal canal stenosis frequently requires in Petition 870250079895, dated 05 / 09 / 2025, page 107 / 354 98 / 309 surgical intervention, for example, to correct narrowing of the foramen magnum (FM).

[00288] The invention provides the use of the FGFR3 signaling inhibitor or NPR-B agonist for use in accordance with the invention or in accordance with any of the claims, wherein said use gives rise to an increase in spinal height, such as increased thoracic height; increased interpedicular distance or increased pedicle width.

[00289] The invention provides the use of the NPR-B agonist for use according to the invention or as any of the claims, wherein such use results in an increase in spinal height, such as an increase in thoracic height; an increase in interpedicular distance or an increase in pedicle width. The invention provides a method for treating a spinal pedicle deformity in an individual in need of treatment, comprising administering a therapeutically effective amount of an FGFR3 signaling inhibitor, or an NPR-B agonist, to the individual. Suitably, the method may comprise an initial step of (i) diagnosing or measuring the spinal pedicle deformity in the individual and then (ii) administering a therapeutically effective amount of an FGFR3 signaling inhibitor, an NPR-B agonist, to the individual. Suitably, the measurement step may involve one or more radiographs, such as an anteroposterior (AP) radiograph and / or a lateral radiograph.Lateral radiographs are useful for measuring, for example, pedicle width, and AP radiographs are useful for measuring, for example, interpedicular distance. Radiographs of the spine or spinal deformity obtained before and after administration can be used to determine the effectiveness of the treatment. The diagnostic or measurement step may involve measuring one or more parameters, such as spinal height, thoracic height, interpedicular distance, and pedicle width. The diagnostic step... Petition 870250079895, dated 05 / 09 / 2025, page 108 / 354 99 / 309 tico and measurement may be or include measurement of spinal pedicle morphology or spinal stenosis / spinal canal stenosis.

[00290] In certain modalities, administration results in improvement of sleep apnea, obstructive sleep apnea, or otitis media. Sleep apnea is a condition in which an individual's breathing stops and restarts many times during sleep. This can prevent the individual's body from receiving enough oxygen. Obstructive sleep apnea (OSA) is a form of sleep apnea that occurs when the throat muscles relax and block airflow to the lungs. Otitis media is an infection of the middle ear that causes inflammation (redness and swelling) and fluid buildup behind the eardrum and is associated with midface hypoplasia. Otitis media can result in hearing loss. Optionally, improvement in sleep apnea, obstructive sleep apnea, or otitis media occurs through improved muscle function.These conditions can occur in chondrodysplastic disease, and preferably, the individual with sleep apnea, obstructive sleep apnea, or otitis media presents with chondrodysplastic disease, such as a selected disease from the group consisting of achondroplasia, hypochondroplasia, and thanatophoric dysplasia. It is believed that an improvement in muscle function will result in benefit in these conditions, given the association between sleep-disordered breathing and upper airway muscle weakness (e.g., laryngeal and pharyngeal).

[00291] In some embodiments, the invention relates to a method of treating obstructive sleep apnea. Sleep apnea, such as obstructive sleep apnea, can be monitored, for example, by means of nocturnal polysomnography / respiratory monitoring.

[00292] Otitis media is defined as an infection of the middle ear and is typically diagnosed and monitored through a physical examination. Several diagnostic tools are available, such as pneumatic otoscopy, tympanometry, and acoustic reflectometry. Otitis Petition 870250079895, dated 05 / 09 / 2025, p. 109 / 354 Otitis media is frequently associated with ear pain, hearing loss, and fever, which can also be monitored. In some embodiments, otitis media is acute otitis media, and the present invention provides an effective treatment that can reduce the frequency of acute otitis media events, reduce the severity of acute otitis media, or both. In some embodiments, the invention relates to a prophylactic treatment of otitis media. Monitoring otitis media can therefore assess the frequency or severity of acute otitis media events, or both.

[00293] In certain modalities, administration results in a reduction in obesity. When individuals who have undergone prior treatment suffer from low muscle function, this makes it more difficult for them to exercise and to exercise well and effectively for weight control and overall physical health. By improving muscle function in an individual, a reduction in obesity can also be achieved. This problem has been observed in patients with chondrodysplasia disease, and obesity is noted as a major health problem in achondroplasia that requires early, yet complex, clinical treatment (see SaintLaurent, C., Garde-Etayo, L. & Gouze, E. Obesity in achondroplasia patients: from evidence to medical surveillance. Orphanet J Rare Dis 14, 253 (2019). https: / / doi.org / 10.(1186 / s13023-019-1247-6) which notes that children with achondroplasia are limited by their psychomotor development and physical condition, and the early onset of overweight and obesity contributes to worsening a sedentary lifestyle and / or excluding these children from sports practiced by children of their age. Optionally, obesity reduction occurs through improved muscle function. Obesity can occur in chondrodysplasia, and preferably, the obese individual has chondrodysplasia, such as a selected disease from the group consisting of achondroplasia, hypochondroplasia, and dysplasia. Petition 870250079895, dated 05 / 09 / 2025, page 110 / 354 101 / 309 thanatophoric.

[00294] Obesity is defined as a body mass index (BMI) greater than 30. Therefore, a reduction in obesity may be a reduction in BMI. The individual may have a BMI greater than 30 at the start of administration, for example, a BMI greater than 30, 32, 35, 38, or 40 before administration. In certain modalities, the individual has a BMI of 25 to 30 before administration, for example, greater than 26, 27, 28, or 29. Modalities related to hand length

[00295] Hand deformities are a feature of achondroplasia and include short fingers, trident deformity, and inability to fully extend the fingers.

[00296] The invention provides an FGFR3 signaling inhibitor or an NPR-B agonist, for use in promoting hand length or finger length growth in a human individual under 18 years of age or whose bony epiphyses are not closed.

[00297] The invention provides an FGFR3 signaling inhibitor or an NPR-B agonist, for use in correcting a hand deformity in a human individual under 18 years of age or whose bone epiphysis has not closed.

[00298] The invention provides an FGFR3 signaling inhibitor or an NPR-B agonist, for use in accordance with the invention or in accordance with any of the claims, wherein the use increases hand length growth or finger length growth in a human individual, such as a human individual under 18 years of age or whose bony epiphyses have not closed.

[00299] The invention provides a method for increasing the rate of hand or finger lengthening in an individual in need of Petition 870250079895, dated 05 / 09 / 2025, page 111 / 354 102 / 309 treatment, the said method comprising administering a therapeutically effective amount of an FGFR3 signaling inhibitor, or an NPR-B agonist to said individual.

[00300] Appropriately, the method of the invention may comprise the steps of (i) assessing the hand length or finger length(s) in the individual in need of treatment, and (ii) administering a therapeutically effective amount of an FGFR3 signaling inhibitor, or an NPR-B agonist, to the individual, and (iii) optionally measuring the increase in hand length or finger length(s) after said administration.

[00301] The invention provides a method for correcting hand deformity in an individual in need of treatment, said method comprising administering a therapeutically effective amount of an FGFR3 signaling inhibitor, or an NPRB agonist to said individual.

[00302] Appropriately, the method of the invention may comprise the steps of (i) assessing hand deformity in the individual in need of treatment and (ii) administering a therapeutically effective amount of an FGFR3 signaling inhibitor or an NPR-B agonist to the individual and (iii) optionally assessing the change in hand deformity in the individual after said administration. Methods that encompass evaluation stages.

[00303] In certain embodiments, the invention provides methods for improving muscle function in an individual suffering from a disease or condition in which muscle function is impaired. The methods include assessing muscle function at least once in the individual suffering from a disease or condition in which muscle function is impaired and administering a therapeutically effective amount or regimen of an FGFR3 signaling inhibitor, an NPR-B agonist, or an NPR-C agonist to the individual. Petition 870250079895, dated 05 / 09 / 2025, page 112 / 354 103 / 309

[00304] This can be described as a method for improving muscle function in an individual suffering from a disease or condition in which muscle function is impaired, the method comprising: (i) Assess muscle function at least once in an individual suffering from a disease or condition in which muscle function is impaired, and (ii) administer a therapeutically effective amount of an FGFR3 signaling inhibitor, an NPR-B agonist, or an NPR-C agonist to the individual.

[00305] The assessment step can be performed before the administration step, for example, to determine a baseline value or to determine muscle function before the start of administration. This can be useful, for example, for comparison with subsequent values ​​or for determining muscle function, which can be assessed after administration. For example, in this case, the assessment step can be performed, for example, up to one week, one month, or three months before the start of administration. The pre-administration assessment step can be used as a comparison, for example, to determine the effectiveness of the treatment. The administration step can be initiated in response to the assessment step.

[00306] The administration phase will generally comprise the administration of the FGFR3 signaling inhibitor, NPR-B agonist, or NPR-C agonist multiple times. Muscle function assessment may also be performed at least twice or multiple times. Optionally, it is performed once or at least once before the start of the administration phase (e.g., to determine a baseline) and once or at least once after the start of the administration phase. The assessment phase may also be performed at least three times, once or at least once before the Petition 870250079895, dated 05 / 09 / 2025, page 113 / 354 104 / 309 beginning of the administration phase (for example, to determine a baseline) and two or at least two times after the beginning of the administration phase.

[00307] It can be informative to compare muscle function determined before starting the administration phase with muscle function determined after the start of the administration phase, or to compare successive determinations of muscle function, or to use regular determinations of muscle function, for example, to observe trends in muscle function, for example, in response to treatment. This can be used to determine treatment outcomes or to inform modifications to a treatment protocol.

[00308] Assessment of muscle function prior to administration may also be used, optionally in combination with other signs or symptoms of an individual, to diagnose an individual as having a disease or condition in which muscle function is impaired. The methods mentioned here may therefore additionally include diagnosing the individual as having impaired muscle function and / or a disease or condition in which muscle function is impaired. Administration may be initiated in response to the assessment step and / or diagnosis of the disease or condition in the individual. Administration may also be initiated in response to the assessment of impaired muscle function relative to reference values, for example, which may be obtained through assessment performed on normal or control individuals (e.g., individuals who do not suffer from a disease or condition in which muscle function is impaired).

[00309] An assessment step may be performed additionally or alternatively after the start of administration, for example, between successive doses of the drug. The assessment step performed after the start of administration may be performed once or several times. A Petition 870250079895, dated 05 / 09 / 2025, page 114 / 354 The assessment phase (105 / 309) can be performed at least 4, 5, 6, 7, 8, 9, or 10 times, for example, weekly, monthly, or annually, at regular intervals. The assessment phase can be performed throughout the duration of the treatment.

[00310] The assessment of muscle function may include a) skeletal muscle strength, b) skeletal muscle tone, c) skeletal muscle endurance, d) skeletal muscle mass, e) skeletal muscle fatigue, f) cardiovascular endurance, g) cardiovascular fitness, h) exercise intolerance, i) exercise capacity, j) exercise-induced fatigue, k) hypotonia, l) skeletal muscle mass and / or muscle-to-fat ratio (as skeletal muscle-to-fat ratio), m) musculoskeletal pain, n) posture or curvature of the spine, optionally kyphosis, lordosis, spinal stenosis or scoliosis, o) sleep apnea, obstructive sleep apnea, otitis media or p) obesity.

[00311] Such assessments include those described elsewhere. Examples include measurements of muscle weight, muscle length, muscle density, muscle size and / or volume. Assessments may include images of the individual and observation of their performance. Assessments may be with or without quantitative metrics in physical tests, such as muscle fatigue and cardiovascular tests, or by biochemical assays in muscle biopsy or for muscle metabolism products released into body fluids.

[00312] The assessment may include imaging, for example, at least one imaging step (such as X-ray examination, spine radiography, computed tomography or magnetic resonance imaging).

[00313] Evaluation may involve determining a metric of an individual's performance, which may be, for example, a measurement or observation of the individual's ability to perform certain tasks, for example, with reference to functional tests. Petition 870250079895, dated 05 / 09 / 2025, page 115 / 354 106 / 309 physical training, such as those described elsewhere (for example, to determine muscle fatigue and endurance levels, such as sit-to-stand tests and six-minute walk tests).

[00314] If more than one assessment is carried out, a composite index may be generated. In certain modalities, a composite index is generated for at least 2, 3, 4, 5, 6, 7 (or 1-6, 2-5, 3-4) of the assessments carried out, for example, for at least 2, 3, 4, 5, 6, 7 (or 1-6, 2-5, 3-4) of the assessments a) ap) set out above. If a composite index is generated, it may form the basis of any comparisons mentioned elsewhere.

[00315] An improvement in muscle function can be any improvement in muscle function as defined elsewhere.

[00316] In some methods, an assessment step is performed at least once before starting the administration step, for example, to determine a baseline value or determination of muscle function, and one, two or more times after starting administration, for example, to allow the determination of changes in muscle function responsive to administration.

[00317] Comparing muscle function values ​​before and after administration may indicate increased muscle function, unchanged muscle function, or decreased muscle function. Increased muscle function after the start of administration and response to treatment may be an indicator of a positive treatment response, i.e., that the treatment was successful.

[00318] In some modalities, an increase in muscle function or progressive increases with additional dosage, or an increase in muscle function when muscle function was declining in the individual before treatment or shows decline in historical control individuals are indicators of a positive response to treatment.

[00319] The finding of unchanged or decreased muscle function Petition 870250079895, dated 05 / 09 / 2025, page 116 / 354 A 107 / 309 ratio may indicate a positive response to treatment or the need for a change in the treatment protocol (e.g., increased dosage and / or frequency), depending on the specific condition and the expected outcome. For example, if muscle function was impaired but stable in an individual before starting drug administration, unchanged or decreased muscle function after drug administration may be a negative indicator of treatment response. However, if muscle function was impaired and declining in an individual before starting drug administration, unchanged muscle function after drug administration and the response to its administration may indicate a positive treatment response.Similarly, even a decrease in muscle function after the start of drug administration that is less than expected, based on the individual's decline before the start of administration or on untreated historical control subjects, may indicate a positive response to treatment. A decrease in muscle function beyond any expectation, based on the individual's decline before the start of drug administration or on untreated historical control subjects, may indicate a negative response to drug administration. Expectations may depend on comparison with control values ​​determined in the same individual before starting drug administration, reference subjects, or normal and / or control subjects.

[00320] The assessment of changes in muscle function in response to administration can be used to guide treatment decisions regarding whether to continue administering the drug, modify the regimen (e.g., change dosage or frequency), or discontinue administration. For example, if the assessment indicates a positive response to administration, the same treatment may continue to be administered, for example, under the same regimen. A Petition 870250079895, dated 05 / 09 / 2025, p. 117 / 354 108 / 309 Dosage and / or frequency variations, either upwards or downwards, may also be considered, depending on the magnitude of the response and any side effects the individual is experiencing. For example, an increased dose and / or frequency may be administered to increase the response, or a decreased dose and / or frequency to reduce any side effects. If the assessment indicates a negative response to treatment (or no positive response to treatment) and the individual is tolerating the administered drug without unacceptable side effects, a higher dose or frequency of the same drug may be administered to attempt to obtain a positive response to treatment. If the assessment continues to indicate a negative response to treatment (or no positive response to treatment) or the individual does not tolerate a higher dose or frequency due to side effects, administration of the drug may be discontinued.

