Treatment and prevention of muscular dystrophy and its related diseases or disorders with satralizumab

Abstract

All currently available treatment options for muscular dystrophy such as Duchenne muscular dystrophy (DMD) carry substantial potential safety risks. Further, no approved therapies exist for DMD that specifically target progressive bone loss and recurrent fragility fractures. The invention provides a means for a treatment for muscular dystrophy, such as DMD, and its related diseases or disorders, comprising an IL-6 inhibitor such as anti-IL-6 receptor antibody or antigen binding fragment thereof.

Description

TREATMENT AND PREVENTION OF MUSCULAR DYSTROPHY AND ITS RELATED DISEASES OR DISORDERS WITH SATRALIZUMAB

[0001] The present invention relates to a medicament or a pharmaceutical composition for treating a muscular dystrophy, and / or preventing or treating one or more diseases or disorders associated with muscular dystrophy, comprising an anti-IL-6 receptor antibody or antigen binding fragment thereof. The present invention also relates to a method for treating a muscular dystrophy, and / or preventing or treating one or more diseases or disorders associated with muscular dystrophy, by administering an anti-IL-6 receptor antibody or antigen binding fragment thereof to a subject in need thereof.

[0002] Duchenne muscular dystrophy (DMD) is a debilitating genetic disorder resulting from mutations in the DMD gene, leading to a deficiency in dystrophin production. Dystrophin is a critically important part of the protein complex that connects the cytoskeleton of a muscle fiber to the cell membrane and extracellular matrix and acts to prevent muscle membrane damage during eccentric contraction (Mendell et al. 2012: NPL 1). The absence of dystrophin leads to muscle fiber damage, progressive muscle weakness and eventual replacement of muscle with fat and fibrotic tissue, ultimately resulting in loss of ambulation, cardiomyopathy, respiratory failure, and death (Birnkrant et al. 2018: NPL 2). DMD also impacts bone health, with a high occurrence of osteoporosis and vertebral and long-bone fractures because of disease progression and long-term use of glucocorticoids (GC) (Ward et al. 2018: NPL 3). The elevation of pro-inflammatory and fibrotic biomarkers in serum due to muscle cell damage, including IL-6, plays a significant role in the pathophysiology of DMD (Starosta et al. 2021).

[0003] DMD is usually diagnosed between the ages of 3-5 years (Ciafaloni et al. 2009: NPL 4), when toddlers develop a waddling gait, lordosis, toe walking, calf hypertrophy, and difficulty climbing stairs. Over time, ambulation becomes increasingly abnormal. By 10-14 years of age, most boys lose ambulation and are wheelchair dependent. GC are currently the standard of care for the treatment of DMD due to their broad spectrum of anti-inflammatory and immunomodulatory effects, delaying the loss of ambulation by 2-4 years and preserving respiratory and cardiac function in the later stages (Gloss et al. 2016: NPL 5; Zambon et al. 2022: NPL 6). However, their long-term use is associated with several major side effects, including cushingoid appearance, obesity, puberty delay, short stature, osteoporosis, and fractures (Rhen et al. 2005: NPL 7). Additionally, GCs do not effectively target all pro-inflammatory factors, such as IL-6, and only normalize a small subset of serum protein biomarkers of inflammation in DMD (Hathout et al. 2019: NPL 8).

[0004] IL-6 plays a critical role in the pathophysiology of DMD, contributing to inflammation, fibrosis, and bone health issues (Birnkrant et al. 2018: NPL 2; Hathout et al. 2019: NPL 8). Specifically, IL-6 promotes the activation of the JAK / STAT pathway, mitogen-activated protein kinase pathways, and nuclear factor-kappa B (NF-kB). Elevated levels of IL-6 in muscle tissue are correlated with muscle atrophy, fibroadipogenic progenitor accumulation, increased inflammatory response, and satellite cell exhaustion (Forcina et al. 2018: NPL 9). In addition, IL-6 mediates bone loss by increasing the expression of RANKL, a strong inductor of bone resorption, and inhibits osteoblast differentiation and function (Rhen et al. 2005: NPL 7; Ward et al. 2018: NPL 10; Zambon et al. 2022: NPL 6). Preclinical and clinical studies have demonstrated a synergistic effect between GC and IL-6 receptor inhibitors, such as tocilizumab, in the treatment of inflammatory diseases (Pedersen et al. 2001: NPL 11, Hunter et al. 2015: NPL 12, Forcina et al. 2018: NPL 9). GCs have been shown to upregulate the IL-6 receptor in some cell types (Pederson et al. 2001: NPL 11; Mammen et al. 2015: NPL 13), and to increase circulating levels of IL6R and gp130 in multiple sclerosis patients (Dovio et al. 2006: NPL 14), a mechanism that could be mediating the osteoporosis caused by GCs, which can be effectively targeted by an IL6R inhibitor.

[0005] Bone loss is a highly neglected aspect of DMD that affects patients from an early age onwards. The mechanism of bone loss in DMD is guided by a constellation of low bone mass and deterioration of bone microarchitecture directly caused by the myopathy, which is after exacerbated by corticosteroid treatment and reduced activity and weight bearing associated with this condition. Even in those patients who are ambulatory, BMD decreases significantly over time (Ronsley et al. 2020: NPL 15). Severe osteoporosis with clinically significant bone fragility and increased incidence of bone fractures has been reported in pediatric patients with DMD (Morgenroth et al. 2012: NPL 16; Ma et al. 2017: NPL 17). Fractures occur in 21-60% of DMD patients, and up to 75% of patients treated with long-term glucocorticoid therapy (Bothwell et al. 2003: NPL 18). Significantly, this contrasts to a fracture prevalence of 9% in healthy children (Perera et al. 2016: NPL 19). It has been reported that the long-bone fracture incidence rate in DMD is at least 4 times higher than in healthy boys. On the other hand, the incidence of VF in DMD is 535 times higher than normal developing children (Joseph et al. 2019: NPL 20). The incidence of VF is likely underestimated given that nearly half of the VF are asymptomatic and go unnoticed without screening via spine X-rays or until they are more advanced and show back pain and spinal deformity. A study by Phung et al showed an incidence of VF (using VF screening) that is more than 11000 times higher than healthy boys, pointing to the high unmet medical need in DMD (Phung et al. 2023: NPL 21). Fracture probabilities at ages 6, 9, 12, and 15 years have been described to be 4%, 9%, 31%, and 60% respectively, accelerating around the time of ambulation loss (mean age 11.8 + / - 2.7 years) (Perera et al. 2016: NPL 19). Fracture incidence is normally age dependent: the probability of experiencing a fracture accelerates around the age of 8, 1-2 years after commencing glucocorticoid therapy (Joseph et al. 2019: NPL 20; James et al. 2015: NPL 22), and peaks at age 14 to 15 years (Joseph et al. 2019: NPL 20).

[0006] A long bone fracture or vertebral compression fracture is a sentinel event in the life of boys with DMD. A long bone fracture often leads to early and permanent loss of ambulation due to prolonged immobilization (Suthar et al. 2021: NPL 23; Tian et al. 2016: NPL 24; Crabtree et al. 2018: NPL 25). The presence of VF is associated with back pain, scoliosis, increased respiratory weakness and poor quality of life (Suthar et al. 2021: NPL 23;). They are a significant cause of morbidity and an indicator of future incident VFs in children (Morgenroth et al. 2012: NPL 16; Mammen et al. 2015: NPL 13) and adults (Saraff et al. 2015: NPL 26). A phenomenon known as the VF cascade is a likely factor that further contributes to new VF following initial vertebral collapse (Ma et al. 2017: NPL 17). Fractures in corticosteroid treated DMD boys most frequently occur in the distal femur, proximal tibia and vertebrae, all areas of high trabecular bone content. In comparison with steroid-naive DMD boys, corticosteroids are reported to increase VF risk but not long-bone fracture risk (Mayo et al. 2012: NPL 27).

[0007] Preventing the first fracture, and thereby further incidence of fractures, is of crucial importance for DMD patients to preserve their ambulation and quality of life for an extended period of time, as well as to prevent the severe and life-threatening complications arising from the underlying osteoporosis and associated fractures.

[0008] Management of DMD requires both preventive and therapeutic measures, as recommended by DMD Care Considerations Working Group and the American Academy of Neurology (AAN) (Birnkrant et al. 2018: NPL 2). There are currently no approved therapies to treat osteoporosis and prevent bone loss in DMD. The DMD care guidelines recommend the use of anti-resorptive therapy with bisphosphonates, even though they are not approved to treat DMD. A recent systematic literature review found high-quality evidence that bisphosphonates significantly increase the areal lumbar spine BMD Z-score in glucocorticoid-treated patients with DMD, however, the evidence of benefits to fracture risks was inconclusive and / or of low quality, primarily due to lack of controlled data and small sample sizes (Landfeldtet al. 2024: NPL 28). This highlights a significant unmet medical need for the treatment of DMD-induced bone loss.