[00321] An evaluation step may follow any of the treatment methods mentioned. For example, the invention provides the method according to any of Items 34 to 114.

[00322] Methods related to the treatment or prevention of a disease or condition associated with impaired neuromuscular function, such as a neurodegenerative disease in an individual, may also incorporate assessment steps related to determining muscle function (e.g., skeletal muscle function, as mentioned above). Alternatively or additionally, such methods may incorporate assessment steps related to determining mitochondrial dysfunction, neuromuscular function, for example, to establish whether treatment results in a slowing, delay, or reduction in disease progression, such as a reduced rate of muscle function loss or decline, or a reduced rate of neuromuscular function loss or decline. Petition 870250079895, dated 05 / 09 / 2025, page 118 / 354 109 / 309 Combination with growth hormone

[00323] Human growth hormone is approved for the pediatric treatment of achondroplasia in Japan, and combined treatment with CNP is under clinical investigation. Combined treatment with growth hormone in the methods and uses of the present invention is expected to be advantageous.

[00324] In some embodiments, growth hormone is or comprises somatropin or is a somatropin conjugate, such as a PEGylated somatropin, or a fatty acid growth hormone conjugate.

[00325] In some embodiments, growth hormone is a growth hormone conjugate, such as a human growth hormone conjugate. The conjugate portion may, for example, comprise a PEG portion, a fatty acid portion, a serum albumin-binding portion, an antibody portion, or an antibody fragment portion.

[00326] In some embodiments, growth hormone is a long-acting growth hormone, such as a growth hormone for weekly administration. For example, long-acting growth hormone may be administered weekly or less frequently than weekly.

[00327] Correct, the growth hormone may be a controlled-release hGH. Long-acting human growth hormone and controlled-release hGH are described in document WO 2018 / 060314 A1, which is incorporated herein by reference in its entirety.

[00328] In some modalities, the growth hormone is lonapegsomatropin (lonapegsomatropin-tcgd). In some modalities, the growth hormone conjugate, such as human growth hormone conjugate, human growth hormone Petition 870250079895, dated 05 / 09 / 2025, page 119 / 354 Long-acting or controlled-release hGH, such as lonapegsomatropin, is administered to an individual at a dose ranging from about 0.021 mg / kg / week to about 0.7 mg / kg / week, as in or about 0.21 mg / kg / week (mg / kg refers to the mass of growth hormone polypeptide without the conjugated portion administered per week).

[00329] In some embodiments, the growth hormone is selected from the group consisting of somapacitan or somapacitanbeco (marketed as SOGROYA® Novo Nordisk), somatrogon (marketed as NGENLA™ by (Pfizer / OPKO), eftansomatropin alfa (also known as eftansomatropin), efpegsomatropin, albusomatropin, somavaratan, ibutamoren and lonapegsomatropin-tcgd. Exemplary Administration Protocol for CNP Medications, such as medications comprising Conjugated CNP, such as Formula CNP (IIf ') or Formula (IIf) or Compound (1)

[00330] Before subcutaneous administration to a patient in need, the solid unit dosage form is reconstituted. Reconstitution of the solid unit dosage form into a reconstituted formulation is done by adding a predefined amount of reconstitution solution to the solid unit dosage form. Therefore, a further aspect of the present invention is a method of reconstituting the solid unit dosage form of the present invention, wherein the method comprises the step of (a) contacting the solid unit dosage form of the present invention with a reconstitution solution.

[00331] Reconstitution may occur in the container in which the solid unit dose form is supplied, such as in a vial for injection; syringe, such as a double-chamber syringe; ampoule; cartridge, such as a double-chamber cartridge; or the unit dose form. Petition 870250079895, dated 05 / 09 / 2025, page 120 / 354 111 / 309 solid can be transferred to a different container, where it is then reconstituted. In certain embodiments, the container in which the reconstitution of the solid unit dose form occurs is a vial for injection. In certain embodiments, the container in which the reconstitution of the solid unit dose form occurs is a syringe. In certain embodiments, the container in which the reconstitution of the solid unit dose form occurs is a double-chamber syringe. In certain embodiments, the container in which the reconstitution of the solid unit dose form occurs is a cartridge. In certain embodiments, the container in which the reconstitution of the solid unit dose form occurs is a double-chamber cartridge.

[00332] In certain embodiments, the solid unit dosage form according to the present invention is provided in a first chamber of the double-chamber syringe and the reconstitution solution is provided in a second chamber of the double-chamber syringe.

[00333] The reconstitution solution is a sterile liquid, such as water or buffer, which may contain other additives, such as preservatives and / or antimicrobials.

[00334] In certain embodiments, the reconstituted solution comprises one or more preservatives and / or antimicrobials and / or antioxidants.

[00335] In certain embodiments, the reconstituted solution comprises one or more preservatives.

[00336] The preservative may be selected from the group consisting of m-cresol, benzoic acid, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, potassium sorbate, chlorobutanol, benzyl alcohol, phenylmercuric nitrate, thimerosal, sorbic acid, potassium sorbate, chlorocresol, benzalkonium chloride, 2-ethoxyethanol, chlorhexidine, chlorobutanol, phenylethyl alcohol, phenylmercuric acetate and mixtures thereof.

[00337] In certain forms, the preservative is m-cresol. In cer Petition 870250079895, dated 05 / 09 / 2025, page 121 / 354 112 / 309 In certain embodiments, the preservative is benzyl alcohol. In certain embodiments, the preservative is benzoic acid. In certain embodiments, the preservative is phenol. In certain embodiments, the preservative is methylparaben. In certain embodiments, the preservative is ethylparaben. In certain embodiments, the preservative is propylparaben. In certain embodiments, the preservative is butylparaben. In certain embodiments, the preservative is potassium sorbate. In certain embodiments, the preservative is benzyl alcohol. In certain embodiments, the preservative is phenylmercuric nitrate. In certain embodiments, the preservative is thimerosal. In certain embodiments, the preservative is sorbic acid. In certain embodiments, the preservative is potassium sorbate. In certain embodiments, the preservative is chlorocresol. In certain embodiments, the preservative is benzalkonium chloride. In certain embodiments, the preservative is 2-ethoxyethanol. In certain formulations, the preservative is chlorhexidine. In certain formulations, the preservative is chlorobutanol.In certain forms, the preservative is phenylethyl alcohol. In certain forms, the preservative is phenylmercuric acetate.

[00338] In certain embodiments, the preservative has a concentration ranging from 1 to 10 mg / ml. In certain embodiments, the preservative has a concentration ranging from 1.5 to 3.5 mg / ml. In certain embodiments, the preservative has a concentration ranging from 2 to 3 mg / ml.

[00339] The antioxidant may be selected from the group consisting of methionine, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, propyl gallate, ascorbic acid, ethylenediaminetetraacetic acid (EDTA), poly(ethyleneimine), vitamin E and mixtures thereof.

[00340] In certain embodiments, the preservative is methionine. In certain embodiments, the preservative is butylated hydroxytoluene. In certain embodiments, the preservative is butylated hydroxyanisole. In certain embodiments, the preservative is tocopherol. In certain embodiments, the preservative Petition 870250079895, dated 05 / 09 / 2025, p. 122 / 354 113 / 309 is propyl gallate. In certain embodiments, the preservative is ethylenediaminetetraacetic acid. In certain embodiments, the preservative is poly(ethyleneimine). In certain embodiments, the preservative is vitamin E.

[00341] As defined herein, the term “methionine” encompasses both D-methionine and L-methionine, and mixtures thereof. In certain embodiments, the term “methionine” refers to L-methionine. In certain embodiments, the term “methionine” refers to D-methionine. In certain embodiments, the term “methionine” refers to a mixture of D-methionine or L-methionine. In certain embodiments, the term “methionine” refers to the hydrochloride salt of L-methionine.

[00342] As defined herein, the term “EDTA” encompasses all forms of EDTA known in the art, such as EDTA salts, including metallic EDTA salts, such as disodium EDTA salt, dipotassium EDTA salt, calcium EDTA salt, dimagnesium EDTA salt, or mixtures thereof. In certain embodiments, EDTA refers to the disodium salt of EDTA. In certain embodiments, the term “EDTA” refers to the dicalcium salt of EDTA. In certain embodiments, the term “EDTA” refers to anhydrous EDTA.

[00343] In certain embodiments, the molar ratio of antioxidant to CNP portion varies from about 0.1:1 to about 100:1. In certain embodiments, the molar ratio of antioxidant to CNP portion varies from about 0.1:1 to about 70:1. In certain embodiments, the molar ratio of antioxidant to CNP portion varies from about 0.1:1 to about 15:1. In certain embodiments, the molar ratio of antioxidant to CNP portion varies from about 1:1 to about 10:1. In certain embodiments, the molar ratio of antioxidant to CNP portion varies from about 3:1 to about 7:1.

[00344] In certain embodiments, the reconstituted solution does not contain an antimicrobial. In certain embodiments, the reconstituted solution comprises one or more excipients. Petition 870250079895, dated 05 / 09 / 2025, p. 123 / 354 114 / 309

[00345] In certain embodiments, the reconstitution solution is sterile water. In certain embodiments, the reconstitution solution is sterile water containing 0.7% to 1.1% benzyl alcohol. In certain embodiments, the reconstitution solution is sterile water containing 0.9% benzyl alcohol.

[00346] In certain embodiments, the reconstituted solution comprises a pH modifying agent.

[00347] As used herein, the term “pH modifying agent” refers to a chemical compound that is used to modify the pH of the reconstitution solution.

[00348] In certain embodiments, the pH modifying agent may be an acid or an acid salt thereof. The acid may be selected from the group consisting of acetic acid, citric acid, succinic acid, hydrochloric acid, phosphoric acid, carbonic acid, nitric acid and mixtures thereof.

[00349] In certain embodiments, the pH modifying agent may be a base or a basic salt thereof. The base may be selected from the group consisting of Tris(tris(hydroxymethyl)aminomethane), sodium hydroxide, potassium hydroxide, lysine, and mixtures thereof.

[00350] In certain embodiments, the volume of the reconstitution solution varies from about 0.1 ml to about 4 ml. In certain embodiments, the volume of the reconstitution solution is about 1 ml, about 2 ml, about 3 ml, or about 4 ml.

[00351] In certain embodiments, the volume of the reconstitution solution is approximately 0.79 ml. In certain embodiments, the volume of the reconstitution solution is approximately 1.1 ml. In certain embodiments, the volume of the reconstitution solution is approximately 1 ml. In certain embodiments, the volume of the reconstitution solution is approximately 1.25 ml. In certain embodiments, the volume of the reconstitution solution Petition 870250079895, dated 05 / 09 / 2025, page 124 / 354 115 / 309 The concentration is approximately 1.25 ml.

[00352] It is understood that the unit dose volume or injection volume is based on the patient's actual body weight and the concentration of the reconstituted solution. In certain embodiments, the concentration of CNP in the reconstituted solution is not greater than 7 mg / ml. In certain embodiments, the concentration of CNP in the reconstituted solution is not less than 0.5 mg / ml. In certain embodiments, the concentration of CNP in the reconstituted solution is 0.75 mg / ml. In certain embodiments, the concentration of CNP in the reconstituted solution is 1 mg / ml. In certain embodiments, the concentration of CNP in the reconstituted solution is 2.2 mg / ml. In certain embodiments, the concentration of CNP in the reconstituted solution is 3.6 mg / ml. In certain embodiments, the concentration of CNP in the reconstituted solution is 4.6 mg / ml. In certain embodiments, the concentration of CNP in the reconstituted solution is 5 mg / ml. In certain formulations, the concentration of CNP in the reconstituted solution is 5.5 mg / ml.

[00353] After reconstitution, a single dose has a volume not exceeding 4 ml. In certain embodiments, the volume of the unit dose varies from about 0.01 ml to about 1.1 ml. In certain embodiments, the volume of the single dose varies from 0.01 ml to 0.75 ml. In certain embodiments, the volume of the single dose varies from 0.01 ml to 0.50 ml.

[00354] In certain embodiments, the volume of a single dose is approximately 0.03 ml. In certain embodiments, the volume of a single dose is approximately 0.05 ml. In certain embodiments, the volume of a unit dose is approximately 0.1 ml. In certain embodiments, the volume of a unit dose is approximately 0.2 ml. In certain embodiments, the volume of a unit dose is approximately 0.25 ml. In certain embodiments, the volume of a unit dose is approximately 0.3 ml. In certain embodiments, the volume of a single dose is approximately 0.35 ml. In certain embodiments, the volume of a unit dose is approximately 0.4 ml. In certain embodiments, the Petition 870250079895, dated 05 / 09 / 2025, page 125 / 354 116 / 309 The unit dose volume is approximately 0.5 ml. In certain embodiments, the unit dose volume is approximately 0.6 ml. In certain embodiments, the unit dose volume is approximately 0.75 ml. In certain embodiments, the unit dose volume is approximately 1 ml.

[00355] In certain modalities, the patient is an infant and the unit dose volume varies from approximately 10 pl to 100 pl. In certain modalities, the patient is an infant and the unit dose volume varies from approximately 10 pl to 50 pl. In certain modalities, the patient is an infant and the unit dose volume varies from approximately 10 pl to 30 pl.

[00356] In certain modalities, the patient is an infant and the unit dose volume is approximately 10 pl. In certain modalities, the patient is an infant and the unit dose volume is approximately 15 pl. In certain modalities, the patient is an infant and the unit dose volume is approximately 20 pl.

[00357] In certain modalities, the patient is an infant and the unit dose volume is 10 pl. In certain modalities, the patient is an infant and the unit dose volume is 15 pl. In certain modalities, the patient is an infant and the unit dose volume is 20 pl.

[00358] In certain embodiments, the patient is an infant, the unit dose is 20 pg of CNP / kg and the unit dose volume is approximately 10 pl. In certain embodiments, the patient is an infant, the unit dose is 20 pg of CNP / kg and the unit dose volume is approximately 15 pl. In certain embodiments, the patient is an infant, the unit dose is 20 pg of CNP / kg and the unit dose volume is approximately 20 pl.

[00359] In certain embodiments, the unit dose is 6 pg of CNP / kg and the unit dose volume is 0.06 ml. In certain embodiments, the unit dose is 20 pg of CNP / kg and the unit dose volume is 0.3 ml of CNP / kg and the unit dose volume is 0.4 ml. In certain embodiments, the unit dose is 100 pg of CNP / kg and the unit dose volume is Petition 870250079895, dated 05 / 09 / 2025, page 126 / 354 117 / 309 0.5 ml. In certain formulations, the unit dose is 150 pg of CNP / kg and the unit dose volume is 0.5 ml.

[00360] In certain embodiments, the pH of the liquid unit dosage form ranges from approximately 4 to approximately 6. In certain embodiments, the pH of the liquid unit dosage form ranges from approximately 4.5 to approximately 5.5. In certain embodiments, the pH of the liquid unit dosage form ranges from approximately 5.

[00361] In certain embodiments, the unit dosage form of the present invention further comprises a buffering agent, an isotonicity agent and a pH modifying agent.

[00362] In certain embodiments, the buffering agent has a concentration ranging from 1.3 to 57.6 mM in unit dosage form. In certain embodiments, the buffering agent has a concentration ranging from 1.7 to 33 mM in unit dosage form. In certain embodiments, the buffering agent has a concentration ranging from 5.1 to 20.3 mM in unit dosage form. In certain embodiments, the buffering agent has a concentration of approximately 10 mM in unit dosage form.

[00363] Exemplary buffering agents may be selected from the group consisting of succinic acid, citric acid, lactic acid, acetic acid, glutamic acid, fumaric acid, aspartic acid, glutaric acid, phosphoric acid, histidine, gluconic acid, tartaric acid, malic acid, and mixtures thereof. It is evident to those skilled in the art that the corresponding bases or conjugate salts of the buffering agents, such as succinate, citrate, lactate, acetate, glutamate, fumarate, aspartate, glutarate, phosphate, gluconate, tartrate, malate, and mixtures thereof, respectively, may also be included.

[00364] In certain embodiments, the buffering agent is the acid Petition 870250079895, dated 05 / 09 / 2025, page 127 / 354 118 / 309 succinic acid. In certain embodiments, the buffering agent is citric acid. In certain embodiments, the buffering agent is lactic acid. In certain embodiments, the buffering agent is acetic acid. In certain embodiments, the buffering agent is glutamic acid. In certain embodiments, the buffering agent is fumaric acid. In certain embodiments, the buffering agent is aspartic acid. In certain embodiments, the buffering agent is glutaric acid. In certain embodiments, the buffering agent is phosphoric acid. In certain embodiments, the buffering agent is histidine. In certain embodiments, the buffering agent is gluconic acid. In certain embodiments, the buffering agent is tartaric acid. In certain embodiments, the buffering agent is malic acid.

[00365] The isotonic agent may be selected from the group consisting of trehalose, mannitol, sucrose, raffinose, gelatin, lactose, dibasic calcium phosphate, sorbitol, xylitol, glycine, histidine, hydroxyethyl starch, dextrose, dextran, Ficoll®, propylene glycol and mixtures thereof.

[00366] In certain embodiments, the isotonic agent may be selected from the group consisting of trehalose, mannitol, sucrose, raffinose, gelatin, lactose, dibasic calcium phosphate, sorbitol, xylitol, glycine, histidine, hydroxyethyl starch, dextrose, dextran, propylene glycol and mixtures thereof.

[00367] In certain embodiments, the isotonic agent is selected from the group consisting of trehalose, sucrose, and glycine. In certain embodiments, the isotonic agent is a non-reducing sugar, such as trehalose or sucrose.

[00368] In certain embodiments, the isotonic agent is trehalose.

[00369] As defined herein, the term “trehalose” encompasses all salts and hydration states of trehalose, such as anhydrous trehalose or trehalose dihydrate. In certain embodiments, the term “trehalose” refers to Petition 870250079895, dated 05 / 09 / 2025, page 128 / 354 119 / 309 to anhydrous trehalose. In certain embodiments, the term "trehalose" refers to trehalose dihydrate.

[00370] In certain embodiments, the unit dosage form comprises succinic acid and trehalose.

[00371] In certain embodiments, the unit dosage form comprises CNP conjugate succinic acid trehalose dihydrate 0.9 - 82.1 mg / ml 1.3 - 57.6 mM - 111.6 mg / ml, and has a pH ranging from pH 4.0 to pH 6.0.

[00372] In certain embodiments, the unit dosage form includes: comConjugated CNP succinic acid trehalose dihydrate 19.8 - 73.6 mg / ml 1.7 - 50 mM - 100 mg / ml has a pH ranging from pH 4.0 to pH 6.0.

[00373] In certain embodiments, the unit dosage form includes: comConjugated CNP succinic acid trehalose dihydrate 27.5 - 50.5 mg / ml 5.1 - 20.3 mM - 95 mg / ml has a pH ranging from pH 4.0 to pH 6.0.

[00374] In certain embodiments, the unit dosage form comprises about 8.2 mg / ml of CNP conjugate, about 10 mM of succinic acid, about 89 mg / ml of trehalose dihydrate and optionally Tris and / or hydrochloric acid and has a pH of about 5.

[00375] In certain embodiments, the unit dosage form comprises 8.2 mg / ml of CNP conjugate, 10 mM of succinic acid, 89 mg / ml of trehalose dihydrate and optionally Tris and / or hydrochloric acid and has a pH of 5. Petition 870250079895, dated 05 / 09 / 2025, page 129 / 354 120 / 309

[00376] In certain embodiments, the unit dosage form comprises about 11 mg / ml of CNP conjugate, about 10 mM of succinic acid, about 88.5 mg / ml of trehalose dihydrate and optionally Tris and / or hydrochloric acid and has a pH of about 5.

[00377] In certain embodiments, the unit dosage form comprises 11 mg / ml of CNP conjugate, 10 mM of succinic acid, 88.5 mg / ml of trehalose dihydrate and optionally Tris and / or hydrochloric acid and has a pH of 5.

[00378] In certain embodiments, the unit dosage form comprises about 24.2 mg / ml of CNP conjugate, about 10 mM of succinic acid, about 85 mg / ml of trehalose dihydrate and optionally Tris and / or hydrochloric acid and has a pH of about 5.

[00379] In certain embodiments, the unit dosage form comprises 24.2 mg / ml of CNP conjugate, 10 mM of succinic acid, 85 mg / ml of trehalose dihydrate and optionally Tris and / or hydrochloric acid and has a pH of 5.

[00380] In certain embodiments, the unit dosage form comprises about 39.6 mg / ml of CNP conjugate, about 10 mM of succinic acid, about 80 mg / ml of trehalose dihydrate and optionally Tris and / or hydrochloric acid and has a pH of about 5.

[00381] In certain embodiments, the unit dosage form comprises 39.6 mg / ml of CNP conjugate, 10 mM of succinic acid, 80 mg / ml of trehalose dihydrate and optionally Tris and / or hydrochloric acid and has a pH of 5.

[00382] In certain embodiments, the unit dosage form comprises about 50.5 mg / ml of CNP conjugate, about 10 mM of succinic acid, about 77 mg / ml of trehalose dihydrate and optionally Tris and / or hydrochloric acid and has a pH of about 5.

[00383] In certain embodiments, the unit dosage form comprises 50.5 mg / ml of CNP conjugate, 10 mM of succinic acid, 77 Petition 870250079895, dated 05 / 09 / 2025, p. 130 / 354 121 / 309 mg / ml of trehalose dihydrate and optionally Tris and / or hydrochloric acid and has a pH of 5.

[00384] In certain embodiments, the unit dosage form comprises about 54.9 mg / ml of CNP conjugate, about 10 mM of succinic acid, about 75 mg / ml of trehalose dihydrate and optionally Tris and / or hydrochloric acid and has a pH of about 5.

[00385] In certain embodiments, the unit dosage form comprises 54.9 mg / ml of CNP conjugate, 10 mM succinic acid, 75 mg / ml trehalose dihydrate and optionally Tris and / or hydrochloric acid and has a pH of about 5.

[00386] In certain embodiments, the unit dosage form comprises about 60.4 mg / ml of CNP conjugate, about 10 mM of succinic acid, about 73 mg / ml of trehalose dihydrate and optionally Tris and / or hydrochloric acid and has a pH of about 5.

[00387] In certain embodiments, the unit dosage form comprises 60.4 mg / ml of CNP conjugate, 10 mM of succinic acid, 73 mg / ml of trehalose dihydrate and optionally Tris and / or hydrochloric acid and has a pH of 5.

[00388] In certain embodiments, the unit dosage form comprises, based on the total weight of the solid unit dosage form: CNP conjugate succinic acid trehalose dihydrate Tris 8.2 - 44.4% (w / w) 0.9 - 1.2% (w / w) 53.7 - 89.1 % (w / w) 1.0 - 1.5 % (w / w).

[00389] In certain embodiments, the unit dosage form comprises, based on the total weight of the solid unit dosage form, approximately 8.2% (w / w) of CNP conjugate, approximately 1.2% (w / w) of succinic acid, approximately 89.1% (w / w) of trehalose dihydrate and approximately 1.5% (w / w) of Tris.

[00390] In certain embodiments, the unit dosage form with Petition 870250079895, dated 05 / 09 / 2025, pp. 131 / 354 122 / 309 comprises, based on the total weight of the solid unit dosage form, 8.2% (w / w) CNP conjugate, 1.2% (w / w) succinic acid, 89.1% (w / w) trehalose dihydrate and 1.5% (w / w) Tris.

[00391] In certain embodiments, the unit dosage form comprises, based on the total weight of the solid unit dosage form, approximately 10.7% (w / w) of CNP conjugate, approximately 1.2% (w / w) of succinic acid, approximately 86.8% (w / w) of trehalose dihydrate and approximately 1.3% (w / w) of Tris.

[00392] In certain embodiments, the unit dosage form comprises, based on the total weight of the solid unit dosage form, 10.7% (w / w) CNP conjugate, 1.2% (w / w) succinic acid, 86.8% (w / w) trehalose dihydrate and 1.3% (w / w) Tris.

[00393] In certain embodiments, the unit dosage form comprises, based on the total weight of the solid unit dosage form, approximately 21.6% (w / w) of CNP conjugate, approximately 1.1% (w / w) of succinic acid, approximately 76.1% (w / w) of trehalose dihydrate and approximately 1.2% (w / w) of Tris.

[00394] In certain embodiments, the unit dosage form comprises, based on the total weight of the solid unit dosage form, 21.6% (w / w) CNP conjugate, 1.1% (w / w) succinic acid, 76.1% (w / w) trehalose dihydrate and 1.2% (w / w) Tris.

[00395] In certain embodiments, the unit dosage form comprises, based on the total weight of the solid unit dosage form, approximately 32.4% (w / w) of CNP conjugate, approximately 1.0% (w / w) of succinic acid, approximately 65.4% (w / w) of trehalose dihydrate and approximately 1.2% (w / w) of Tris.

[00396] In certain embodiments, the unit dosage form comprises, based on the total weight of the solid unit dosage form, 32.4% (w / w) CNP conjugate, 1.0% (w / w) succinic acid, 65.4% (w / w) trehalose dihydrate and 1.2% (w / w) Tris. Petition 870250079895, dated 05 / 09 / 2025, p. 132 / 354 123 / 309

[00397] In certain embodiments, the unit dosage form comprises, based on the total weight of the solid unit dosage form, approximately 38.9% (w / w) of CNP conjugate, approximately 0.9% (w / w) of succinic acid, approximately 59.2% (w / w) of trehalose dihydrate and approximately 1% (w / w) of Tris.

[00398] In certain embodiments, the unit dosage form comprises, based on the total weight of the solid unit dosage form, 38.9% (w / w) CNP conjugate, 0.9% (w / w) succinic acid, 59.2% (w / w) trehalose dihydrate and 1% (w / w) Tris.

[00399] In certain embodiments, the unit dosage form comprises, based on the total weight of the solid unit dosage form, approximately 41.5% (w / w) of CNP conjugate, approximately 0.9% (w / w) of succinic acid, approximately 56.6% (w / w) of trehalose dihydrate and approximately 1% (w / w) of Tris.

[00400] In certain embodiments, the unit dosage form comprises, based on the total weight of the solid unit dosage form, 41.5% (w / w) CNP conjugate, 0.9% (w / w) succinic acid, 56.6% (w / w) trehalose dihydrate and 1% (w / w) Tris.

[00401] In certain embodiments, the unit dosage form comprises, based on the total weight of the solid unit dosage form, approximately 44.4% (w / w) of CNP conjugate, approximately 0.9% (w / w) of succinic acid, approximately 53.7% (w / w) of trehalose dihydrate and approximately 1% (w / w) of Tris.

[00402] In certain embodiments, the unit dosage form comprises, based on the total weight of the solid unit dosage form, 44.4% (w / w) CNP conjugate, 0.9% (w / w) succinic acid, 53.7% (w / w) trehalose dihydrate and 1% (w / w) Tris.

[00403] It was surprisingly discovered that, after administering to a patient in need of the unit dosage form of the CNP conjugate, as a compound of formula (IIf') or formula (IIf) or Petition 870250079895, dated 05 / 09 / 2025, pp. 133 / 354 124 / 309 compound (1), the incidence of hypotension is less than 10%, preferably less than 8%, more preferably less than 5%, and even more preferably less than 3%. In certain embodiments, after administration to a patient in need of the unit dosage form of the present invention, the incidence of hypotension is less than 1%. In certain embodiments, there is no incidence of hypotension.

[00404] Furthermore, surprisingly, it was found that no treatment-emergent anti-CNP antibodies were detected after treatment with CNP conjugate (CNP conjugate, as a compound of formula (IIf') or formula (IIf) or compound). In certain embodiments, no anti-CNP binding antibodies were detected after 1 to 9 months of repeated weekly exposure to the conjugate of the present invention. In certain embodiments, no anti-CNP binding antibodies were detected after 52 weeks of repeated weekly exposure to the conjugate of the present invention.

[00405] Furthermore, it was surprisingly found that administering 100 pg of CNP / kg (CNP conjugate, as a formula compound (IIf') or formula (IIf) or compound (1) per week to pediatric patients aged 2 to 10 years, as aged 2 to 5 years or as aged 5 to 10 years, who required treatment with CNP resulted in similar responses measured as annualized growth rate.

[00406] In certain embodiments, the CNP portion of the CNP conjugate has the sequence SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, or SEQ ID NO:30. In certain embodiments, the CNP portion has the sequence SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, or SEQ ID NO:25. In certain Petition 870250079895, dated 05 / 09 / 2025, pp. 134 / 354 In certain modes, the CNP portion has the sequence SEQ ID NO:20. In certain modes, the CNP portion has the sequence SEQ ID NO:21. In certain modes, the CNP portion has the sequence of SEQ ID NO:22. In certain embodiments, the CNP portion has the sequence SEQ ID NO:23. In certain embodiments, the CNP portion has the sequence SEQ ID NO:24. In certain embodiments, the CNP portion has the sequence SEQ ID NO:25. Exemplary CNP conjugates and CNP prodrugs

[00407] In certain forms, the CNP conjugate is of formula (Ia) or (Ib): (Ia), y(Ib), where - D is a CNP portion; - L1- is a reversible binding moiety; - L2- is a single chemical bond or a spacer moiety; Z is a polymeric portion; 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; ey is an integer selected from the group consisting of 1, 2, 3, 4, and 5. - D of formula (Ia) or (Ib) is covalently and reversibly conjugated to -L1-.