[0009] [NPL 1] Mendell JR, Al-Zaidy SA, Rodino-Klapac LR, et al. Neurosci Lett 2012;527:90-9. [NPL 2] Birnkrant D, Ashwal S, Swoboda K, et al. Lancet Neurol 2018;17(4):347-61. [NPL 3] Ward L., Kilmer D, Morgenroth V, et al. Neuromuscular Disorders 2018;28(1):64-76. [NPL 4] Ciafaloni E, Fox DJ, Pandya S, et al. J Pediatrics 2009;155(3):380-5. [NPL 5] Gloss D, Johnson M, Lee S, et al. Neurology 2018;86(5):465-72. [NPL 6] Zambon A, Jones B, Patel S, et al. Dev Med Child Neurol 2022;64(8):979-88. [NPL 7] Rhen T, Wilson L, Anderson P, et al. N Engl J Med 2005;353(16):1711-23. [NPL 8] Hathout Y, Smith A, Davis B, et al. Sci Rep 2019;9(1):12167. [NPL 9] Forcina, L, Brown, M, Miller, C, et al. Cytokine Growth Factor Rev 2018;41:1-9. [NPL 10] Ward L, Smith J, Johnson R, et al. Pediatrics 2018;142(s2):e20180333E. [NPL 11] Pedersen B, Olsen C, Jensen E, et al. Journal of Physiology 2001;536.2:329-37. [NPL 12] Hunter C, Patel S, White D, et al. Nat Immunol 2015;16(5):448-57. [NPL 13] Mammen A, Brown M, Miller C, et al. EBioMedicine 2015;2(4):274-75. [NPL 14] Dovio A, Tanaka, T, Johnson R, et al. Eur J Endocrinol 2006;154(5):745-51. [NPL 15] Ronsley R, Patel S, Kumar A, et al. Clinical Med Insights: Endocrinology and diabetes 2020;13:1-8. [NPL 16] Morgenroth V, Jones A, Smith B, et al. BoneKEy Reports 2012;1(9). [NPL 17] Ma J, Smith C, Johnson L, et al. Osteoporos Int 2017;28:597-608. [NPL 18] Bothwell JE, Gordon KE, Dooley JM, et al. Clin Pediatr (Phila) 2003;42(4):353-6. [NPL 19] Perera N, Campbell C, Darras B, et al. Journal of Child Neurology 2016;31(9):1181-87. [NPL 20] Joseph S. JAMA Neurol 2019;76(6):701-09. [NPL 21] Phung T, Nguyen H, Tran Q, et al. J Clin Endocrin & Metab 2023;00:1-13. [NPL 22] James A, Brown M, Miller C, et al. J Pediatr Orthop,35:640-44. [NPL 23] Suthar R, Patel S, Gupta M, et al. J Pediatr Endocrinol Metab 2021;34(5):573-81. [NPL 24] Tian C, Granzier H, Wang K, et al. Neuromuscular Disorders 2016;26:760-67. [NPL 25] Crabtree N, Khan I, Davidson K, et al. Bone 2018;116:181-6. [NPL 26] Saraff V, Jones M, Patel A, et al. European Journal of Endocrinology 2015;173:R185-197. [NPL 27] Mayo A, Singh R, Chen D, et al. Neuromuscular Disorders 2012;22:1040-45. [NPL 28] Landfeldt E, Thompson R, Sejerson T, et al. Bisphosphonates in Glucocorticoid-Treated Patients with Duchenne Muscular Dystrophy: A Systematic Review and Grading of the Evidence. Neurology 2024;102:e207948.

[0010] Current treatment options for DMD aim to target the underlying myopathy caused by a lack of dystrophin production, mainly due to out-of-frame mutations in the DMD gene, including therapies available to a small proportion of patients (e.g., exon-skipping or gene transfer therapies). Systemic corticosteroids (either prednisone / prednisolone or deflazacort) are considered the standard of care in DMD (Sejerson et al. 2009), and while they confer limited benefit in extending ambulation (Gloss et al. 2016), they introduce significant unwanted side effects such as progressive osteotoxicity that leads to osteoporosis and fragility fractures. The mechanism of bone loss in DMD is thought to be mainly driven by two factors: the progressive loss of muscle strength with reduced mobility and glucocorticoid-induced osteotoxicity (Ward et al. 2018). Fractures are often reported in young DMD patients even prior to steroid treatment commencement (Perera et al. 2016), which highlights the critical role of muscle strength and mechanical load input into natural bone development, which is lacking in DMD. In addition, well known severe complications from recurrent fractures include permanent loss of ambulation (Tian et al. 2016; Crabtree et al. 2018, Suthar et al. 2021), spinal deformities, chronic back pain (Suthar et al. 2021), fat embolism syndrome and increased mortality (Feder et al. 2017). The elevation of serum pro-inflammatory and fibrotic biomarkers due to muscle cell membrane damage and chronic activation of inflammatory processes, including interleukin-6 (IL-6), further exacerbates the progression of DMD (Starosta et al. 2021). This increased IL-6 signaling is thought to be promoting both the underlying muscle atrophy and the increased bone resorption reported in DMD patients (Rufo et al. 2011).

[0011] There are currently no approved treatments for DMD that specifically target progressive bone loss and recurrent fragility fractures. The 2018 Duchenne care guidelines recommend the use of bisphosphonates (anti-resorptive therapies not approved for DMD) once a certain level of bone fragility is reached, i.e., when osteoporosis manifests as bone fragility fractures, especially the compression vertebral fractures (VF) (Birnkrant et al 2018). Although bisphosphonates have been shown to increase bone mineral density (BMD) in glucocorticoid treated DMD patients, the uptake of bisphosphonates in DMD is overall low. This may be in part due to the high frequency of acute phase reactions and other harmful adverse events, inconsistent systemic effects between oral and intravenous routes of administration, and because they are not recommended before adolescence (Zhao 2022; Landfeldt 2024; Zoledronic acid USPI). In addition, they do not significantly reduce the incidence of fractures in DMD patients, despite increasing the BMD (Landfeldt et al 2024). Therefore, there is a high unmet medical need for the development of an efficacious treatment to prevent bone loss and the associated fragility fractures in all patients with DMD.

[0012] To solve the above-mentioned problem, the inventors designed a phase 2 multicenter, open-label study to evaluate the safety, efficacy, pharmacokinetics and pharmacodynamics of satralizumab in pediatric patients with duchenne muscular dystrophy (DMD). The study demonstrates that satralizumab addresses the above noted unmet needs, and also establishes the effectiveness of satralizumab in patients with muscular dystrophy such as DMD for treating a muscular dystrophy, and / or for preventing or treating one or more diseases or disorders associated with muscular dystrophy.

[0013] The present disclosure includes but not limited to the embodiments as exemplarily described below. [A1.1] A medicament for use in a method for treating a muscular dystrophy in a subject, comprising an IL-6 inhibitor as an active ingredient. [A1.2] A medicament for use in a method for preventing or treating one or more diseases or disorders associated with muscular dystrophy in a subject, comprising an IL-6 inhibitor as an active ingredient. [A1.3] The medicament of A1.2, wherein the one or more diseases or disorders associated with muscular dystrophy are osteoporosis, bone loss, decreased bone mineral density (BMD), abnormal bone metabolism, increased bone resorption, decreased bone formation, bone fracture, fragility fracture, decreased motor function, decreased muscle strength, or inflammation in microenvironment in a muscle. [A1.4] The medicament of any one of A1.1-A1.3, wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Fukuyama congenital muscular dystrophy (FCMD), Limb-girdle muscular dystrophy (LGMD), or Facio-scapulo-humeral muscular dystrophy (FSHD). [A1.5] The medicament of A1.4, wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD). [A1.6] The medicament of any one of A1.1-A1.5, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [A1.7] The medicament of any one of A1.1-A1.6, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2. [A1.8] The medicament of any one of A1.1-A1.7, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 3 and a light chain comprising the amino acid sequence of SEQ ID NO: 4. [A1.9] The medicament of any one of A1.1-A1.8, wherein the IL-6 inhibitor is satralizumab. [A1.10] The medicament of any one of A1.1-A1.9, wherein the method comprises administering 60 mg of the IL-6 inhibitor to the subject with body weight of less than 40 kg for each administration, or 120 mg of the IL-6 inhibitor to the subject with body weight of equal to or more than 40 kg for each administration. [A1.11] The medicament of any one of A1.1-A1.10, wherein the method comprises administering the IL-6 inhibitor to the subject every two weeks (Q2W) for three times, and thereafter every 4 weeks (Q4W). [A1.12] The medicament of any one of A1.1-A1.11, wherein the method comprises administering the IL-6 inhibitor to the subject subcutaneously. [A1.13] The medicament of any one of A1.1-A1.12, wherein the subject is adolescent or pre-adolescent. [A1.14] The medicament of any one of A1.1-A1.13, wherein the subject is aged from 8 to less than 16 years. [A1.15] The medicament of any one of A1.1-A1.14, wherein the subject is aged from 8 to less than 12 years. [A1.16] The medicament of any one of A1.1-A1.15, wherein the subject is ambulatory. [A1.17] The medicament of any one of A1.1-A1.15, wherein the subject is non-ambulatory. [A1.18] The medicament of any one of A1.1-A1.17, wherein the subject is male at birth. [A1.19] The medicament of any one of A1.1-A1.18, wherein the subject has a history of fractures, optionally low-trauma fractures. [A1.20] The medicament of any one of A1.1-A1.19, wherein the subject has existing fractures, optionally low-trauma fractures. [A1.21] The medicament of any one of A1.1-A1.18, wherein the subject has no history of prior fractures, optionally low-trauma fractures. [A1.22] The medicament of any one of A1.1-A1.21, wherein the subject has not experienced steroid treatment. [A1.23] The medicament of any one of A1.1-A1.21, wherein the subject is receiving no ongoing chronic immunosuppressive therapy. [A1.24] The medicament of any one of A1.1-A1.21, wherein the subject is receiving ongoing treatment with systemic corticosteroid(s). [A1.25] The medicament of A1.24, wherein the corticosteroid is prednisone, prednisolone, deflazacor, or equivalent thereof. [A1.26] The medicament of any one of A1.1-A1.25, wherein the method further comprises administering an immunosuppressive agent to the subject. [A1.27] The medicament of A1.26, wherein the immunosuppressive agent is any one or more selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [A1.28] The medicament of any one of A1.1-A1.27, which prevents / reduces / minimizes bone resorption, promotes / increases bone formation, prevents / reduces / minimizes bone loss, increases bone mineral density (BMD), reduces risk of fractures, and / or prevents / reduces / minimizes fragility fractures in the subject. [A1.29] The medicament of any one of A1.1-A1.28, which increases levels of one or more of the following biomarkers: osteocalcin (OC), bone alkaline phosphatase (BSAP), procollagen type 1 N-terminal propeptide (P1NP), and osteoprotegerin (OPG) in serum of the subject [A1.30] The medicament of any one of A1.1-A1.29, which reduces levels of one or more of the following biomarkers: tartrate-resistant acid phosphatase 5b (TRAP 5b), carboxy-terminal crosslinked telopeptide of type 1 collagen (CTX-1), receptor activator of NF-kB ligand (RANKL), dickkopf-1 (DDK-1), sclerostin, and creatine kinase (CK) in serum of the subject.