[00408] In certain embodiments, x of formula (Ia) is an integer selected from the group consisting of 1, 2, 3, 4, 6 and 8. In certain embodiments, x of formula (Ia) is an integer selected from the group consisting of 1, 2, 4 and 6. In certain embodiments, x of formula Petition 870250079895, dated 05 / 09 / 2025, pp. 135 / 354 126 / 309 la (Ia) is an integer selected from the group consisting of 1, 4 and 6 and in certain forms, x of formula (Ia) is 1.

[00409] In certain embodiments, y of formula (Ib) is an integer selected from the group consisting of 2, 3, 4, and 5. In certain embodiments, y of formula (Ib) is an integer selected from the group consisting of 2, 3, and 4. In certain embodiments, y of formula (Ib) is an integer selected from the group consisting of 2 and 3. In certain embodiments, y of formula (Ib) is an integer selected from the group consisting of 1, 2, and 3. In certain embodiments, y of formula (Ib) is 1. In certain embodiments, y of formula (Ib) is 2.

[00410] In certain forms, the CNP conjugate is of formula (Ia) with x = 1.

[00411] In certain embodiments, -D of formula (Ia) or (Ib) has the sequence SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQID NO:16, SEQ ID NO:17, SEQID NO:20, SEQ ID NO:21, SEQID NO:24, SEQ ID NO:25 or SEQ ID NO:14, SEQ ID NO:15, SEQID NO:18, SEQ ID NO:19, SEQID NO:22, SEQ ID NO:23, SEQID NO:30. In certain modalities, -D of formula (Ia) or (Ib) has the sequence SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24 or SEQ ID NO:25.

[00412] In certain embodiments, -D of formula (Ia) or (Ib) has the sequence SEQ ID NO:20. In certain embodiments, -D of formula (Ia) or (Ib) has the sequence SEQ ID NO:21. In certain embodiments, -D of formula (Ia) or (Ib) has the sequence SEQ ID NO:22. In certain embodiments, -D of formula (Ia) or (Ib) has the sequence SEQ ID NO:23. In certain embodiments, -D of formula (Ia) or (Ib) has the sequence SEQ ID NO:24. In certain embodiments, -D of formula (Ia) or (Ib) has the sequence SEQ ID NO:25.

[00413] In certain modalities, -D of formula (Ia) or (Ib) has the se Petition 870250079895, dated 05 / 09 / 2025, pp. 136 / 354 127 / 309 sequence of SEQ ID NO:30, SEQ ID NO:98, SEQ ID NO:99 or SEQ ID NO 90.

[00414] The -L1- portion of formula (Ia) or (Ib) is conjugated to a side-chain functional group of an amino acid residue of -D, to the N-terminal amine functional group or to the C-terminal carboxyl functional group of -D, or to a nitrogen atom in the polypeptide chain of the D main structure. The attachment to the N-terminal or C-terminal can be direct via the corresponding amine or carboxyl functional group, respectively, or indirect, wherein a spacer portion is first conjugated to the amine or carboxyl functional group to which the spacer portion -L1- is conjugated.

[00415] The -L1- portion of formula (Ia) or (Ib) is a reversible ligand from which the drug, i.e., DH, is released in its free form, i.e., -L1 is a traceless ligand. Suitable reversible ligands are known in the art, such as, for example, the reversible ligand portions described in WO 2005 / 099768 A2, WO 2006 / 136586 A2, WO 2011 / 089216 A1 and WO 2013 / 024053 A1, which are incorporated by reference herein.

[00416] In certain embodiments, -L1- is a reversible ligand as described in WO 2011 / 012722 A1, WO 2011 / 089214 A1, WO 2011 / 089215 A1, WO 2013 / 024052 A1 and WO 2013 / 160340 A1, which are incorporated by reference herein.

[00417] The -L1- portion can be connected to D by any type of linkage, provided it is reversible. In certain embodiments, -L1- is connected to -D by a linkage selected from the group consisting of amide, ester, carbamate, acetal, amino, imine, oxime, hydrazone, disulfide, and acylguanidine. In certain embodiments, -L1- is connected to D by a linkage selected from the group consisting of amide, ester, carbamate, and acylguanidine. It is understood that these connections may not be reversible on their own, but that groups Petition 870250079895, dated 05 / 09 / 2025, pp. 137 / 354 128 / 309 neighbors included in -L1- can make the connection reversible.

[00418] In certain embodiments, the -L1- portion is connected to -D via an amide linkage.

[00419] A portion -L1- is described in WO 2009 / 095479 A2.

[00420] Consequently, in certain embodiments, the -L1 portion of formula (II): THE R (II) where the dashed line indicates bonding to a nitrogen of -D which is a CNP moiety forming an amide bond; -X- is -C(R4R4a)-; -N(R4)-; -THE-; -C(R4R4a)-C(R5R5a)-; -C(R5R5a)-C(R4R4a)-; -C(R4R4a)-N(R6)-; -N(R6)-C(R4R4a)-; -C(R4R4a)-O-; -OC(R4R4a)-; or -C(R7R7a)-; X1 is C; or S(O); -X2- is -C(R8R8a)-; or -C(R8R8a)-C(R9R9a)-; =X3 is =O; =S; or =N-CN; - R1, -R1a, -R2, -R2a, -R4, -R4a, -R5, -R5a, -R6, -R8, -R8a, -R9, -R9a are independently selected from the group consisting of -H; and C1-6 alkyl; -R3, -R3a are selected independently of the group consisting of -H; and C1-6 alkyl, provided that, in the case of one of -R3, -R3a or both being different from -H, they are connected to the N to which they are attached by means of a sp3 hybridized carbon atom; - R7is -N(R10R10a); or -NR10-(C=O)-R11; - R7a, -R10, -R10a, -R11 are independently of each other -H; or C1-6 alkyl; optionally, one or more of the pairs -R1a / -R4a, -R1a / -R5a, Petition 870250079895, dated 05 / 09 / 2025, pp. 138 / 354 129 / 309 -R1a / -R7a, -R4a / -R5a, -R8a / -R9a formed a chemical bond; optionally, one or more of the pairs -R1 / -R1a, -R2 / -R2a, -R4 / -R4a, -R5 / -R5a, -R8 / -R8a, - R9 / -R9 atoms are linked together with the atom to which they are attached to form a C3-10 cycloalkyl group; or a 3-membered heterocyclyl group; optionally, one or more of the pairs -R1 / -R4, -R1 / -R5, -R1 / -R6, -R1 / -R7a, -R4 / -R5, -R4 / -R6, - R8 / -R9, -R2 / -R3 are linked together with the atoms to which they are attached to form an A-ring; Optionally, -R3 / -R3a are linked together with the nitrogen atom to which they are attached to form a heterocycle of 3 to 10 members; 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-Z and wherein -L1- is optionally also substituted, provided that the hydrogen marked with the asterisk in formula (II) is not substituted by -L2-Z or a substituent; in what - L2- is a single chemical bond or a spacer; and Z is a water-soluble polymeric moiety;

[00421] In certain embodiments, -L1- of formula (II) is replaced with a -L2-Z portion. In certain embodiments, -L1- of formula (II) is also not replaced.

[00422] It is understood that if -R3 / -R3 of formula (II) are linked 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 Petition 870250079895, dated 05 / 09 / 2025, pp. 139 / 354 130 / 309 members, in which the atoms directly bonded to nitrogen are sp3 hybridized carbon atoms, could be formed. In other words, such a 3 to 10 membered heterocycle formed by -R3 / -R3a together with the nitrogen atom to which they are bonded has the following structure. where the dashed line indicates a connection to the rest of -L1-; The ring comprises 3 to 10 atoms, including at least one nitrogen atom; and R# and R## represent a carbon atom hybridized with sp3.

[00423] It is also understood that the heterocycle of 3 to 10 members can also be replaced.

[00424] Exemplary embodiments of suitable 3- to 10-membered heterocycles formed by -R3 / -R3 of formula (II) together with the nitrogen atom to which they are attached are as follows: where dashed lines indicate attachment to the rest of the molecule; and -R is selected from the group consisting of -H and C1-6 alkyl. -L1- of formula (II) may optionally be substituted as well. In general, any substituent may be used provided that the Petition 870250079895, dated 05 / 09 / 2025, pp. 140 / 354 131 / 309 cleavage principle is not affected, that is, the hydrogen marked with the asterisk in formula (II) is not substituted and the nitrogen of the portion of formula (II) remains part of a primary, secondary or tertiary amine, that is, -R3 and -R3 are independently of each other -H or are connected to -N< through a sp3 hybridized carbon atom.

[00425] In certain embodiments, -R1 or -R1 of formula (II) is replaced with -L2-Z. In certain embodiments, -R2 or -R2 of formula (II) is replaced with -L2-Z. In certain embodiments, -R3 or -R3 of formula (II) is replaced with -L2-Z. In certain embodiments, -R4 of formula (II) is replaced with -L2-Z. In certain embodiments, -R5 or -R5 of formula (II) is replaced with -L2-Z. In certain embodiments, -R6 of formula (II) is replaced with -L2-Z. In certain embodiments, -R7 or -R7 of formula (II) is replaced with -L2-Z. In certain embodiments, -R8 or -R8 of formula (II) is replaced with -L2-Z. In certain embodiments, -R9 or -R9 of formula (II) is replaced with -L2-Z.

[00426] In certain embodiments, -R4 of formula (II) is replaced with -L2-Z.

[00427] In certain forms, -X- of formula (II) is -C(R4R4a)- or -N(R4)-.

[00428] In certain forms, -X- of formula (II) is -C(R4R4a)-.

[00429] In certain modalities, X1 of formula (II) is C.

[00430] In certain modalities, =X3 of formula (II) is =O.

[00431] In certain modalities, -X2- of formula (II) is -C(R8R8a)-.

[00432] In certain embodiments, -R8e -R8ade formula (II) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R8e -R8ade formula Petition 870250079895, dated 05 / 09 / 2025, pp. 141 / 354 132 / 309 (II) is -H. In certain embodiments, both -R8 and -R8 of formula (II) are -H.

[00433] In certain embodiments, -R1 and -R1 of formula (II) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R1 and -R1 of formula (II) is -H. In certain embodiments, both -R1 and -R1 of formula (II) are -H.

[00434] In certain embodiments, -R2 and -R2 of formula (II) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R2 and -R2 of formula (II) is -H. In certain embodiments, both -R2 and -R2 of formula (II) are H.

[00435] In certain embodiments, -R3 and -R3 of formula (II) are independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, at least one of -R3 and -R3 of formula (II) is methyl. In certain embodiments, -R3 and -R3 of formula (II) are both -H. In certain embodiments, -R3 and -R3 of formula (II) are both methyl. In certain embodiments, -R3 of formula (II) is -H and -R3 of formula (II) is methyl.

[00436] In certain embodiments, -R4 and -R4 of formula (II) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R4 and -R4 of formula (II) is -H. In certain embodiments, both -R4 and -R4 of formula (II) are -H.

[00437] In certain embodiments, the portion -L1- is of formula (IIa): (IIa) where the dashed line indicates bonding to a nitrogen of -D which is a CNP moiety forming an amide bond; -R1, -R1a, -R2, -R2a, -R3, -R3a, -R4, -R4a and -X2- are used Petition 870250079895, dated 05 / 09 / 2025, pp. 142 / 354 133 / 309 as defined in formula (II); and wherein -L1- is replaced with -L2-Z and wherein -L1- is optionally also replaced, provided that the hydrogen marked with the asterisk in formula (IIa) is not replaced by -L2-Z or a substituent.

[00438] In certain embodiments, -L1- of formula (IIa) is replaced with a -L2-Z portion. In certain embodiments, the -L1- portion of formula (IIa) is also not replaced.

[00439] In certain embodiments, -R1 and -R1 of formula (IIa) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R1 and -R1 of formula (IIa) is -H. In certain embodiments, both -R1 and -R1 of formula (IIa) are -H.

[00440] In certain embodiments, -R4e -R4ade formula (IIa) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R4e -R4ade formula (IIa) is -H. In certain embodiments, both -R4e and -R4ade formula (IIa) are -H.

[00441] In certain modalities, -X2- of formula (IIa) is -C(R8R8a)-.

[00442] In certain embodiments, -R8 and -R8 of formula (IIa) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R8 and -R8 of formula (IIa) is -H. In certain embodiments, both -R8 and -R8 of formula (IIa) are -H.

[00443] In certain embodiments, -R2e -R2ade formula (IIa) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R2e -R2ade formula (IIa) is -H. In certain embodiments, both -R2e -R2ade formula (IIa) are H.

[00444] In certain embodiments, -R3e -R3ade formula (IIa) are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. In certain embodiments, at least one of -R3e Petition 870250079895, dated 05 / 09 / 2025, pp. 143 / 354 134 / 309 -R3 of formula (IIa) is methyl. In certain embodiments, -R3 and -R3 of formula (IIa) are both -H. In certain embodiments, -R3 and -R3 of formula (IIa) are both methyl. In certain embodiments, -R3 of formula (IIa) is -H and -R3 of formula (IIa) is methyl.

[00445] In certain embodiments, the portion -L1- is of formula (IIb): (Ilb) where the dashed line indicates linkage to a nitrogen of -D that is a CNP moiety forming an amide linkage; -R2, -R2a, -R3, -R3a and -X2- are used as defined in formula (II); and wherein -L1- is replaced with -L2-Z and wherein -L1- is optionally also replaced, provided that the hydrogen marked with the asterisk in formula (IIb) is not replaced by -L2-Z or a substituent.

[00446] In certain embodiments, -L1- of formula (IIb) is replaced with a -L2-Z portion. In certain embodiments, the -L1- portion of formula (IIb) is also not replaced.

[00447] In certain modalities, -X2- of formula (IIb) is -C(R8R8a)-.

[00448] In certain embodiments, -R8e -R8ade formula (IIb) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R8e -R8ade formula (IIb) is -H. In certain embodiments, both -R8 and -R8ade formula (IIb) are -H.

[00449] In certain embodiments, -R2e and -R2ade formula (IIb) are independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, at least one of -R2e and -R2ade formula (IIb) is -H. In certain embodiments, both -R2e and -R2ade formula Petition 870250079895, dated 05 / 09 / 2025, pp. 144 / 354 135 / 309 (IIb) are H.

[00450] In certain embodiments, -R3e -R3ade formula (IIb) are independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, at least one of -R3e -R3ade formula (IIb) is methyl. In certain embodiments, -R3e -R3ade formula (IIb) are both -H. In certain embodiments, -R3e -R3ade formula (IIb) are both methyl. In certain embodiments, -R3de formula (IIb) is -H and -R3ade formula (IIb) is methyl.

[00451] In certain forms, the portion -L1- is of formula (IIb'): where the dashed line indicates the bond to a nitrogen of -D that is a CNP portion forming an amide bond; The dashed line marked with an asterisk indicates a connection to -L2-; -R2, -R2a, -R3, -R3ae -X2- are used as defined in formula (II); and wherein -L1- is optionally also substituted, provided that the hydrogen marked with the asterisk in formula (IIb') is not replaced by a substituent.

[00452] In certain embodiments, the -L1- portion of formula (IIb') is also unsubstituted.

[00453] In certain modalities, -X2- of formula (IIb') is -C(R8R8a)-.

[00454] In certain embodiments, -R8e and -R8ade formula (IIb') are independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, at least one of -R8e and -R8ade formula (IIb') is -H. In certain embodiments, both -R8 and -R8ade formula Petition 870250079895, dated 05 / 09 / 2025, pp. 145 / 354 136 / 309 (IIb') are -H.

[00455] In certain embodiments, -R2e -R2ade formula (IIb') are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R2e -R2ade formula (IIb') is -H. In certain embodiments, both -R2e -R2ade formula (IIb') are H.

[00456] In certain embodiments, -R3 and -R3 of formula (IIb') are independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, at least one of -R3 and -R3 of formula (IIb') is methyl. In certain embodiments, -R3 and -R3 of formula (IIb') are both -H. In certain embodiments, -R3 and -R3 of formula (IIb') are both methyl. In certain embodiments, -R3 of formula (IIb') is -H and -R3 of formula (IIb') is methyl.

[00457] In certain embodiments, the portion -L1- is of formula (IIc): (IIc) where the dashed line indicates bonding to a nitrogen of -D that is a CNP moiety forming an amide linkage; and wherein -L1- is substituted with -L2-Z and wherein -L1- is optionally also substituted, provided that the hydrogen marked with the asterisk in formula (IIc) is not substituted by -L2-Z or a substituent.

[00458] In certain embodiments, -L1- of formula (IIc) is replaced with a -L2-Z portion. In certain embodiments, the -L1- portion of formula (IIc) is also not replaced.

[00459] In certain embodiments, the portion -L1- is selected from the group consisting of the formula (iIc-i), (Iic-ii), (IIc-iii), (IIc-iv) and (IIc-v): Petition 870250079895, dated 05 / 09 / 2025, pp. 146 / 354 137 / 309 N (IIc-i), H* O (IIc-iv), and (IIc-v) where the unmarked dashed line indicates linkage to a nitrogen of -D that is a CNP moiety forming an amide linkage; and the dashed line marked with the asterisk indicates linkage to -L2-Z; and -L1- is optionally also substituted, provided that the hydrogen marked with the asterisk in formulas (IIc-i), (Iic-ii), (IIc-iii), (IIc-iv) and (IIc-v) is not replaced by a substituent.

[00460] In certain embodiments, the -L1- portion of formula (iIc-i), (Iicii), (IIc-iii), (IIc-iv) and (IIc-v) is also not substituted.

[00461] In certain embodiments, the portion -L1- is of formula (IIc-ii): Petition 870250079895, dated 05 / 09 / 2025, pp. 147 / 354 138 / 309 O N H (IIc-ii), where the unmarked dashed line indicates linkage to a nitrogen of -D that is a CNP moiety forming an amide linkage; and the dashed line marked with the asterisk indicates linkage to -L2-Z.

[00462] In certain embodiments, -L1- of formula (IIc-ii) is replaced with a -L2-Z portion.

[00463] The optional additional substituents of -L1- of formula a (II), (IIa), (IIb), (IIb'), (IIc), (iIc-a), (iIc-b), (iIc-i), (Iic-ii), (IIc-iii), (Iic-iv), (IIcv) are, in certain embodiments, as described above.

[00464] Another portion -L1- is described in WO2016 / 020373A1. Consequently, in certain embodiments, portion -L1- is of formula (III): where the dashed line indicates linkage to a primary or secondary amine or hydroxyl group of -D that is a CNP moiety forming an amide or ester linkage, respectively; -R1, -R1a, -R2, -R2a, -R3e -R3a are independently selected from the group consisting of -H, -C(R8R8aR8b), -C(=O)R8, -C=N, -C(=NR8)R8a, -CR8(=CR8aR8b), -CeCR8e -T; -R4, -R5 and -R5a are independently selected from the group consisting of -H, -C(R9R9aR9b) and -T; a1 and a2 are independently 0 or 1; Petition 870250079895, dated 05 / 09 / 2025, pp. 148 / 354 139 / 309 each -R6, -R6a, -R7, -R7a, -R8, -R8a, -R8b, -R9, -R9a, -R9b are independently selected from the group consisting of -H, halogen, -CN, -COOR10, - OR10, -C(O)R10, -C(O)N(R10R10a), -S(O)2N(R10R10a), -S(O)N(R10R10a), -S(O)2R10, -S(O)R10, -N(R10)S(O)2N(R10aR10b), -SR10, -N(R10R10a), -NO2, -OC(O)R10, -N(R10)C(O)R10a, -N(R10)S(O)2R10a, -N(R10)S(O)R10a, -N(R10)C(O)OR10a, -N(R10)C(O)N(R10aR10b), -OC(O)N(R10R10a), -T, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl; wherein -T, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are optionally substituted with one or more -R11 groups, which are the same or different, and wherein C1-20 alkyl, C2-20 alkenyl, and C2-20 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(R12)-, -S(O)2N(R12)-, - S(O)N(R12)-, -S(O)2-, -S(O)-, -N(R12)S(O)2N(R12a)-, -S-, -N(R12)-, - OC(OR12)(R12a)-, -N(R12)C(O)N(R12a)-, and -OC(O)N(R12)-; each -R10, -R10a, -R10b independently selected from the group consisting of -H, -T, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl; wherein -T, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are optionally substituted with one or more -R11 groups, which are the same or different, and wherein C1-20 alkyl, C2-20 alkenyl, and C2-20 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(R12)-, S(O)2N(R12)-, - S(O)N(R12)-, -S(O)2-, -S(O)-, -N(R12)S(O)2N(R12a)-, -S-, -N(R12)-, - OC(OR12)(R12a)-, -N(R12)C(O)N(R12a)-, and -OC(O)N(R12)-; 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 -R11, which are the same or different; Petition 870250079895, dated 05 / 09 / 2025, pp. 149 / 354 140 / 309 each -R11 is independently selected from halogen, -CN, oxo (=O), -COOR13, -OR13, -C(O)R13, ​​-C(O)N(R13R13a), -S(O)2N(R13R13a), - S(O)N(R13R13a), -S(O)2R13, -S(O)R13, ​​-N(R13)S(O)2N(R13aR13b), -SR13, -N(R13R13a), -NO2, -OC(O)R13, ​​-N(R13)C(O)R13a, -N(R13)S(O)2R13a, -N(R13)S(O)R13a, -N(R13)C(O)OR13a, -N(R13)C(O)N(R13aR13b), - OC(O)N(R13R13a), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogens, which are the same or different; each -R12, -R12a, -R13, -R13a, -R13b independently selected from the group consisting of -H, and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogens, which are the same or different; Optionally, one or more of the pairs -R1 / -R1a, -R2 / -R2a, -R3 / -R3a, -R6 / -R6a, -R7 / -R7a are linked together with the atom to which they are attached to form a C3-10 cycloalkyl or a 3- to 10-membered heterocycline; Optionally, one or more of the pairs -R1 / -R2, -R1 / -R3, -R1 / -R4, -R1 / -R5, -R1 / -R6, -R1 / -R7, -R2 / -R3, -R2 / -R4, -R2 / -R5, -R2 / -R6, -R2 / -R7, -R3 / -R4, -R3 / -R5, -R3 / -R6, -R3 / -R7, -R4 / -R5, -R4 / -R6, -R4 / -R7, -R5 / -R6, -R5 / -R7, -R6 / -R7 are linked together with the atoms to which they are attached to form a ring A; 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; where -L1- is replaced with -L2-Z and where -L1- is optionally also replaced; in what -L2- is a single chemical bond or a spacer; and -Z is a water-soluble polymeric moiety.

[00465] The other optional substituents for -L1- of formula (III) Petition 870250079895, dated 05 / 09 / 2025, pp. 150 / 354 141 / 309 are, in certain embodiments, as described above. In certain embodiments, -L1- of formula (III) is replaced with a -L2-Z portion. In certain embodiments, -L1- of formula (III) is also not replaced.

[00466] Additional modalities for -L1- are described in EP1536334B1, WO2009 / 009712A1, WO2008 / 034122A1, WO2009 / 143412A2, WO2011 / 082368A2, and US8618124B2, which are incorporated herein by reference in their entirety.

[00467] Additional embodiments for -L1- are described in US8946405B2 and US8754190B2, which are incorporated herein by reference in their entirety. Consequently, a portion of -L1- is of formula (IV): (IV), where the dashed line indicates the linkage to -D which is a CNP moiety and where the linkage is through a functional group of -D selected from the group consisting of -OH, -SH and -NH2; m is 0 or 1; at least one or both of -R1 and -R2 are / are independently 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)2R3, and -SR4, one and only one of -R1 and -R2 is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; - R3 is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, hetero Petition 870250079895, dated 05 / 09 / 2025, pp. 151 / 354 142 / 309 optionally substituted roarylalkyl, -OR9e -N(R9)2; - R4 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; Each -R5 is independently selected from the group consisting of -H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; - R9 is selected from the group consisting of -H and optionally substituted alkyl; - Y- is absent and -X- is -O- or -S-; or - Y- is -N(Q)CH2- and -X- is -O-; Q is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl; Optionally, -R1 and -R2 can be connected to form a 3- to 8-membered ring; and optionally, both -R9 together with the nitrogen to which they are attached form a heterocyclic ring; where -L1- is replaced with -L2-Z and where -L1- is optionally also replaced; in what - L2- is a single chemical bond or a spacer; and Z is a water-soluble polymeric moiety.

[00468] The other optional substituents of -L1- of formula (IV) are in certain embodiments, as described above. In certain embodiments Petition 870250079895, dated 05 / 09 / 2025, pp. 152 / 354 143 / 309 dades, -L1- of formula (IV) is replaced with a portion -L2-Z. In certain embodiments, -L1- of formula (IV) is also not replaced.

[00469] Only in the context of formula (IV), the terms used have the following meanings:

[00470] The term “alkyl”, as used, includes linear, branched or cyclic saturated hydrocarbon groups of 1 to 8 carbons, or in certain embodiments of 1 to 6 or 1 to 4 carbon atoms.

[00471] The term “alkoxy” includes alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy and the like.

[00472] The term “alkenyl” includes non-aromatic unsaturated hydrocarbons with carbon-carbon double bonds.

[00473] The term “alkynyl” includes non-aromatic unsaturated hydrocarbons with carbon-carbon triple bonds.

[00474] The term “aryl” includes aromatic hydrocarbon groups of 6 to 18 carbons, in certain embodiments, of 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, in certain embodiments, of 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 the like.

[00475] In certain embodiments, alkenyl, alkynyl, aryl, or heteroaryl groups may be linked to the rest of the molecule by means of an alkylene bond. In these circumstances, the substituent will be called alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that an alkylene group is between the alkenyl, alkynyl, aryl, or heteroaryl group and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl is attached.

[00476] The term “halogen” includes bromine, fluorine, chlorine, and iodine.

[00477] The term “heterocyclic ring” refers to an aromatic ring Petition 870250079895, dated 05 / 09 / 2025, pp. 153 / 354 144 / 309 or non-aromatic of 4 to 8 members, 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.

[00478] 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 substituted. Optional substituents in any group, including the above, include halo, nitro, cyano, -OR, -SR, -NR2, -OCOR, -NRCOR, -COOR, -CONR2, -SOR, -SO2R, -SONR2, -SO2NR2, where each R is independently alkyl, alkenyl, alkynyl, aryl, or heteroaryl, or two R groups taken together with the atoms to which they are attached as a ring.

[00479] Another embodiment for -L1- is described in WO2013 / 036857A1, which is incorporated herein by reference in its entirety. Consequently, in certain embodiments, the portion -L1 has the formula (V): OHR II IR—SC-II II o (V), where the dashed line indicates the connection to -D which is a portion CNP and where the linkage is through an amine functional group of -D; - R1 is selected from the group consisting of C1-C6 linear, branched, cyclic, optionally substituted alkyl; optionally substituted aryl; optionally substituted heteroaryl; alkoxy; and -NR52; - R2 is selected from the group consisting of -H; C1-C6 optionally substituted alkyl; optionally substituted aryl; and he Petition 870250079895, dated 05 / 09 / 2025, pp. 154 / 354 145 / 309 optionally substituted teroaryl; - R3 is selected from the group consisting of -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl; - R4 is selected from the group consisting of -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl; Each -R5 is independently selected from the group consisting of -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl; or when taken together, two -R5s may be cycloalkyl or cycloheteroalkyl; where -L1- is replaced with -L2-Z and where -L1- is optionally also replaced; in what - L2- is a single chemical bond or a spacer; and Z is a water-soluble polymer.

[00480] The other optional substituents for -L1- of formula (V) are, in certain embodiments, as described above.

[00481] In certain embodiments, -L1- of formula (V) is replaced with a -L2-Z portion.

[00482] In certain embodiments, -L1- of formula (V) is also not substituted.

[00483] Only in the context of formula (V) do the terms used have the following meanings:

[00484] “Alkyl”, “alkenyl” and “alkynyl” include linear, branched or cyclic hydrocarbon groups of 1 to 8 carbons or 1 to 6 carbons or 1 to 4 carbons, where 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 Petition 870250079895, dated 05 / 09 / 2025, pp. 155 / 354 146 / 309 which, indicated otherwise, these groups contain from 1 to 6 carbons.

[00485] “Aryl” includes aromatic hydrocarbon groups of 6 to 18 carbons, in certain embodiments, of 6 to 10 carbons, including groups such as phenyl, naphthyl and anthracene. “Heteroaryl” includes aromatic rings comprising 3 to 15 carbons containing at least one N, O or S atom, in certain embodiments, of 3 to 7 carbons containing at least one N, O or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, tizolyl, isothiazolyl, quinolyl, indolyl, indenyl and the like.

[00486] 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 halogens, 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; carbamates; urea; thiocarbamates; thiourea; ketones; sulfones; sulfonamides; aryl compounds including phenyl, naphthyl and anthracenyl;heteroaryl compounds including 5-membered heteroaryl compounds, including pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole and tetrazole; 6-membered heteroaryl compounds, including pyridine, pyrimidine, pyrazine; and fused heteroaryl compounds, including benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzisoxazole and benzisothiazole.

[00487] Another modality for -L1- is described in WO 2022 / 115563 A1, which is incorporated herein by reference in full. Consequently, in certain modalities, -L1- has the formula (Va): Petition 870250079895, dated 05 / 09 / 2025, pages 156 / 354 147 / 309

[00488] Where the dashed line marked with the asterisk indicates the attachment to -L 2-Z and the unmarked dashed line indicates the attachment to -D.