[0014] [A2.1] A pharmaceutical composition for use in a method for treating a muscular dystrophy in a subject, comprising an IL-6 inhibitor as an active ingredient. [A2.2] A pharmaceutical composition for use in a method for preventing or treating one or more diseases or disorders associated with muscular dystrophy in a subject, comprising an IL-6 inhibitor as an active ingredient. [A2.3] The pharmaceutical composition of A2.2, wherein the one or more diseases or disorders associated with muscular dystrophy are osteoporosis, bone loss, decreased bone mineral density (BMD), abnormal bone metabolism, increased bone resorption, decreased bone formation, bone fracture, fragility fracture, decreased motor function, decreased muscle strength, or inflammation in microenvironment in a muscle. [A2.4] The pharmaceutical composition of any one of A2.1-A2.3, wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Fukuyama congenital muscular dystrophy (FCMD), Limb-girdle muscular dystrophy (LGMD), or Facio-scapulo-humeral muscular dystrophy (FSHD). [A2.5] The pharmaceutical composition of A2.4, wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD). [A2.6] The pharmaceutical composition of any one of A2.1-A2.5, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [A2.7] The pharmaceutical composition of any one of A2.1-A2.6, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2. [A2.8] The pharmaceutical composition of any one of A2.1-A2.7, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 3 and a light chain comprising the amino acid sequence of SEQ ID NO: 4. [A2.9] The pharmaceutical composition of any one of A2.1-A2.8, wherein the IL-6 inhibitor is satralizumab. [A2.10] The pharmaceutical composition of any one of A2.1-A2.9, wherein the method comprises administering 60 mg of the IL-6 inhibitor to the subject with body weight of less than 40 kg for each administration, or 120 mg of the IL-6 inhibitor to the subject with body weight of equal to or more than 40 kg for each administration. [A2.11] The pharmaceutical composition of any one of A2.1-A2.10, wherein the method comprises administering the IL-6 inhibitor to the subject every two weeks (Q2W) for three times, and thereafter every 4 weeks (Q4W). [A2.12] The pharmaceutical composition of any one of A2.1-A2.11, wherein the method comprises administering the IL-6 inhibitor to the subject subcutaneously. [A2.13] The pharmaceutical composition of any one of A2.1-A2.12, wherein the subject is adolescent or pre-adolescent. [A2.14] The pharmaceutical composition of any one of A2.1-A2.13, wherein the subject is aged from 8 to less than 16 years. [A2.15] The pharmaceutical composition of any one of A2.1-A2.14, wherein the subject is aged from 8 to less than 12 years. [A2.16] The pharmaceutical composition of any one of A2.1-A2.15, wherein the subject is ambulatory. [A2.17] The pharmaceutical composition of any one of A2.1-A2.15, wherein the subject is non-ambulatory. [A2.18] The pharmaceutical composition of any one of A2.1-A2.17, wherein the subject is male at birth. [A2.19] The pharmaceutical composition of any one of A2.1-A2.18, wherein the subject has a history of fractures, optionally low-trauma fractures. [A2.20] The pharmaceutical composition of any one of A2.1-A2.19, wherein the subject has existing fractures, optionally low-trauma fractures. [A2.21] The pharmaceutical composition of any one of A2.1-A2.18, wherein the subject has no history of prior fractures, optionally low-trauma fractures. [A2.22] The pharmaceutical composition of any one of A2.1-A2.21, wherein the subject has not experienced steroid treatment. [A2.23] The pharmaceutical composition of any one of A2.1-A2.21, wherein the subject is receiving no ongoing chronic immunosuppressive therapy. [A2.24] The pharmaceutical composition of any one of A2.1-A2.21, wherein the subject is receiving ongoing treatment with systemic corticosteroid(s). [A2.25] The pharmaceutical composition of A2.24, wherein the corticosteroid is prednisone, prednisolone, deflazacor, or equivalent thereof. [A2.26] The pharmaceutical composition of any one of A2.1-A2.25, wherein the method further comprises administering an immunosuppressive agent to the subject. [A2.27] The pharmaceutical composition of A2.26, wherein the immunosuppressive agent is any one or more selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [A2.28] The pharmaceutical composition of any one of A2.1-A2.27, which prevents / reduces / minimizes bone resorption, promotes / increases bone formation, prevents / reduces / minimizes bone loss, increases bone mineral density (BMD), reduces risk of fractures, and / or prevents / reduces / minimizes fragility fractures in the subject. [A2.29] The pharmaceutical composition of any one of A2.1-A2.28, which increases levels of one or more of the following biomarkers: osteocalcin (OC), bone alkaline phosphatase (BSAP), procollagen type 1 N-terminal propeptide (P1NP), and osteoprotegerin (OPG) in serum of the subject. [A2.30] The pharmaceutical composition of any one of A2.1-A2.29, which reduces levels of one or more of the following biomarkers: tartrate-resistant acid phosphatase 5b (TRAP 5b), carboxy-terminal crosslinked telopeptide of type 1 collagen (CTX-1), receptor activator of NF-kB ligand (RANKL), dickkopf-1 (DDK-1), sclerostin, and creatine kinase (CK) in serum of the subject.

[0015] [B1] Use of an IL-6 inhibitor in the preparation of a medicament for treating a muscular dystrophy in a subject. [B2] Use of an IL-6 inhibitor in the preparation of a medicament for preventing or treating one or more diseases or disorders associated with muscular dystrophy in a subject. [B3] The use of B2, wherein the one or more diseases or disorders associated with muscular dystrophy are osteoporosis, bone loss, decreased bone mineral density (BMD), abnormal bone metabolism, increased bone resorption, decreased bone formation, bone fracture, fragility fracture, decreased motor function, decreased muscle strength, or inflammation in microenvironment in a muscle. [B4] The use of any one of B1-B3, wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Fukuyama congenital muscular dystrophy (FCMD), Limb-girdle muscular dystrophy (LGMD), or Facio-scapulo-humeral muscular dystrophy (FSHD). [B5] The use of B4, wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD). [B6] The use of any one of B1-B5, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [B7] The use of any one of B1-B6, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2. [B8] The use of any one of B1-B7, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 3 and a light chain comprising the amino acid sequence of SEQ ID NO: 4. [B9] The use of any one of B1-B8, wherein the IL-6 inhibitor is satralizumab. [B10] The use of any one of B1-B9, wherein the medicament is used such that 60 mg of the IL-6 inhibitor is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of the IL-6 inhibitor is administered to the subject with body weight of equal to or more than 40 kg for each administration. [B11] The use of any one of B1-B10, wherein the medicament is used such that the IL-6 inhibitor is administered to the subject every two weeks (Q2W) for three times, and thereafter every 4 weeks (Q4W) . [B12] The use of any one of B1-B11, wherein the medicament is used such that the IL-6 inhibitor is administered to the subject subcutaneously. [B13] The use of any one of B1-B12, wherein the subject is adolescent or pre-adolescent. [B14] The use of any one of B1-B13, wherein the subject is aged from 8 to less than 16 years. [B15] The use of any one of B1-B14, wherein the subject is aged from 8 to less than 12 years. [B16] The use of any one of B1-B15, wherein the subject is ambulatory. [B17] The use of any one of B1-B15, wherein the subject is non-ambulatory. [B18] The use of any one of B1-B17, wherein the subject is male at birth. [B19] The use of any one of B1-B18, wherein the subject has a history of fractures, optionally low-trauma fractures. [B20] The use of any one of B1-B19, wherein the subject has existing fractures, optionally low-trauma fractures. [B21] The use of any one of B1-B18, wherein the subject has no history of prior fractures, optionally low-trauma fractures. [B22] The use of any one of B1-B21, wherein the subject has not experienced steroid treatment. [B23] The use of any one of B1-B21, wherein the subject is receiving no ongoing chronic immunosuppressive therapy. [B24] The use of any one of B1-B21, wherein the subject is receiving ongoing treatment with systemic corticosteroid(s). [B25] The use of B24, wherein the corticosteroid is prednisone, prednisolone, deflazacor, or equivalent thereof. [B26] The use of any one of B1-B25, wherein the medicament is used in combination with an immunosuppressive agent. [B27] The use of B26, wherein the immunosuppressive agent is any one or more selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [B28] The use of any one of B1-B27, wherein the medicament prevents / reduces / minimizes bone resorption, promotes / increases bone formation, prevents / reduces / minimizes bone loss, increases bone mineral density (BMD), reduces risk of fractures, and / or prevents / reduces / minimizes fragility fractures in the subject. [B29] The use of any one of B1-B28, wherein the medicament increases levels of one or more of the following biomarkers: osteocalcin (OC), bone alkaline phosphatase (BSAP), procollagen type 1 N-terminal propeptide (P1NP), and osteoprotegerin (OPG) in serum of the subject. [B30] The use of any one of B1-B29, wherein the medicament reduces levels of one or more of the following biomarkers: tartrate-resistant acid phosphatase 5b (TRAP 5b), carboxy-terminal crosslinked telopeptide of type 1 collagen (CTX-1), receptor activator of NF-kB ligand (RANKL), dickkopf-1 (DDK-1), sclerostin, and creatine kinase (CK) in serum of the subject.

[0016] [C1] An IL-6 inhibitor for use in treating a muscular dystrophy in a subject. [C2] An IL-6 inhibitor for use in preventing or treating one or more diseases or disorders associated with muscular dystrophy in a subject. [C3] The IL-6 inhibitor for use of C2, wherein the one or more diseases or disorders associated with muscular dystrophy are osteoporosis, bone loss, decreased bone mineral density (BMD), abnormal bone metabolism, increased bone resorption, decreased bone formation, bone fracture, fragility fracture, decreased motor function, decreased muscle strength, or inflammation in microenvironment in a muscle. [C4] The IL-6 inhibitor for use of any one of C1-C3, wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Fukuyama congenital muscular dystrophy (FCMD), Limb-girdle muscular dystrophy (LGMD), or Facio-scapulo-humeral muscular dystrophy (FSHD). [C5] The IL-6 inhibitor for use of C4, wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD). [C6] The IL-6 inhibitor for use of any one of C1-C5, which is an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [C7] The IL-6 inhibitor for use of any one of C1-C6, which is an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2. [C8] The IL-6 inhibitor for use of any one of C1-C7, which is an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 3 and a light chain comprising the amino acid sequence of SEQ ID NO: 4. [C9] The IL-6 inhibitor for use of any one of C1-C8, which is satralizumab. [C10] The IL-6 inhibitor for use of any one of C1-C9, wherein 60 mg of the IL-6 inhibitor is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of the IL-6 inhibitor is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C11] The IL-6 inhibitor for use of any one of C1-C10, which is administered to the subject every two weeks (Q2W) for three times, and thereafter every 4 weeks (Q4W). [C12] The IL-6 inhibitor for use of any one of C1-C11, which is administered to the subject subcutaneously. [C13] The IL-6 inhibitor for use of any one of C1-C12, wherein the subject is adolescent or pre-adolescent. [C14] The IL-6 inhibitor for use of any one of C1-C13, wherein the subject is aged from 8 to less than 16 years. [C15] The IL-6 inhibitor for use of any one of C1-C14, wherein the subject is aged from 8 to less than 12 years. [C16] The IL-6 inhibitor for use of any one of C1-C15, wherein the subject is ambulatory. [C17] The IL-6 inhibitor for use of any one of C1-C15, wherein the subject is non-ambulatory. [C18] The IL-6 inhibitor for use of any one of C1-C17, wherein the subject is male at birth. [C19] The IL-6 inhibitor for use of any one of C1-C18, wherein the subject has a history of fractures, optionally low-trauma fractures. [C20] The IL-6 inhibitor for use of any one of C1-C19, wherein the subject has existing fractures, optionally low-trauma fractures. [C21] The IL-6 inhibitor for use of any one of C1-C18, wherein the subject has no history of prior fractures, optionally low-trauma fractures. [C22] The IL-6 inhibitor for use of any one of C1-C21, wherein the subject has not experienced steroid treatment. [C23] The IL-6 inhibitor for use of any one of C1-C21, wherein the subject is receiving no ongoing chronic immunosuppressive therapy. [C24] The IL-6 inhibitor for use of any one of C1-C21, wherein the subject is receiving ongoing treatment with systemic corticosteroid(s). [C25] The IL-6 inhibitor for use of C24, wherein the corticosteroid is prednisone, prednisolone, deflazacor, or equivalent thereof. [C26] The IL-6 inhibitor for use of any one of C1-C25, which is used in combination with an immunosuppressive agent. [C27] The IL-6 inhibitor for use of C26, wherein the immunosuppressive agent is any one or more selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [C28] The IL-6 inhibitor for use of C1-C27, which prevents / reduces / minimizes bone resorption, promotes / increases bone formation, prevents / reduces / minimizes bone loss, increases bone mineral density (BMD), reduces risk of fractures, and / or prevents / reduces / minimizes fragility fractures in the subject. [C29] The IL-6 inhibitor for use of any one of C1-C28, which increases levels of one or more of the following biomarkers: osteocalcin (OC), bone alkaline phosphatase (BSAP), procollagen type 1 N-terminal propeptide (P1NP), and osteoprotegerin (OPG) in serum of the subject. [C30] The IL-6 inhibitor for use of any one of C1-C29, which reduces levels of one or more of the following biomarkers: tartrate-resistant acid phosphatase 5b (TRAP 5b), carboxy-terminal crosslinked telopeptide of type 1 collagen (CTX-1), receptor activator of NF-kB ligand (RANKL), dickkopf-1 (DDK-1), sclerostin, and creatine kinase (CK) in serum of the subject.