[00489] In certain embodiments, -L1- is of the formula (Va), the dashed line marked with the asterisk indicates linkage to -L2-Z and the unmarked dashed line indicates linkage to -D, where -D is a CNP portion of the following amino acid sequence: SEQ ID NO:97 (CNP-38 N6Q, N14Q): LQEHPQARKYKGAQKKGLSKGCFGLKLDRIGSMSGLGC, in which the cysteines at positions 22 and 38 are connected by a disulfide bridge; and in which the linkage to -L1- occurs at the N-terminal or ring of the peptide.

[00490] Another embodiment for -L1- is described in US7585837B2, which is incorporated herein by reference in its entirety. Consequently, in certain embodiments, a portion of -L1- is of formula (VI): (VI), where the dashed line indicates linkage to -D, which is a CNP portion and where the linkage occurs through an amine functional group of -D; R1 and R2 are selected independently from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkaryl, Petition 870250079895, dated 05 / 09 / 2025, pp. 157 / 354 148 / 309 aralkyl, halogen, nitro, -SO3H, -SO2NHR5, amino, ammonium, carboxyl, PO3H2 and OPO3H2; R3, R4 and R5 are selected independently from the group consisting of hydrogen, alkyl and aryl; where -L1- is replaced by L2-Z and where -L1- is optionally replaced additionally; in what -L2- is a single chemical bond or a spacer; and -Z is a water-soluble polymeric moiety.

[00491] Suitable substituents for formulas (VI) are alkyl (as C1-6 alkyl), alkenyl (as C2-6 alkenyl), alkynyl (as C2-6 alkynyl), aryl (as phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (as 4- to 7-membered aromatic heterocycle) or halogen moieties.

[00492] In certain embodiments, -L1- of formula (VI) is replaced by an L2-Z moiety. Optional additional substituents for -L1- of formula (VI) are, in certain embodiments, as described above.

[00493] In certain forms, -L1- of formula (VI) is no longer replaced.

[00494] Only in the context of formula (VI) do the terms used have the following meaning:

[00495] The terms “alkyl”, “alkoxy”, “alkoxyalkyl”, “aryl”, “alcaryl” and “aralkyl” mean alkyl radicals of 1 to 8, in certain embodiments, of 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl and butyl, and aryl radicals of 6 to 10 carbon atoms, for example, phenyl and naphthyl. The term “halogen” includes bromine, fluorine, chlorine and iodine.

[00496] Another embodiment for -L1- is described in WO2002 / 089789A1, which is incorporated herein by reference in its entirety. Consequently, a portion of -L1- has the formula (VII): Petition 870250079895, dated 05 / 09 / 2025, pp. 158 / 354 149 / 309 (VII), where the dashed line indicates linkage to -D, which is a CNP portion and where the linkage occurs through an amine functional group of -D; L1 is a bifunctional linking group, Yi and Y2 are independently O, S, or NR7; R2, R3, R4, R5, R6 and R7 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, C1-6 substituted heteroalkyls, C1-6 alkoxy, phenoxy, and C1-6 heteroalkoxy; Ar is a moiety that when included in formula (VII) forms a multisubstituted aromatic hydrocarbon or multisubstituted heterocyclic group; X is a chemical bond or a portion that is actively transported in a target cell, a hydrophobic portion or a combination thereof, y is 0 or 1; where -L1- is replaced with -L2-Z and where -L1- is optionally also replaced; in what - L2- is a single chemical bond or a spacer; and Z is a water-soluble polymeric moiety.

[00497] In certain embodiments, -L1- of formula (VII) is replaced Petition 870250079895, dated 05 / 09 / 2025, pp. 159 / 354 150 / 309 with a portion -L2-Z. The other optional substituents of -L1- of formula (VII) are in certain embodiments, as described above.

[00498] In certain embodiments, -L1- of formula (VII) is also not substituted.

[00499] Only in the context of formula (VII) do the terms used have the following meanings:

[00500] The term “alkyl” should be understood to include, for example, linear, branched, substituted C1-12 alkyls, including alkoxy, C38 cycloalkyls or substituted cycloalkyls, etc.

[00501] The term “substituted” should be understood as including the addition or substitution of one or more atoms contained within a functional group or compounds with one or more different atoms.

[00502] Substituted alkyls include carboxyalkyls, aminoalkyls, dialkylaminos, hydroxyalkyls, and mercaptoalkyls; cycloalkyls include moieties such as 4-chlorocyclohexyl; aryls include moieties such as naphthyl; substituted aryls include moieties such as 3-bromophenyl; aralkyls include moieties such as tolyl; heteroalkyls include moieties such as ethylthiophene; substituted heteroalkyls include moieties such as 3-methoxythiophone; alkoxy includes moieties such as methoxy; and phenoxy includes moieties such as 3-nitrophenoxy. Halo- should be understood to include fluorine, chlorine, iodine, and bromine.

[00503] In certain embodiments, -L1- comprises a formula substructure (VIII): O, IJ T° (viii), where the dashed line marked with the asterisk indicates the linkage to a nitrogen of -D which is a CNP portion forming a linkage Petition 870250079895, dated 05 / 09 / 2025, pp. 160 / 354 151 / 309 amide; Unmarked dashed lines indicate a connection to the rest of -L1-; and where -L1- is replaced with -L2-Z and where -L1- is optionally also replaced; in what - L2- is a single chemical bond or a spacer; and Z is a water-soluble polymeric moiety.

[00504] In certain embodiments, -L1- of formula (VIII) is replaced with a -L2-Z moiety. The other optional substituents of -L1- of formula (VIII) are as described above.

[00505] In certain embodiments, -L1- of formula (VIII) is also not substituted.

[00506] In certain embodiments, -L1- comprises a formula substructure (IX): I _Y / For-( The J0 Ar (IX), where the dashed line marked with the asterisk indicates the linkage to a nitrogen of -D that is a CNP moiety forming a carbamate linkage; Unmarked dashed lines indicate a connection to the rest of -L1-; and where -L1- is replaced with -L2-Z and where -L1- is optionally also replaced; in what -L2- is a single chemical bond or a spacer; and Petition 870250079895, dated 05 / 09 / 2025, pp. 161 / 354 152 / 309 Z is a water-soluble polymeric moiety.

[00507] The other optional substituents of -L1- of formula (IX) are as described above. In certain embodiments, -L1- of formula (IX) is replaced with an -L2-Z moiety. In certain embodiments, -L1- of formula (IX) is also left unsubstituted.

[00508] The -D portion can be connected to -L1- through any DH functional group and is connected to -L1- through an amine functional group of DH. This can be an N-terminal amine functional group or an amine functional group provided by a lysine side chain, i.e., by the lysines at positions 9, 11, 15, 16, 20 and 26, if the CNP has the sequence SEQ ID NO:24.

[00509] The attachment of -L1- to the ring of a CNP portion significantly reduces the affinity of the CNP conjugate to NPR-B compared to the N-terminal or non-ring portion of CNP, whose reduced affinity to NPR-B in turn reduces the risk of cardiovascular side effects, such as hypotension.

[00510] Consequently, in certain embodiments, -L1- is conjugated to the side chain of an amino acid residue of said ring portion of -D or to the main structure of said ring portion of -D. In certain embodiments, -L1- is covalently and reversibly conjugated to the side chain of an amino acid residue of said ring portion of -D. If -D is a CNP portion with the sequence SEQ ID NO:24, -L1- is, in certain embodiments, conjugated to the amine functional group provided by lysine at position 26 of the corresponding drug DH.

[00511] The -L2- portion is a chemical bond or a spacer portion. In certain embodiments, -L2- is a chemical bond. In certain embodiments, -L2- is a spacer portion.

[00512] The portion -L2- can be linked to -L1- by replacing any -H present, except where explicitly excluded.

[00513] When -L2- is different from a single chemical bond, Petition 870250079895, dated 05 / 09 / 2025, p. 162 / 354 153 / 309 - 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(Ry1)S(O)2N(Ry1a)-, -S-, -N(Ry1)-, -OC(ORy1)(Ry1a)-, - N(Ry1)C(O)N(Ry1a)-, - OC(O)N(Ry1)-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2 groups, 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)-; -Ry1e -Ry1asão are independently of each other selected from the group consisting of -H, -T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2 groups, which are the same or different, and wherein C1-50 alkyl, C2-50 alkynyl, 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(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)-; 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 11-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each T is independently, optionally substituted with one or more -Ry2, which are the same or different; each -Ry2 is independently selected from the group that Petition 870250079895, dated 05 / 09 / 2025, pp. 163 / 354 154 / 309 consists of halogen, -CN, oxo (=O), -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 halogens, which are the same or different; and each -Ry3, -Ry3a, -Ry4, -Ry4a, -Ry5, -Ry5a and -Ry5b independently selected from the group consisting of -H, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogens, which are the same or different.

[00514] When -L2- is different from a single chemical bond, -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(Ry1)S(O)2N(Ry1a)-, -S-, -N(Ry1)-, -OC(ORy1)(Ry1a)-, -N(Ry1)C(O)N(Ry1a)-, - OC(O)N(Ry1)-, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl; wherein -T-, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are optionally substituted with one or more -Ry2 groups, which are the same or different, and wherein C1-20 alkyl, C2-20 alkenyl, and C2-20 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)-; -Ry1e and -Ry1a are independently 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 groups, which are the same or different, and wherein C1-10 alkyl, C2-10 alkynyl, and C2-10 alkynyl Petition 870250079895, dated 05 / 09 / 2025, pp. 164 / 354 155 / 309 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)-; 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 11-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each T is independently, optionally substituted with one or more -Ry2, which are the same or different; -Ry2 is selected from the group consisting of halogen, -CN, oxo (=O), -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 halogens, which are the same or different; and each -Ry3, -Ry3a, -Ry4, -Ry4a, -Ry5, -Ry5a and -Ry5b 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 halogens, which are the same or different.

[00515] When -L2- is different from a single chemical bond, -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(Ry1)S(O)2N(Ry1a)-, -S-, -N(Ry1)-, -OC(ORy1)(Ry1a)-, - N(Ry1)C(O)N(Ry1a)-, -OC(O)N(Ry1)-, C1-50 alkyl, C2-50 alkenyl, and C250 alkynyl; where -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl Petition 870250079895, dated 05 / 09 / 2025, pp. 165 / 354 156 / 309 are optionally replaced with one or more -Ry2 groups, which are the same or different, and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl groups 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)-; -Ry1e -Ry1asão are independently selected from the group consisting of -H, -T, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl; Each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 11-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; each -Ry2 is independently selected from the group consisting of halogen and C1-6 alkyl; and each -Ry3, -Ry3a, -Ry4, -Ry4a, -Ry5, -Ry5a and -Ry5 is independently selected from each other from the group consisting of -H and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogens, which are the same or different.

[00516] In certain embodiments, -L2- is a C1-20 alkyl chain, which is optionally interrupted by one or more independently selected groups of -O-, -T- and -C(O)N(Ry1)-; and whose C1-20 alkyl chain is optionally substituted with one or more independently selected groups of -OH, -T and -C(O)N(Ry6Ry6a); wherein -Ry1, -Ry6, -Ry6a are independently selected from the group consisting of H and C1.4 alkyl and wherein T is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterocyclyl, carbopolycyl Petition 870250079895, dated 05 / 09 / 2025, pp. 166 / 354 157 / 309 clila of 8 to 11 members, and heteropoliciclila of 8 to 30 members.

[00517] In certain embodiments, -L2- has a molecular weight in the range of 14 g / mol to 750 g / mol.

[00518] In certain embodiments, -L2- has a chain length of 1 to 20 atoms.

[00519] As used herein, the term “chain length” with respect to the -L2- portion refers to the number of -L2- atoms present in the shortest connection between -L1- and -Z.

[00520] In certain modes, -L2- is of formula (i): R i ' n * the (i), where the dashed line marked with the asterisk indicates a connection to -L1-; The unmarked dashed line indicates a connection to -Z; -R1 is selected from the group consisting of -H, C1-6 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 where the formula portion (i) is optionally also replaced.

[00521] In certain embodiments, -R1 of formula (i) is selected from the group consisting of -H, methyl, ethyl, propyl and butyl. In certain embodiments, -R1 of formula (i) is selected from the group consisting of -H, methyl, ethyl and propyl. In certain embodiments, -R1 of formula (i) is selected from the group consisting of -H and methyl. In certain embodiments, -R1 of formula (i) is methyl.

[00522] In certain modes, n of formula (i) is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain modes Petition 870250079895, dated 05 / 09 / 2025, p. 167 / 354 158 / 309 embodiments, n of formula (i) is selected from the group consisting of 0, 1, 2, 3, 4 and 5. In certain embodiments, n of formula (i) is selected from the group consisting of 0, 1, 2 and 3. In certain embodiments, n of formula (i) is selected from the group consisting of 0 and 1. In certain embodiments, n of formula (i) is 0.

[00523] In certain embodiments, -L2- is a selected portion of the group consisting of: (ii), (iii), (iv), (v), (viii), (ix), (x), (xiii), (xii), the (xiv), (xv), (xvi) and (xvii); in what Petition 870250079895, dated 05 / 09 / 2025, pp. 168 / 354 159 / 309 the dashed line marked with an asterisk indicates a connection to -L1-; The unmarked dashed line indicates a link to -Z and where portions (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi) and (xvii) are optionally also replaced.

[00524] In certain modalities, -L2- is selected from the group consisting of (xiv), (xv), The (xvi) and H (xvii); where the dashed line marked with an asterisk indicates a connection to -L1-; and the unmarked dashed line indicates a connection to -Z.

[00525] In certain modalities, -L2- is selected from the group consisting of (xiv) and (xvi) where the dashed line marked with the asterisk indicates a connection to -L1-; and the unmarked dashed line indicates a connection to -Z.

[00526] In certain forms, -L2- is of formula (xvi): (xvi) Petition 870250079895, dated 05 / 09 / 2025, p. 169 / 354 160 / 309 where the dashed line marked with an asterisk indicates a connection to -L1-; and the unmarked dashed line indicates a connection to -Z.

[00527] In certain embodiments, the portion -L^L2- is selected from the group consisting of (IId-i), (IId-iii), where the unmarked dashed line indicates bonding to a nitrogen of -D that is a CNP moiety forming an amide bond; and the dashed line marked with the asterisk indicates bonding to -Z.

[00528] In certain embodiments, the portion -L1-L2- is of formula (IIdii): Petition 870250079895, dated 05 / 09 / 2025, p. 170 / 354 161 / 309 N H O (IId-ii), where the unmarked dashed line indicates linkage to a nitrogen of -D that is a CNP moiety forming an amide linkage; and the dashed line marked with the asterisk indicates linkage to -Z.

[00529] In certain forms, the portion -L1-L2- is of the formula (IId-ii '): (IId-ii '), where the unmarked dashed line indicates linkage to a nitrogen of -D that is a CNP moiety forming an amide linkage; and the dashed line marked with the asterisk indicates linkage to -Z.