[0017] [C2.1] Satralizumab for use in treating DMD in a subject. [C2.2] Satralizumab for use in treating one or more diseases or disorders associated with DMD in a subject. [C2.3] Satralizumab for use in preventing one or more diseases or disorders associated with DMD in a subject. [C2.4] Satralizumab for use in treating osteoporosis in a subject having DMD. [C2.5] Satralizumab for use in preventing bone loss in a subject having DMD. [C2.6] Satralizumab for use in increasing bone mineral density (BMD) in a subject having DMD. [C2.7] Satralizumab for use in preventing bone fractures, optionally fragility fractures, in a subject having DMD. [C2.8] Satralizumab for use in improving an inflammatory microenvironment in a muscle of a subject having DMD. [C2.9] Satralizumab for use in increasing motor function in a subject having DMD. [C2.10] Satralizumab for use in increasing muscle strength in a subject having DMD. [C2.11] Satralizumab for use in preventing bone loss and improving an inflammatory microenvironment in a muscle of a subject having DMD. [C2.12] Satralizumab for use in preventing fragility fractures and increasing motor function in a subject having DMD. [C2.13] Satralizumab for use in treating DMD in a subject, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [C2.14] Satralizumab for use in treating one or more diseases or disorders associated with DMD in a subject, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [C2.15] Satralizumab for use in preventing one or more diseases or disorders associated with DMD in a subject, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [C2.16] Satralizumab for use in treating osteoporosis in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [C2.17] Satralizumab for use in preventing bone loss in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [C2.18] Satralizumab for use in increasing bone mineral density (BMD) in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [C2.19] Satralizumab for use in preventing bone fractures, optionally fragility fractures, in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [C2.20] Satralizumab for use in improving an inflammatory microenvironment in a muscle of a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [C2.21] Satralizumab for use in increasing motor function in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [C2.22] Satralizumab for use in increasing muscle strength in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [C2.23] Satralizumab for use in preventing bone loss and improving an inflammatory microenvironment in a muscle of a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [C2.24] Satralizumab for use in preventing fragility fractures and increasing motor function in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [C2.25] Satralizumab for use in treating DMD in a subject, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.26] Satralizumab for use in treating one or more diseases or disorders associated with DMD in a subject, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kgfor each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.27] Satralizumab for use in preventing one or more diseases or disorders associated with DMD in a subject, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.28] Satralizumab for use in treating osteoporosis in a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.29] Satralizumab for use in preventing bone loss in a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.30] Satralizumab for use in increasing bone mineral density (BMD) in a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.31] Satralizumab for use in preventing bone fractures, optionally fragility fractures, in a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.32] Satralizumab for use in improving an inflammatory microenvironment in a muscle of a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.33] Satralizumab for use in increasing motor function in a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.34] Satralizumab for use in increasing muscle strength in a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.35] Satralizumab for use in preventing bone loss and improving an inflammatory microenvironment in a muscle of a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.36] Satralizumab for use in preventing fragility fractures and increasing motor function in a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.37] Satralizumab for use in treating DMD in a subject, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.38] Satralizumab for use in treating one or more diseases or disorders associated with DMD in a subject, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.39] Satralizumab for use in preventing one or more diseases or disorders associated with DMD in a subject, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.40] Satralizumab for use in treating osteoporosis in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.41] Satralizumab for use in preventing bone loss in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.42] Satralizumab for use in increasing bone mineral density (BMD) in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.43] Satralizumab for use in preventing bone fractures, optionally fragility fractures, in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.44] Satralizumab for use in improving an inflammatory microenvironment in a muscle of a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.45] Satralizumab for use in increasing motor function in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.46] Satralizumab for use in increasing muscle strength in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.47] Satralizumab for use in preventing bone loss and improving an inflammatory microenvironment in a muscle of a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.48] Satralizumab for use in preventing fragility fractures and increasing motor function in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration. [C2.49] Satralizumab for use in treating DMD in a subject, wherein the subject is aged from 8 to less than 16 years. [C2.50] Satralizumab for use in treating one or more diseases or disorders associated with DMD in a subject, wherein the subject is aged from 8 to less than 16 years. [C2.51] Satralizumab for use in preventing one or more diseases or disorders associated with DMD in a subject, wherein the subject is aged from 8 to less than 16 years. [C2.52] Satralizumab for use in treating osteoporosis in a subject having DMD, wherein the subject is aged from 8 to less than 16 years. [C2.53] Satralizumab for use in preventing bone loss in a subject having DMD, wherein the subject is aged from 8 to less than 16 years. [C2.54] Satralizumab for use in increasing bone mineral density (BMD) in a subject having DMD, wherein the subject is aged from 8 to less than 16 years. [C2.55] Satralizumab for use in preventing bone fractures, optionally fragility fractures, in a subject having DMD, wherein the subject is aged from 8 to less than 16 years. [C2.56] Satralizumab for use in improving an inflammatory microenvironment in a muscle of a subject having DMD, wherein the subject is aged from 8 to less than 16 years. [C2.57] Satralizumab for use in increasing motor function in a subject having DMD, wherein the subject is aged from 8 to less than 16 years. [C2.58] Satralizumab for use in increasing muscle strength in a subject having DMD, wherein the subject is aged from 8 to less than 16 years. [C2.59] Satralizumab for use in preventing bone loss and improving an inflammatory microenvironment in a muscle of a subject having DMD, wherein the subject is aged from 8 to less than 16 years. [C2.60] Satralizumab for use in preventing fragility fractures and increasing motor function in a subject having DMD, wherein the subject is aged from 8 to less than 16 years. [C2.61] Satralizumab for use in treating DMD in a subject, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein the subject is aged from 8 to less than 16 years. [C2.62] Satralizumab for use in treating one or more diseases or disorders associated with DMD in a subject, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein the subject is aged from 8 to less than 16 years. [C2.63] Satralizumab for use in preventing one or more diseases or disorders associated with DMD in a subject, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein the subject is aged from 8 to less than 16 years. [C2.64] Satralizumab for use in treating osteoporosis in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein the subject is aged from 8 to less than 16 years. [C2.65] Satralizumab for use in preventing bone loss in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein the subject is aged from 8 to less than 16 years. [C2.66] Satralizumab for use in increasing bone mineral density (BMD) in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein the subject is aged from 8 to less than 16 years. [C2.67] Satralizumab for use in preventing bone fractures, optionally fragility fractures, in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein the subject is aged from 8 to less than 16 years. [C2.68] Satralizumab for use in improving an inflammatory microenvironment in a muscle of a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein the subject is aged from 8 to less than 16 years. [C2.69] Satralizumab for use in increasing motor function in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein the subject is aged from 8 to less than 16 years. [C2.70] Satralizumab for use in increasing muscle strength in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein the subject is aged from 8 to less than 16 years. [C2.71] Satralizumab for use in preventing bone loss and improving an inflammatory microenvironment in a muscle of a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein the subject is aged from 8 to less than 16 years. [C2.72] Satralizumab for use in preventing fragility fractures and increasing motor function in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein the subject is aged from 8 to less than 16 years. [C2.73] Satralizumab for use in treating DMD in a subject, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.74] Satralizumab for use in treating one or more diseases or disorders associated with DMD in a subject, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.75] Satralizumab for use in preventing one or more diseases or disorders associated with DMD in a subject, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.76] Satralizumab for use in treating osteoporosis in a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.77] Satralizumab for use in preventing bone loss in a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.78] Satralizumab for use in increasing bone mineral density (BMD) in a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.79] Satralizumab for use in preventing bone fractures, optionally fragility fractures, in a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.80] Satralizumab for use in improving an inflammatory microenvironment in a muscle of a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.81] Satralizumab for use in increasing motor function in a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.82] Satralizumab for use in increasing muscle strength in a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.83] Satralizumab for use in preventing bone loss and improving an inflammatory microenvironment in a muscle of a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.84] Satralizumab for use in preventing fragility fractures and increasing motor function in a subject having DMD, wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.85] Satralizumab for use in treating DMD in a subject, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.86] Satralizumab for use in treating one or more diseases or disorders associated with DMD in a subject, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.87] Satralizumab for use in preventing one or more diseases or disorders associated with DMD in a subject, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.88] Satralizumab for use in treating osteoporosis in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.89] Satralizumab for use in preventing bone loss in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.90] Satralizumab for use in increasing bone mineral density (BMD) in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.91] Satralizumab for use in preventing bone fractures, optionally fragility fractures, in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.92] Satralizumab for use in improving an inflammatory microenvironment in a muscle of a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.93] Satralizumab for use in increasing motor function in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.94] Satralizumab for use in increasing muscle strength in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.95] Satralizumab for use in preventing bone loss and improving an inflammatory microenvironment in a muscle of a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years. [C2.96] Satralizumab for use in preventing fragility fractures and increasing motor function in a subject having DMD, wherein satralizumab is used in combination with an immunosuppressive agent selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof, and wherein 60 mg of satralizumab is administered to the subject with body weight of less than 40 kg for each administration, or 120 mg of satralizumab is administered to the subject with body weight of equal to or more than 40 kg for each administration, and wherein the subject is aged from 8 to less than 16 years.

[0018] [D1] A kit for treating a muscular dystrophy in a subject, comprising: (1) the pharmaceutical composition of any one of A2.1-A2.30; and (2) a package insert or label instructing administration of the pharmaceutical composition to a subject. [D2] A kit for preventing or treating one or more diseases or disorders associated with muscular dystrophy in a subject, comprising: (1) the pharmaceutical composition of any one of A2.1-A2.30; and (2) a package insert or label instructing administration of the pharmaceutical composition to a subject.

[0019] [E1] A method for treating a muscular dystrophy in a subject, the method comprising administering to the subject an effective amount of an IL-6 inhibitor. [E2-1] A method for preventing one or more diseases or disorders associated with muscular dystrophy in a subject, the method comprising administering to the subject an effective amount of an IL-6 inhibitor. [E2-2] A method for treating one or more diseases or disorders associated with muscular dystrophy in a subject, the method comprising administering to the subject an effective amount of an IL-6 inhibitor. [E3] The method of E2, wherein the one or more diseases or disorders associated with muscular dystrophy are osteoporosis, bone loss, decreased bone mineral density (BMD), abnormal bone metabolism, increased bone resorption, decreased bone formation, bone fracture, fragility fracture, decreased motor function, decreased muscle strength, or inflammation in microenvironment in a muscle. [E4] The method of any one of E1-E3, wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Fukuyama congenital muscular dystrophy (FCMD), Limb-girdle muscular dystrophy (LGMD), or Facio-scapulo-humeral muscular dystrophy (FSHD). [E5] The method of E4, wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD). [E6] The method of any one of E1-E5, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [E7] The method of any one of E1-E6, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2. [E8] The method of any one of E1-E7, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 3 and a light chain comprising the amino acid sequence of SEQ ID NO: 4. [E9] The method of any one of E1-E8, wherein the IL-6 inhibitor is satralizumab. [E10] The method of any one of E1-E9, wherein the subject is determined to have a body weight of less than or equal to 40 kg, and the amount of the IL-6 inhibitor administered to the subject in each administration is 60 mg; or the subject is determined to have a body weight of equal to or more than 40 kg, and the amount of the IL-6 inhibitor administered to the subject in each administration is 120 mg. [E11] The method of any one of E1-E10, wherein the IL-6 inhibitor is administered to the subject every two weeks (Q2W) for three times, and thereafter every 4 weeks (Q4W). [E12] The method of any one of E1-E11, wherein the IL-6 inhibitor is administered to the subject subcutaneously. [E13] The method of any one of E1-E12, wherein the subject is adolescent or pre-adolescent. [E14] The method of any one of E1-E13, wherein the subject is aged from 8 to less than 16 years. [E15] The method of any one of E1-E14, wherein the subject is aged from 8 to less than 12 years. [E16] The method of any one of E1-E15, wherein the subject is ambulatory. [E17] The method of any one of E1-E15, wherein the subject is non-ambulatory. [E18] The method of any one of E1-E17, wherein the subject is male at birth. [E19] The method of any one of E1-E18, wherein the subject has a history of fractures, optionally low-trauma fractures. [E20] The method of any one of E1-E19, wherein the subject has existing fractures, optionally low-trauma fractures. [E21] The method of any one of E1-E18, wherein the subject has no history of prior fractures, optionally low-trauma fractures. [E22] The method of any one of E1-E21, wherein the subject has not experienced steroid treatment. [E23] The method of any one of E1-E21, wherein the subject is receiving no ongoing chronic immunosuppressive therapy. [E24] The method of any one of E1-E21, wherein the subject is receiving ongoing treatment with systemic corticosteroid(s). [E25] The method of E24, wherein the corticosteroid is prednisone, prednisolone, deflazacor, or equivalent thereof. [E26] The method of any one of E1-E25, wherein the method further comprises administering an immunosuppressive agent to the subject. [E27] The method of E26, wherein the immunosuppressive agent is any one or more selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof. [E28] The method of E1-E27, wherein administering the IL-6 inhibitor to the subject prevents / reduces / minimizes bone resorption, promotes / increases bone formation, prevents / reduces / minimizes bone loss, increases bone mineral density (BMD), reduces risk of fractures, and / or prevents / reduces / minimizes fragility fractures in the subject. [E29] The medicament of any one of E1-E28, wherein administering the IL-6 inhibitor to the subject increases levels of one or more of the following biomarkers: osteocalcin (OC), bone alkaline phosphatase (BSAP), procollagen type 1 N-terminal propeptide (P1NP), and osteoprotegerin (OPG) in serum of the subject. [E30] The medicament of any one of E1-E29, wherein administering the IL-6 inhibitor to the subject reduces levels of one or more of the following biomarkers: tartrate-resistant acid phosphatase 5b (TRAP 5b), carboxy-terminal crosslinked telopeptide of type 1 collagen (CTX-1), receptor activator of NF-kB ligand (RANKL), dickkopf-1 (DDK-1), sclerostin, and creatine kinase (CK) in serum of the subject.

[0020] The present invention can provide a medicament (a pharmaceutical composition) comprising satralizumab for treating a muscular dystrophy, and / or for preventing or treating one or more diseases or disorders associated with muscular dystrophy.

[0021] Figure 1 shows the study schema of Phase 2 multicenter, open-label study to evaluate the safety, efficacy, pharmacokinetics and pharmacodynamics of satralizumab in pediatric patients with duchenne muscular dystrophy (DMD). BMD = bone mineral density; SFU = Safety follow up; PK = pharmacokinetic; DEXA = dual x-ray absorptiometry; SC = subcutaneous.Figure 2 shows the dependencies of steady-state exposure parameters on weight following 120 mg Q4W (weight more than or equal to 40 kg), 60 mg Q4W (weight more than or equal to and less than 40 kg), and 60 mg Q6W (weight weight more than or equal to 10 and less than 20 kg) dosing: Cmaxand Ctrough. Cmax= maximum concertation observed; Ctr= trough concentration; Q4W = every 4 weeks; Q6W = every 6 weeks. Note: Points are simulated data. Dashed horizontal lines have been added for reference.

[0022] In one aspect, the present invention relates to a medicament (a pharmaceutical composition) for treating a muscular dystrophy and / or for preventing or treating one or more diseases or disorders associated with muscular dystrophy in a subject, comprising an IL-6 inhibitor as an active ingredient. In another aspect, the present invention also relates to use of an IL-6 inhibitor in the preparation of a medicament for treating a muscular dystrophy and / or for preventing or treating one or more diseases or disorders associated with muscular dystrophy in a subject. In yet another aspect, the present invention relates to an IL-6 inhibitor for use in treating a muscular dystrophy and / or for preventing or treating one or more diseases or disorders associated with muscular dystrophy in a subject. Additionally, the present invention also relates to a kit for treating a muscular dystrophy and / or for preventing or treating one or more diseases or disorders associated with muscular dystrophy in a subject, which comprises a pharmaceutical composition comprising an IL-6 inhibitor, and a package insert or label instructing administration of the pharmaceutical composition to a subject. Furthermore, the present invention also relates to a method for treating a muscular dystrophy in a subject, the method comprising administering to the subject an effective amount of an IL-6 inhibitor. Moreover, the present invention also relates to a method for preventing or treating one or more diseases or disorders associated with muscular dystrophy in a subject, the method comprising administering to the subject an effective amount of an IL-6 inhibitor.

[0023] In certain embodiments in the present disclosure, the muscular dystrophy includes but not limited to Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Fukuyama congenital muscular dystrophy (FCMD), Limb-girdle muscular dystrophy (LGMD), or Facio-scapulo-humeral muscular dystrophy (FSHD).

[0024] In certain embodiments in the present disclosure, the one or more diseases or disorders associated with muscular dystrophy includes but not limited to osteoporosis, bone loss, decreased bone mineral density (BMD), abnormal bone metabolism, increased bone resorption, decreased bone formation, bone fracture, fragility fracture, decreased motor function, decreased muscle strength, or inflammation in microenvironment in a muscle.

[0025] In the present disclosure, "a subject", which may be referred as "a patient", has the above-described muscular dystrophy such as Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Fukuyama congenital muscular dystrophy (FCMD), Limb-girdle muscular dystrophy (LGMD), or Facio-scapulo-humeral muscular dystrophy (FSHD). In certain embodiments, the subject has been diagnosed with DMD based on documentation of clinical findings and prior confirmatory genetic testing. In certain embodiments, the subject is male at birth. In certain embodiments, the subject is adolescent or pre-adolescent. In certain embodiments, the subject is aged from 8 to less than 16 years. In certain embodiments, the subject is aged from 8 to less than 12 years. In certain embodiments, the subject is ambulatory, defined as able to walk independently without assistive devices. In certain embodiments, the subject is non-ambulatory.

[0026] In certain embodiments, the subject has a history of fractures such as low-trauma fractures. In certain embodiments, the subject has existing fractures such as low-trauma fractures. In certain embodiments, the subject has no history of prior fractures (i.e. the subject is fracture naive). In certain embodiments, the subject has no history of prior low-trauma fractures. In connection with the present invention, low-trauma fractures are defined as those occurring spontaneously or from a fall from a standing height or less, without major trauma or the influence of an external force.

[0027] In one aspect, the subject has received, has not received, is receiving, or is not receiving chronic immunosuppressive therapy (IST). In certain embodiments, the subject has not experienced steroid treatment. In certain embodiments, the subject is receiving no ongoing chronic immunosuppressive therapy. In certain embodiments, the subject is receiving ongoing treatment with systemic corticosteroids such as prednisone, prednisolone, deflazacor, or equivalent thereof.

[0028] An "IL-6 inhibitor" of the present disclosure is a substance that blocks signal transduction by IL-6 and inhibits the biological activities of IL-6. The IL-6 inhibitor is preferably a substance that inhibits binding between IL-6 and IL-6 receptor and / or between the IL-6 / IL-6 receptor complex and gp130. Examples of an IL-6 inhibitor of the present disclosure include, but are not particularly limited to, an anti-IL-6 antibody or antigen binding fragment thereof, an anti-IL-6 receptor antibody or antigen binding fragment thereof, an anti-gp130 antibody or antigen binding fragment thereof, an IL-6 variant, a soluble IL-6 receptor variant, or a partial peptide of IL-6 or IL-6 receptor, and a low-molecular-weight substance showing a similar activity. Examples of an IL-6 inhibitor of the present disclosure may be preferably an anti-IL-6 antibody or antigen-binding fragment thereof, or an anti-IL-6 receptor antibody or antigen binding fragment thereof, more preferably an anti-IL-6 receptor antibody or antigen binding fragment thereof, optionally a humanized antibody.

[0029] In some embodiments of the present disclosure, the IL-6 inhibitor is an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. In certain embodiments in the present disclosure, the anti-IL-6 receptor antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In certain embodiments in the present disclosure, the IL-6 inhibitor is an anti-IL-6 receptor antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 3 and a light chain comprising the amino acid sequence of SEQ ID NO: 4. In certain embodiments in the present disclosure, the IL-6 inhibitor is satralizumab. In some embodiments of the present disclosure, the term "satralizumab" is an anti-IL-6 receptor antibody that comprises a heavy-chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a heavy-chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a heavy-chain CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light-chain CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a light-chain CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a light-chain CDR3 comprising the amino acid sequence of SEQ ID NO: 10; preferably comprises a heavy-chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light-chain variable region comprising the amino acid sequence of SEQ ID NO: 2; and most preferably comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 3 and a light chain comprising the amino acid sequence of SEQ ID NO: 4.

[0030] Satralizumab (RO5333787) is a humanized a aIL-6R IgG2 monoclonal antibody that was constructed by modifying the amino acid sequence of tocilizumab to prolong its plasma drug-elimination half-life. In addition, satralizumab has the following distinguishing characteristics: pH-dependent binding to its antigen (IL-6R) (Igawa et al. 2010), decreased antibody molecule isoelectric point (Igawa et al. 2010), and stronger binding to neonatal Fc receptor (Petkova et al. 2006). Moreover, its Fc region has been modified to minimize antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity effector activity. Satralizumab maintains pharmacological effects of IL-6R blockade using a 4-week dosing frequency by SC injection due to its prolonged plasma drug-elimination half-life. Satralizumab specifically targets the human IL-6R, preventing interleukin (IL)-6 from binding to the membrane-bound and soluble IL-6R (mIL-6R and sIL-6R respectively), thereby inhibiting IL-6 signaling.