[00530] In certain embodiments, the -L1-L2- portion is selected from the group consisting of (IId-ia), * Petition 870250079895, dated 05 / 09 / 2025, p. 171 / 354 162 / 309 H2N N H O (IId-iia), H2N H2N NH THE (IId-iva), NH where the unmarked dashed line indicates bonding to a nitrogen of -D that is a CNP moiety forming an amide bond; and the dashed line marked with the asterisk indicates bonding to -Z.

[00531] In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight ranging from 5 to 200 kDa. In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight ranging from 8 to 100 kDa. In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight ranging from 10 to 80 kDa. In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight ranging from 12 to 60 kDa. In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight ranging from 15 to 40 kDa. In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight of about 20 kDa. In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight of about 40 kDa. Petition 870250079895, dated 05 / 09 / 2025, p. 172 / 354 163 / 309

[00532] The polymeric portion -Z of formula (Ia) or (Ib) comprises a polymer. In certain embodiments, -Z of formula (Ia) or (Ib) comprises a polymer selected from the group consisting of 2-methacryloyl-oxyethylphosphoyl cholines, 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(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyloxazolines), poly(hydroxymethacrylates), poly(hydroxypropylmethacrylamides), poly(hydroxypropylmethacrylates), poly(hydroxypropyloxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-coglycolic acids),poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinylamines), poly(vinyl methyl ethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethylcelluloses, hydroxypropylmethylcelluloses, 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.

[00533] In certain embodiments, -Z of formula (Ia) or (Ib) comprises a protein. Preferred proteins are selected from the group consisting of carboxyl-terminal peptide of chorionic gonadotropin, as described in US 2012 / 0035101 A1, which are incorporated herein by reference; albumin; XTEN sequences as described in WO 2011123813 A2, which are incorporated herein by reference; proline / alanine random helix sequences. Petition 870250079895, dated 05 / 09 / 2025, page 173 / 354 164 / 309 as described in WO 2011 / 144756 A1, which are incorporated herein by reference; random coil sequences of proline / alanine / serine as described in WO 2008 / 155134 A1 and WO 2013 / 024049 A1, which are incorporated herein by reference; and Fc fusion proteins.

[00534] In certain embodiments, -Z of formula (Ia) or (Ib) is a polysarcosine. In certain embodiments, -Z of formula (Ia) or (Ib) comprises poly(N-methylglycine). In certain embodiments, -Z of formula (Ia) or (Ib) comprises a random helix protein moiety. In certain embodiments, -Z of formula (Ia) or (Ib) comprises a random helix protein moiety. In certain embodiments, -Z of formula (Ia) or (Ib) comprises two random helix protein moieties. In certain embodiments, -Z of formula (Ia) or (Ib) comprises three random helix protein moieties. In certain embodiments, -Z of formula (Ia) or (Ib) comprises four random helix protein moieties. In certain embodiments, -Z of formula (Ia) or (Ib) comprises five random helix protein moieties. In certain embodiments, -Z of formula (Ia) or (Ib) comprises six random coiled protein moieties. In certain embodiments, -Z of formula (Ia) or (Ib) comprises seven random coiled protein moieties.In certain embodiments, -Z of formula (Ia) or (Ib) comprises eight randomly coiled protein moieties.

[00535] In certain embodiments, this random helix protein portion comprises at least 25 amino acid residues and at most 2,000 amino acids. In certain embodiments, this random helix protein portion comprises at least 30 amino acid residues and at most 1,500 amino acid residues. In certain embodiments, this random helix protein portion comprises at least 50 amino acid residues and at most 500 amino acid residues.

[00536] In certain modalities, -Z of formula (Ia) or (Ib) buy Petition 870250079895, dated 05 / 09 / 2025, pp. 174 / 354 165 / 309 ende a fatty acid derivative. In certain embodiments, -Z of formula (Ia) or (Ib) is a fatty acid derivative. In certain embodiments, -Z of formula (Ia) is a fatty acid derivative ex is 1.

[00537] In certain embodiments, -Z of formula (Ia) or (Ib) is a fatty acid derivative, as described in WO 2006 / 097537 A2, which is incorporated herein by reference.

[00538] In certain embodiments, -Z of formula (Ia) or (Ib) comprises a fatty acid derivative, as described in WO 2021 / 055497 A1, which is incorporated herein by reference. Consequently, in certain embodiments, -Z of formula (Ia) or (Ib) has the following structure (w): where the dashed line indicates a connection to -L2- or -L1- in formula (Ia) or (Ib).

[00539] In certain modalities, -Z is of formula (w) and -L1- is of formula (V).

[00540] In certain modalities, -Z-L2-L1- has the formula (wa): where the dashed line indicates a link to -D of formula (Ia) or (Ib).

[00541] In certain modalities, CNP has the selected sequence from the group consisting of: PGQEHPQARRYRGAQRRGLSRGCFGLKLDRIGSMSGLGC (SEQ ID NO:98); PGQEHPNARKYKGANKKGLSKGCFGLKLDRIPedição 870250079895, dated 05 / 09 / 2025, p. 175 / 354 166 / 309 GSMSGLGC (SEQ ID NO:30); PGQEHPNARRYRGANRRGLSRGCFGLKLDRIGSMSGLGC (SEQ ID NO:99); and PGQEHPQARKYKGAQKKGLSKGCFGLKLDRIGSMSGLGC (SEQ ID NO:100).

[00542] In certain embodiments, CNP has the selected sequence from the group consisting of SEQ ID NO:98, SEQ ID NO:30, SEQ ID NO:99 and SEQ ID NO:100, -Z is of formula (w) and -L1- is a reversible linking moiety. In certain embodiments, CNP has the selected sequence from the group consisting of SEQ ID NO:98, SEQ ID NO:30, SEQ ID NO:99 and SEQ ID NO:100, -Z is of formula (w) and -L1- is of formula (V). In certain embodiments, CNP has the selected sequence from the group consisting of SEQ ID NO:98, SEQ ID NO:30, SEQ ID NO:99 and SEQ ID NO:100, -Z-L2-L1- is of formula (wa). The aforementioned -L1 can be linked to the aforementioned CNP via a lysine other than lysine within the ring structure, or it can be linked to the N-terminus.

[00543] In certain embodiments, the CNP of SEQ ID NO:98, SEQ ID NO:30, SEQ ID NO:99, and SEQ ID NO:100 also comprises an acetyl group, such as an acetyl group at the N-terminus of the peptide. In certain embodiments, the CNP of SEQ ID NO:98, SEQ ID NO:30, SEQ ID NO:99, and SEQ ID NO:100 also comprises an -OH or -NH2 group at the C-terminus. In certain embodiments, the CNP of SEQ ID NO:98, SEQ ID NO:30, SEQ ID NO:99, and SEQ ID NO:100 and -L1- is linked to a residue of the CNP ring portion at a site other than the CNP portion.

[00544] In certain embodiments, -L1- is linked to a lysine residue, such as the lysine residue in bold in SEQ ID NO:98, SEQ ID NO:30, SEQ ID NO:99 and SEQ ID NO:100: PGQEHPQARRYRGAQRRGLSRGCFGLKLDRIGSMSGLGC (SEQ ID NO:98); Petition 870250079895, dated 05 / 09 / 2025, p. 176 / 354 167 / 309 PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (SEQ ID NO:30); PGQEHPNARRYRGANRRGLSRGCFGLKLDRIGSMSGLGC (SEQ ID NO:99); and PGQEHPQARKYKGAQKKGLSKGCFGLKLDRIGSMSGLGC (SEQ ID NO:100).

[00545] In certain modalities, CNP is selected from the group consisting of: AcPGQEHPQARRYRGAQRRGLSRGCFGLKLDRIGSMSGLGC (SEQ ID NO:101); AcPGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC-NH2 (SEQ ID NO:102); AcPGQEHPNARRYRGANRRGLSRGCFGLKLDRIGSMSGLGC (SEQ ID NO:103); AcPGQEHPNARRYRGANRRGLSRGCFGLKLDRIGSMSGLGC-NH2 (SEQ ID NO:104); and AcPGQEHPQARRYRGAQRRGLSRGCFGLKLDRIGSMSGLGC-NH2 (SEQ ID NO:105).

[00546] In certain embodiments, -Z of formula (Ia) or (Ib) is a hyaluronic acid-based polymer.

[00547] In certain embodiments, -Z of formula (Ia) or (Ib) is a polymeric moiety as described in WO 2013 / 024047 A1 which is hereby incorporated by reference.

[00548] In certain embodiments, -Z of formula (Ia) or (Ib) is a polymeric moiety as described in WO 2013 / 024048 A1 which is at least Petition 870250079895, dated 05 / 09 / 2025, p. 177 / 354 168 / 309 present incorporated by reference.

[00549] In certain embodiments, -Z of formula (Ia) or (Ib) is a PEG-based polymer. In certain embodiments, -Z is a branched or multi-armed PEG-based polymer.

[00550] In certain embodiments, -Z of formula (Ia) or (Ib) is a branched polymer. In certain embodiments, -Z of formula (Ia) or (Ib) is a branched polymer with one, two, three, four, five, or six branching points. In certain embodiments, -Z of formula (Ia) or (Ib) is a branched polymer with one, two, or three branching points. In certain embodiments, -Z of formula (Ia) or (Ib) is a branched polymer with one branching point. In certain embodiments, -Z of formula (Ia) or (Ib) is a branched polymer with two branching points. In certain embodiments, -Z of formula (Ia) or (Ib) is a branched polymer with three branching points.

[00551] In certain embodiments, a branching point is selected from the group consisting of -N<, CH< and >C<.

[00552] In certain embodiments, that branched -Z portion of formula (Ia) or (Ib) is based on PEG.

[00553] In certain embodiments, such a branched -Z portion of formula (Ia) or (Ib) has a molecular weight ranging from, and including, 5 kDa to 500 kDa. In certain embodiments, such a branched -Z portion of formula (Ia) or (Ib) has a molecular weight ranging from, and including, 10 kDa to 250 kDa. In certain embodiments, such a branched -Z portion of formula (Ia) or (Ib) has a molecular weight ranging from, and including, 10 kDa to 150 kDa. In certain embodiments, such a branched -Z portion of formula (Ia) or (Ib) has a molecular weight ranging from, and including, 12 kDa to 100 kDa. In certain embodiments, such a branched -Z portion of formula (Ia) or (Ib) has a molecular weight ranging from, and including, 15 kDa to 80 kDa. In certain embodiments, such a branched -Z moiety of formula (Ia) or (Ib) has a molecular weight ranging from, and including, 10 kDa to Petition 870250079895, dated 05 / 09 / 2025, p. 178 / 354 169 / 309 kDa. In certain embodiments, the molecular weight is about 10 kDa. In certain embodiments, the molecular weight of such a branched -Z portion of formula (Ia) or (Ib) is about 20 kDa. In certain embodiments, the molecular weight of such a branched -Z portion of formula (Ia) or (Ib) is about 30 kDa. In certain embodiments, the molecular weight of such a branched -Z portion of formula (Ia) or (Ib) is about 40 kDa. In certain embodiments, the molecular weight of such a branched -Z portion of formula (Ia) or (Ib) is about 50 kDa. In certain embodiments, the molecular weight of such a branched -Z portion of formula (Ia) or (Ib) is about 60 kDa. In certain embodiments, the molecular weight of such a branched -Z portion of formula (Ia) or (Ib) is about 70 kDa. In certain embodiments, the molecular weight of such a branched -Z portion of formula (Ia) or (Ib) is about 80 kDa. In certain embodiments, such a branched -Z portion of formula (Ia) or (Ib) has a molecular weight of about 40 kDa.

[00554] In certain modalities, -Z comprises a portion THE o .

[00555] In certain embodiments, -Z comprises an amide linkage.

[00556] In certain embodiments, -Z of formula (Ia) or (Ib) comprises a portion of formula (a): S-Pa' ^sa—bp—: s-pa' In which pa(a), Petition 870250079895, dated 05 / 09 / 2025, p. 179 / 354 170 / 309 the dashed line indicates connection to -L2- or to the remainder of Z; BPa is a branching point selected from the group consisting of -N<, CR< and >C<; -R is selected from the group consisting of H and C1-6 alkyl; a is 0 if BPa is -N< or CR< and a is 1 if BPa is >C<; -Sa-, -Sa'-, -Sa- and -Sa'- are independently of each other a chemical bond or are selected from the group consisting of C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -R1 groups, 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)-; 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 11-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each -T- is independently, optionally substituted with one or more -R1s, which are the same or different; Each -R1 is independently selected from the group consisting of halogen, -CN, oxo (=O), -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 halogens, which are the same or different; Petition 870250079895, dated 05 / 09 / 2025, pp. 180 / 354 171 / 309 each -R2, -R2a, -R3, -R3a and -R3b independently selected from the group consisting of -H, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogens, which are the same or different; and -Pa', -Pa'' and -Pa' are independently a polymeric moiety.

[00557] Optionally, the portion of formula (a) is replaced by one or more substituents.

[00558] In certain embodiments, BPa of formula (a) is -N<. In certain embodiments, BPa of formula (a) is -CR<. In certain embodiments, -R is H.

[00559] Thus, in certain modalities, one of the formulas (a) is 0.

[00560] In certain modalities, BPa of formula (a) is >C<.

[00561] In certain embodiments, -Sa- of formula (a) is a chemical bond.

[00562] 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 -R4 and -R4a are 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, 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)-.

[00563] In certain embodiments, -Sa'- of formula (a) is a chemical bond.

[00564] In certain embodiments, -Sa'- of formula (a) is selected from the group consisting of C1-10 alkyl, C2-10 alkenyl and C2-10 alkynyl, Petition 870250079895, dated 05 / 09 / 2025, pp. 181 / 354 172 / 309 whose C1-10 alkyl, C2-10 alkenyl and C2-10 alkynyl groups 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 -R4 and -R4a are 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)-.

[00565] In certain embodiments, -Sa'- of formula (a) is a chemical bond.

[00566] 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 -R4 and -R4a are 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)-.

[00567] In certain embodiments, -Sa'''- of formula (a) is a chemical bond.

[00568] 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 Petition 870250079895, dated 05 / 09 / 2025, pp. 182 / 354 173 / 309 which consists 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 -R4 and -R4a are 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)-.

[00569] In certain embodiments, -Pa', -Pa'' and -Pa' of formula (a) independently comprise a polymer selected from the group consisting of 2-methacryloyl-oxyethyl phosphoyl cholines, 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(ethylene glycols),poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(hydroxymethacrylates), poly(hydroxypropylmethacrylamides), poly(hydroxypropylmethacrylates), poly(hydroxypropyloxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinylamines), poly(vinyl methyl ethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethylcelluloses, hydroxypropylmethylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other polymers, Petition 870250079895, dated 05 / 09 / 2025, pp. 183 / 354 174 / 309 based on carbohydrates, xylans and copolymers thereof.