[0031] The clinical pharmacology, safety, and efficacy of satralizumab has been characterized in four (completed) clinical trials: a single ascending dose (SA-001JP) trial in healthy subjects (both Japanese and Caucasian), a multiple ascending dose (SA-105JP) trial in patients with rheumatoid arthritis (RA), and two Phase III clinical studies in patients with neuromyelitis optica spectrum disorder (NMOSD; BN40898 [SA-307JG] and BN40900 [SA-309JG]). Satralizumab 120 mg every 4 weeks (Q4W) given as monotherapy or in combination with immune suppression therapy was safe and well tolerated by patients with NMOSD. Results from the Phase III clinical studies BN40898 and BN40900 confirmed the adequacy of the selected dosing regimen (doses of 120 mg administered at Weeks 0, 2, and 4 followed by 120 mg Q4W). At this dose, the effective drug-elimination half-life is approximately 30 days based on data pooled between the two studies, supporting the recommended maintenance dosing interval of Q4W. Robust and sustained sIL-6R stabilization and increases in IL-6 were seen to parallel the satralizumab concentration-time course and were maintained for the duration of therapy (average treatment duration 100 weeks in Study BN40898 and 96 weeks in Study BN40900, in the double-blind period), reflecting target engagement of satralizumab. The median predicted occupancy at the sIL-6R and mIL-6R in patients with NMOSD was maintained at > 95% throughout the dose interval, and for the entire duration of therapy (Week 180 and Week 204 in Studies BN40898 and BN40900, respectively). Data from the completed double-blind periods of Phase III Studies BN40898 and BN40900 in adult and adolescent patients demonstrated a statistically significant clinical benefit.

[0032] Pharmacokinetic data are available in 8 adolescent participants (aged 13-17 years) enrolled in Study BN40898 (up to a cut-off date of 1 October 2018). The median age of these participants was 16 years (range 13-17 years), and median body weight was 71.6 kg (range 42.1-140 kg), which was higher than the median adult body weight in Study BN40898 but similar to the adult population when pooled with Study BN40900. Satralizumab exposure (mean and range) and receptor occupancy were similar in adolescents and adults, which is consistent with the observed similar body weight of the adolescent participants and the adults, as well as a similar incidence of anti-drug antibodies (ADA) in both populations. Population-pharmacokinetics (PK) analysis of these data indicated that the pharmacokinetics of satralizumab in this age range were very similar to those in adults, with a similar relationship between body weight and exposure.

[0033] The benefits of satralizumab in patients with NMOSD were coupled with a highly favorable safety profile. In both Phase III studies, most adverse events were mild or moderate in intensity, and the overall rates of serious adverse events were comparable between treatment groups. No deaths were reported. There was a low incidence of treatment withdrawals due to adverse events. The safety profile was generally similar between the add-on to immunosuppressive therapies (ISTs) including steroids Study BN40898 and monotherapy Study BN40900, and no new safety signals were identified in the adolescent population.

[0034] In Studies BN40898 and BN40900, ADAs were observed in 41% and 71% of patients receiving satralizumab in the double-blind period, respectively. Apparent correlations between ADA development and higher body weight and lower exposure, were not reflected in clinical outcomes. Meaningful and comparable efficacy was demonstrated in all exposure subgroups and in all body weight groups. During the Phase III studies BN40898 and BN40900 in NMOSD, satralizumab demonstrated a favorable safety profile. During the DB period, 63 patients were exposed to satralizumab monotherapy, and 41 patients were exposed to satralizumab in combination with IST (please refer to the satralizumab Investigator’s Brochure for further details). In the DB period, patient median exposure to satralizumab was approximately two years in both studies. The median exposure to placebo was approximately one year.

[0035] Overall, satralizumab was well tolerated by patients with NMOSD. The safety profile of satralizumab in combination with corticosteroids (15 mg of prednisolone equivalent per day), azathioprine or mycophenolate mofetil was comparable to satralizumab monotherapy. The PK and safety profiles of satralizumab in adolescent patients were comparable to those in adult patients with NMOSD. The most frequently reported adverse drug reactions were headache, arthralgia, and injection reactions. The majority of adverse events were of mild / moderate severity and resolved without changes to the study drug. Injection reactions were reported in 12.5% of the patients treated with satralizumab (monotherapy or in combination with IST) and were predominantly of mild to moderate severity. The incidence rate of infections was lower in the satralizumab group compared to the placebo group in the monotherapy study (satralizumab: 99.8 events / 100 PY [95% CI: 82.4 to 119.8]; placebo: 162.6 events / 100 PY [95% CI: 125.8 to 206.9]) and comparable in the add-on study (satralizumab + IST: 132.5 events / 100 PY [95% CI: 108.2 to 160.5]; placebo + IST: 149.6 events / 100 PY [95% CI: 120.1 to 184.1].

[0036] Laboratory abnormalities including neutropenia, thrombocytopenia, elevations in liver enzymes, and lipid elevations have been reported in patients treated with satralizumab. Satralizumab (ENSPRYNG (registered trademark)) is approved by multiple health authorities as monotherapy or in combination with IST for the treatment of NMOSD in adult and adolescent patients who are anti-AQP4 seropositive and is currently under review by other health authorities worldwide. Please refer to the satralizumab Investigator’s Brochure for details on nonclinical and clinical studies.

[0037] In certain embodiments, the medicament or the pharmaceutical composition of the present invention is used in combination with an immunosuppressive therapy (IST). In certain embodiments, the IST is one or more immunosuppressive agents selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof.

[0038] In certain embodiments, the medicament or the pharmaceutical composition of the present invention can prevent / reduce / minimize bone resorption, promote / increase bone formation, prevent / reduce / minimize bone loss, increase bone mineral density (BMD), reduce risk of fractures, and / or prevent / reduce / minimize fragility fractures in a subject. In certain embodiments, the medicament or the pharmaceutical composition of the present invention can reduce the chronic inflammation in degenerating muscles, improve the inflammatory microenvironment in the muscles, improve / increase motor function in a subject, and / or improve / increase muscle strength. In certain embodiments, the medicament or the pharmaceutical composition of the present invention can improve motor function and reduce fragility fractures.

[0039] In the present disclosure, efficacy, safety, pharmacokinetics and / or pharmacodynamics of IL-6 inhibitor such as satralizumab for the treatment of muscular dystrophy may be assessed based on one or more aspects and / or scores. In certain embodiments, the medicament or the pharmaceutical composition of the present invention can increase levels of one or more of the following biomarkers: osteocalcin (OC), bone alkaline phosphatase (BSAP), procollagen type 1 N-terminal propeptide (P1NP), and osteoprotegerin (OPG) in serum of the subject. In certain embodiments, the medicament or the pharmaceutical composition of the present invention can further reduce levels of one or more of the following biomarkers: tartrate-resistant acid phosphatase 5b (TRAP 5b), carboxy-terminal crosslinked telopeptide of type 1 collagen (CTX-1), receptor activator of NF-kB ligand (RANKL), dickkopf-1 (DDK-1), sclerostin, and creatine kinase (CK) in serum of the subject.

[0040] In the present disclosure, the term "treatment" is used with the meaning that even if complete remission of the muscular dystrophy and its related diseases or disorders is not achieved, alleviating or improving symptoms to a level at which minimal manifestations (MM) can be maintained, or maintaining such a state, is also included in the "treatment" of the muscular dystrophy.

[0041] The given period of applying the present invention (e.g., administering a medicament or a pharmaceutical composition of the present invention) for evaluating efficacy is not particularly limited and includes 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 48 weeks, 1 year, 2 years, 3 years, 4 years, and 5 years, and the period may be shorter or longer than the exemplified period.

[0042] In the present invention, a subject (e.g., a patient) having a muscular dystrophy and / or its related diseases or disorders may receive a treatment of the present invention (e.g., a medicament, a pharmaceutical composition, a method, or the like), e.g., every two weeks (Q2W) for three times (i.e., at time zero and again at 2 weeks and 4 weeks), and thereafter every 4 weeks (Q4W). In some embodiments, the subject (e.g., patient) can receive an anti-IL-6 receptor antibody (e.g., satralizumab) or antigen binding fragment thereof contained in a medicament or a composition of the present invention via subcutaneous administration route.

[0043] An anti-IL-6 receptor antibody or antigen binding fragment thereof used in the present invention binds to an IL-6 receptor, inhibits the binding of IL-6 to an IL-6 receptor, blocks signal transduction by IL-6, and inhibits the biological activities of IL-6.

[0044] An anti-IL-6 receptor antibody used in the present invention can be obtained using known methods. In particular, an anti-IL-6 receptor antibody used in the present invention is preferably a monoclonal antibody derived from a mammal. Monoclonal antibodies derived from a mammal include those produced by a hybridoma and those produced by a host that has been transformed with an expression vector containing an antibody gene using genetic engineering methods.

[0045] Preferred examples of an "IL-6 receptor antibody" in the present invention include humanized anti-IL-6 receptor antibodies produced by modifying the variable and constant regions of tocilizumab, specifically, antibodies that comprise a heavy-chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a heavy-chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a heavy-chain CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light-chain CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a light-chain CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a light-chain CDR3 comprising the amino acid sequence of SEQ ID NO: 10.

[0046] More preferred antibodies in the present invention include antibodies that comprise a heavy-chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light-chain variable region comprising the amino acid sequence of SEQ ID NO: 2. Still more preferred are antibodies that comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 3 (heavy chain of satralizumab (generic name); SA237 (private name)) and a light chain comprising the amino acid sequence of SEQ ID NO: 4 (light chain of satralizumab). Satralizumab (private name: SA237) is particularly preferred.