[00570] In certain embodiments, -Pa', -Pa'' and -Pa''' of formula (a) independently have a molecular weight ranging from and including 5 kDa to 50 kDa, in certain embodiments ranging from and including 5 kDa to 40 kDa, in certain embodiments ranging from and including 7.5 kDa to 35 kDa, in certain embodiments ranging from and including 7.5 to 30 kDa, in certain embodiments ranging from and including 10 to 30 kDa.

[00571] In certain embodiments, -Pa', -Pa'' and -Pa''' of formula (a) independently have a molecular weight ranging from and including 5 kDa to 50 kDa, in certain embodiments ranging from and including 5 kDa to 40 kDa, in certain embodiments ranging from and including 7.5 kDa to 35 kDa, in certain embodiments ranging from and 7.5 to 30 kDa, in certain embodiments ranging from and including 10 to 30 kDa.

[00572] In certain embodiments, -Pa', -Pa'' and -Pa''' of formula (a) have a molecular weight of about 5 kDa. In certain embodiments, -Pa', -Pa'' and -Pa''' of formula (a) have a molecular weight of about 7.5 kDa. In certain embodiments, -Pa', -Pa'' and -Pa''' of formula (a) have a molecular weight of about 10 kDa. In certain embodiments, -Pa', -Pa'' and -Pa''' of formula (a) have a molecular weight of about 12.5 kDa. In certain embodiments, -Pa', -Pa'' and -Pa''' of formula (a) have a molecular weight of about 15 kDa. In certain embodiments, -Pa', -Pa'' and -Pa''' of formula (a) have a molecular weight of about 20 kDa.

[00573] In certain embodiments, -Pa', -Pa'' and -Pa'' of formula (a) independently comprise a PEG-based portion. In certain embodiments, -Pa', -Pa'' and -Pa''' of formula (a) independently comprise a PEG-based portion comprising at least 20% PEG, in certain embodiments at least 30% PEG, in certain embodiments at least 40% PEG, in certain embodiments at least 50% PEG, in certain embodiments at least 60% PEG, in certain embodiments at least 70% Petition 870250079895, dated 05 / 09 / 2025, pp. 184 / 354 175 / 309 PEG, in certain modalities at least 80% PEG and in certain modalities at least 90% PEG.

[00574] In certain embodiments, -Pa', -Pa'' and -Pa''' of formula (a) independently comprise a protein moiety, in certain embodiments a random spiral protein moiety and in certain embodiments a random spiral protein moiety selected from the group consisting of PA, PAS, PAG, PG and XTEN moieties.

[00575] In certain embodiments, -Pa', -Pa'' and -Pa''' of formula (a) are a PA portion. In certain embodiments, -Pa', -Pa'' and -Pa''' of formula (a) are a PAS portion. In certain embodiments, -Pa', -Pa'' and -Pa''' of formula (a) are a PAG portion. In certain embodiments, -Pa', -Pa'' and -Pa''' of formula (a) are a PG portion. In certain embodiments, -Pa', -Pa'' and -Pa''' of formula (a) are an XTEN portion.

[00576] In certain embodiments, -Z comprises one portion of formula (a). In certain embodiments, -Z comprises two portions of formula (a). In another embodiment, -Z comprises three portions of formula (a). In certain embodiments, -Z comprises four portions of formula (a). In certain embodiments, -Z comprises five portions of formula (a). In certain embodiments, -Z comprises six portions of formula (a).

[00577] In certain embodiments, -Z comprises a portion of formula (b): CH O-CH2-CH2-O-CH - b3 CH-O-CH2-CH2—O-CH f-CH2-C-NH-CH2~O-CH2b4Jb1Jb2 (b), Where the dashed line indicates a connection to -L2- or the rest of Z; b1 is selected from the group consisting of 0, 1, 2, 3, 4, 5, Petition 870250079895, dated 05 / 09 / 2025, pp. 185 / 354 176 / 309 6, 7 and 8; b2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; b3 is an integer ranging from and including 150 to 1000; in certain modalities, ranging from and including 150 to 500; and in certain modalities, ranging from and including 200 to 460; and b4 is an integer ranging from and including 150 to 1000; in certain modalities, ranging from and including 150 to 500; and in certain modalities, ranging from and including 200 to 460.

[00578] Optionally, the portion of formula (b) is replaced by one or more substituents.

[00579] In certain embodiments, b3 and b4 of formula (b) are the same integer. In certain embodiments, b3 and b4 of formula (b) are both integers ranging from 200 to 500 and, in certain embodiments, b3 and b4 of formula (b) are approximately 450.

[00580] In certain embodiments, b1 of formula (b) is selected from the group consisting of 0, 1, 2, 3 and 4. In certain embodiments, b1 of formula (b) is selected from the group consisting of 1, 2 and 3. In certain embodiments, b1 of formula (b) is 2.

[00581] 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.

[00582] In certain embodiments, b1 of formula (b) is 2, b2 of formula (b) is 3, and b3 and b4 are both approximately 450. In certain embodiments, b1 of formula (b) is 2, b2 of formula (b) is 3, and b3 and b4 are both approximately 225.

[00583] In certain embodiments, -Z comprises one formula portion (b). In certain embodiments, -Z comprises two formula portions (b). In certain embodiments, -Z comprises three portions of Petition 870250079895, dated 05 / 09 / 2025, pp. 186 / 354 177 / 309 formula (b). In certain embodiments, -Z comprises four portions of formula (b). In certain embodiments, -Z comprises five portions of formula (b). In certain embodiments, -Z comprises six portions of formula (b).

[00584] In certain embodiments, -Z comprises a portion or formula (c): ch2-o-ch2-ch2-o-ch3 -^ch2-ch2-c-nh-ch2-ch2-ch2-o—ch2ch-o-ch2-ch2-o-ch IL JC2 (c), Where the dashed line indicates a connection to -L2- or the rest of Z; c1 and c2 are independently integers ranging from and including 150 to 500; in certain embodiments, ranging from and including 200 to 460.

[00585] Optionally, the portion of formula (c) is replaced by one or more substituents.

[00586] In certain forms, both c1 and c2 of formula (c) are the same integer.

[00587] In certain embodiments, c1 and c2 of formula (c) vary from and include 200 to 250 and, in certain embodiments, are about 225. In certain embodiments, c1 and c2 of formula (c) vary from and include 400 to 500 and, in certain embodiments, c1 and c2 of formula (c) are about 450.

[00588] In certain embodiments, the -Z portion is a branched PEG-based polymer comprising at least 10% PEG, possessing a branching point and two PEG-based polymeric arms, and having a molecular weight of about 40 kDa. Consequently, each of the two PEG-based polymeric arms has a molecular weight of about 20 kDa. In certain embodiments, the branching point Petition 870250079895, dated 05 / 09 / 2025, pp. 187 / 354 178 / 309 mification is -CH<.

[00589] In certain embodiments, -Z comprises one formula portion (c). In certain embodiments, -Z comprises two formula portions (c). In certain embodiments, -Z comprises three formula portions (c). In certain embodiments, -Z comprises four formula portions (c). In certain embodiments, -Z comprises five formula portions (c). In certain embodiments, -Z comprises six formula portions (c).

[00590] In certain forms, the -Z portion is of formula (d): (d), Where the dashed line indicates a connection in -L2-; -Zb- is 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 groups, 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)-; 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 11-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each -T- is independently, optionally substituted with one or more -R1s, which are the same or different; Each -R1 is independently selected from the group consisting of halogen, -CN, oxo (=O), -COOR3, -OR3, -C(O)R3, -C(O)N(R3R3a), -S(O)2N(R3R3a), -S(O)N(R3R3a), -S(O)2R3, -S(O)R3, Petition 870250079895, dated 05 / 09 / 2025, pp. 188 / 354 179 / 309 - 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 halogens, which are the same or different; each -R2, -R2a, -R3, -R3a and -R3b independently selected from the group consisting of -H, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogens, which are the same or different; and -Zaé -S—BP—- S—Pay this BPa, -Sa-, -Sa'-,...

Claims

1. Use of an NPR-B agonist in the manufacture of a drug for the treatment of a thoracolumbar deformity in a human individual with achondroplasia, characterized in that the human individual has or is at risk of developing said thoracolumbar deformity.

2. Use according to claim 1, characterized in that said use is for the treatment of thoracolumbar kyphosis in said human individual.

3. Use, according to claim 1 or 2, characterized in that said use comprises the step of measuring spinal deformity before and, optionally, during and / or after said treatment.

4. Use, according to any one of claims 1 to 3, characterized in that said use comprises successive administrations of the NPR-B agonist to said individual, during a treatment period of at least about 6 months or at least about 1 year, as daily, weekly, bi-weekly or monthly, during said treatment period.

5. Use, according to any one of claims 1 to 4, characterized in that it comprises measuring the thoracolumbar deformity before treatment and / or approximately every 3 months, or approximately every 6 months, or approximately every 9 months, or approximately annually, during said treatment or treatment period.

6. Use, according to any one of claims 1 to 5, characterized in that it comprises measuring the degree of thoracolumbar kyphosis in the individual, before and, optionally, during and / or after said treatment.

7. Use, according to any of the claims in Petition 870250079895, dated 05 / 09 / 2025, pp. 333 / 354 2 / 6 6, characterized by the fact that said use further includes measuring the degree of lordosis, such as lumbar lordosis, in the individual, before and, optionally, during and / or after said treatment.

8. Use, according to any one of claims 1 to 7, characterized in that said use is for the treatment of a thoracolumbar deformity comprising a deformity of vertebral morphology, such as gibbon deformity, wherein said treatment results in an improvement in vertebral morphology.

9. Use, according to any of claims 1 to 8, characterized in that said use further comprises the step of measuring vertebral morphology, before and during said treatment period, such as the use of vertebral morphometry, such as point morphometry of one or more vertebrae, such as a thoracic and / or lumbar vertebra, such as vertebral morphometry of the L1 and / or L2 vertebra, wherein, optionally, said treatment results in a decrease in the PH / MW ratio of the L1 and / or L2 vertebra.

10. Use in accordance with any of claims 1 to 9, characterized in that said use results in the reduction or normalization of Gibbs deformity, such as Gibbs deformity of the L1, L2, or L1 and L2 vertebrae.

11. Use in accordance with any of claims 1 to 10, characterized in that said use results in the reduction or normalization of the Cobb angle of thoracolumbar kyphosis, such as the Cobb angle of thoracolumbar kyphosis measured between vertebrae T10-L2 or T11-L2 or T12-L2.

12. Use, according to any of claims 1 to 11, characterized in that, prior to said use or treatment, the individual has a Cobb angle in the thoracolumbar kyphosis greater than approximately 20°, or greater than approximately 25°, or greater than approximately 30°, or greater than approximately 35°, or greater than approximately 40°, or greater than approximately 45°, or greater than approximately 50°.

13. Use, according to any of claims 1 to 12, characterized in that said use results in a reduction or normalization of the Cobb angle in thoracolumbar kyphosis, such as a reduction or normalization of the Cobb angle in thoracolumbar kyphosis of at least 3°, such as at least approximately 3° over a treatment period of at least 6 months or at least 12 months; or a reduction in the Z-score related to thoracolumbar kyphosis with achondroplasia or a reduction in the Z-score of healthy thoracolumbar kyphosis.

14. Use, according to any one of claims 1 to 13, characterized in that said use comprises measuring the thoracolumbar deformity before and / or during treatment using spinal radiography, such as a lateral spinal radiograph, wherein, optionally, the spinal radiograph is obtained from the individual standing, sitting or lying on their back, or from an image or radiograph obtained from the individual standing, sitting or lying on their back.

15. Use, according to any one of claims 1 to 14, characterized in that said use is for the treatment of a thoracolumbar deformity in an individual who is a child, such as a child aged 0 to 18 years, such as a child aged 0 to 14 years, such as a child under 12 years of age, such as a child under 10 years of age, or under 8 years of age, or under 6 years of age, such as a child under 5 years of age.

16. Use, according to any of claims 1 to 15, characterized in that said use is for the treatment of a thoracolumbar deformity in an individual who, before and during treatment or the treatment period, has exposed bone epiphysis.

17. Use, according to any one of claims 1 to 16, characterized in that said use is for the treatment of unfixed thoracolumbar kyphosis.

18. Use in accordance with any one of claims 1 to 14, characterized in that said use is for the treatment of an individual with a closed bony epiphysis.

19. Use in accordance with any one of claims 1 to 14 or 18, characterized in that said use is for the treatment of an individual who is at least 18 years of age, or at least 25 years of age, or at least 30 years of age.

20. Use in accordance with any one of claims 1 to 16, 18 or 19, characterized in that said use is for the treatment of fixed thoracolumbar kyphosis.

21. Use in accordance with any of claims 1 to 20, characterized in that said use is to increase growth velocity, such as annualized growth velocity (AGV), or linear growth rate in the individual, or growth Z-score related to achondroplasia.

22. Use, according to any one of claims 1 to 21, characterized in that said use is also for use in increasing the muscular function or physical functioning of said individual, such as for use in one or more of the following: a) increased skeletal muscle strength, b) increased skeletal muscle tone, c) increased skeletal muscle endurance, d) increased skeletal muscle mass, e) decreased skeletal muscle fatigue, Petition 870250079895, dated 05 / 09 / 2025, p. 336 / 354 5 / 6 f) increased cardiovascular endurance, g) increased cardiovascular fitness, h) decreased exercise intolerance, i) increased exercise capacity, j) decreased exercise-induced fatigue, and k) decreased hypotension.

23. Use, according to any of claims 1 to 22, characterized in that said use is, or also is, to improve the physical functioning or daily living functioning of said individual, which may optionally be assessed by means of one or more of the following: (i) ACEM-OSM (ii) ACEM Physical Functioning (iii) ACEM-Daily Living Functioning and (iv) SF-10 Physical Functioning.

24. Use, according to any of claims 1 to 23, characterized in that said use further includes the use of a spinal support or spinal orthosis, such as a thoracolumbar orthosis (TLSO), before, during or after said treatment / treatment period.

25. Use, according to any one of claims 1 to 24, characterized in that the NPR-B agonist is or comprises a C-type natriuretic peptide (CNP), a CNP conjugate or a CNP prodrug; or a pharmaceutically acceptable salt thereof.

26. Use, according to any one of claims 1 to 25, characterized in that the NPR-B agonist is a compound of formula (IIf'), formula (Iif), Navepegritide, compound (1), or a pharmaceutically acceptable salt thereof, wherein, optionally, the NPR-B agonist is administered weekly.

27. Use, according to any of claims 1 to 25, characterized in that the NPR-B agonist is either Petition 870250079895, dated 05 / 09 / 2025, page 337 / 354 6 / 6 includes vosoritide (SEQ ID NO:30), wherein, optionally, the NPR-B agonist is administered daily.

28. Use, according to any of claims 1 to 27, characterized in that the individual has or has been diagnosed with a developmental delay, such as motor developmental delay, and / or a cranial abnormality, such as narrowing of the foramen magnum or compression of the foramen magnum.

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