[0047] Governmental marketing approval of satralizumab has been obtained in many countries including Japan, United States, and Europe based on the indication "prevention of relapses of neuromyelitis optica spectrum disorder (including neuromyelitis optica)". The safety profiles identified during the international joint phase III clinical trials (SA-307JG / BN40898 study and SA-309JG / BN40900 study) targeting a population of patients with neuromyelitis optica spectrum disorder (NMOSD) and / or neuromyelitis optica (NMO) were mostly favorable. No death case was reported. The percentage of patients who experienced severe adverse events in the satralizumab group was about the same as that in the placebo group. There was no big difference between the two groups on the frequency of adverse events that led to discontinuation of administration of the test drug, or on the frequency of adverse events that led to drug withdrawal. Safety profiles were similar between the SA-309JG study, which was a single-agent test, and the SA-307JG study, which was a combined test with preexisting therapy (oral steroids and / or immunosuppressive agents).

[0048] Such antibodies can be obtained according to the methods described in WO2010 / 035769, WO2010 / 107108, WO2010 / 106812, and such. Specifically, antibodies can be produced using genetic recombination techniques known to those skilled in the art, based on the sequence of the above-mentioned IL-6 receptor antibody (see, for example, Borrebaeck CAK and Larrick JW, THERAPEUTIC MONOCLONAL ANTIBODIES, Published in the United Kingdom by MACMILLAN PUBLISHERS LTD, 1990). A recombinant antibody can be obtained by cloning a DNA encoding the antibody from a hybridoma or an antibody-producing cell such as an antibody-producing sensitized lymphocyte, inserting the DNA into an appropriate vector, and introducing the vector into a host (host cell) to produce the antibody.

[0049] Such antibodies can be isolated and purified using isolation and purification methods conventionally used for antibody purification, without limitation. For example, the antibodies can be isolated and purified by appropriately selecting and combining column chromatography, filtration, ultrafiltration, salting-out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, recrystallization, and such.

[0050] The antibodies used in the present invention may be conjugate antibodies that are bound to various molecules such as polyethylene glycol (PEG), radioactive substances, and toxins. Such conjugate antibodies can be obtained by chemically modifying the obtained antibodies. Methods for antibody modification have been already established in this field. Accordingly, the term "antibody" in the present invention encompasses such conjugate antibodies.

[0051] The antibodies used in the present invention may be antibody fragments (also referred to as an antigen binding fragment of the antibody) or modified products thereof, as long as they can be suitably used in the present invention. For example, antibody fragments include Fab, F(ab')2, Fv, and single chain Fv (scFv) in which the Fvs of the H and L chains are linked via an appropriate linker. Specifically, the antibody fragments are produced by treating antibodies with enzymes such as papain or pepsin, or alternatively, by constructing genes encoding these antibody fragments and introducing them into expression vectors, and then expressing the vectors in appropriate host cells (see, for example, Co, M. S. et al., J. Immunol. (1994) 152, 2968-2976; Better, M. & Horwitz, A. H., Methods in Enzymology (1989) 178, 476-496; Plueckthun, A. & Skerra, A., Methods in Enzymology (1989) 178, 497-515; Lamoyi, E., Methods in Enzymology (1989) 121, 652-663; Rousseaux, J. et al., Methods in Enzymology (1989) 121, 663-666; and Bird, R. E. et al., TIBTECH (1991) 9, 132-137).

[0052] An scFv can be obtained by linking the H-chain V region and the L-chain V region of an antibody. In this scFv, the H-chain V region and the L-chain V region are linked via a linker, preferably via a peptide linker (Huston, J. S. et al., Proc. Natl. Acad. Sci. USA (1988) 85, 5879-5883). The V regions of the H and L chains in an scFv may be derived from any of the antibodies described above. Peptide linkers for linking the V regions include, for example, an arbitrary single chain peptide consisting of 12 to 19 amino acid residues.

[0053] A DNA encoding an scFv can be obtained by amplifying a DNA portion that encodes the desired amino acid sequence in template sequences with PCR using a primer pair which defines the termini of the portion, wherein a DNA encoding an H chain or an H-chain V region and a DNA encoding an L chain or an L-chain V region of the aforementioned antibodies are used as the templates, and then further amplifying the amplified DNA portion with a DNA that encodes a peptide linker portion and a primer pair that defines both ends of the linker so that it may be linked to each of the H and L chains. Once an scFv-encoding DNA has been prepared, an expression vector comprising the DNA and a host transformed with the expression vector can be obtained according to conventional methods. In addition, an scFv can be obtained according to conventional methods by using the host. Similar to the above, the antibody fragments can be produced by obtaining their genes, expressing them, and then using a host.

[0054] In the present invention, "as an active ingredient" means that the ingredient is contained in the pharmaceutical composition as a primal active ingredient, and the content thereof is not limited unless specifically indicated, as long as the antibodies or antigen binding fragments thereof used for the present invention are included as medicinal ingredients.

[0055] The dose of an anti-IL-6 receptor antibody or antigen binding fragment thereof contained in a medicament or a composition of the present invention is not particularly limited, and examples include 50 to 800 mg of antibody per administration, preferably 60 to 240 mg of antibody, and more preferably 60 mg or 120 mg of antibody per administration. The dose of an anti-IL-6 receptor antibody or antigen binding fragment thereof contained in a medicament or a composition of the present invention may vary depending on the patient's body weight. In certain embodiments of the present invention, a suitable dose of the anti-IL-6 receptor antibody or antigen binding fragment for a subject with a body weight of less than 40 kg is 60 mg; and a suitable dose for a subject with a body weight of equal to or more than 40 kg is 120 mg. A medicament or a composition comprising an anti-IL-6 receptor antibody or antigen binding fragment thereof of the present invention is administered to a subject via any route, including but not limited to subcutaneously, intravenously, intramuscularly, and by infusion. A preferred embodiment is subcutaneous administration.

[0056] In certain embodiments of the present invention, two or more sequential doses of an anti-IL-6 receptor antibody or antigen binding fragment thereof contained in a medicament or a composition of the present invention is administered to a subject during an initial period, wherein the doses administered during the initial period are spaced by a first dosing interval (also referred to the dosing interval that is shorter than the routine dosing interval), for example 20 weeks, 8 weeks, 4 weeks, or two weeks; and after the final dose administration of the initial period, waiting a second dosing interval that is longer than the first dosing interval and then administering a dose of an anti-IL-6 receptor antibody or antigen binding fragment thereof contained in a medicament or a composition of the present invention to a human patient, wherein optionally multiple consecutive doses are administered after the final dose administration of the initial period, and are spaced by the second dosing interval (also referred to as a "routine dosing interval") that is not particularly limited except that it is longer than the first dosing interval. Examples of the second dosing interval include 1 day to 24 weeks, preferably 2 weeks to 8 weeks, more preferably 3 to 5 weeks, and even more preferably 4 weeks). In certain embodiments of the present invention, an anti-IL-6 receptor antibody or antigen binding fragment thereof contained in a medicament or a composition of the present invention is administered to a subject every two weeks (Q2W) for three times, and thereafter every 4 weeks (Q4W).

[0057] The preferred administration schedule for an anti-IL-6 receptor antibody or antigen binding fragment thereof contained in a medicament or a composition of the present invention can be adjusted, for example, by appropriately extending the administration interval by monitoring the conditions of the disease and changes in the blood test values.

[0058] The present invention also provides an article of manufacture such as a kit, a device, and the like for use in a method of the present invention, which contains a pharmaceutical composition or a medicament of the present invention. The pharmaceutical composition or a medicament of the present invention comprises an IL-6 inhibitor as described herein. The article of manufacture may be packaged with an additional pharmaceutically acceptable carrier or medium, or instruction manual describing how to use the kits, etc.

[0059] In one embodiment, the article of manufacture comprises a container and a label on or a package insert associated with the container. Suitable containers include, for example, bottles, vials, syringes (including a prefilled syringe and an autoinjector), IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. In one embodiment, the container holds a composition which is by itself or combined with another composition effective for treating, preventing and / or diagnosing the condition and may have a sterile access port (for example the container may be a syringe, autoinjector, an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active ingredient in the composition is an IL-6 inhibitor, preferably an anti-IL-6 receptor antibody, and more preferably satralizumab as described in the present disclosure.

[0060] In one embodiment, a device as the article of manufacture of the present invention as described above may be a prefilled syringe (PFS) optionally comprising a needle safety device (PFS-NSD) for injection via any administration route such as intravenously, subcutaneously, or the like, which comprises a fixed dose of an IL-6 inhibitor, preferably an anti-IL-6 receptor antibody, and more preferably satralizumab as described in the present disclosure in a pharmaceutically acceptable excipient. In another embodiment, the device may be an autoinjector (AI) for subcutaneous administration which comprises a fixed dose of an IL-6 inhibitor, preferably an anti-IL-6 receptor antibody, and more preferably satralizumab as described in the present disclosure in a pharmaceutically acceptable excipient. In certain embodiments, the device is a subcutaneous administration device, such as a prefilled syringe (PFS) and autoinjector (AI), which may comprise 60 mg, 120 mg, or 180 mg of satralizumab. In one embodiment, the subcutaneous administration device is a prefilled syringe comprising a needle safety device (PFS-NSD) which comprises 60 mg (for example 60 mg / mL) of satralizumab for delivering 60 mg or 120 mg of satralizumab to a subject. In another embodiment, the subcutaneous administration device is a prefilled syringe comprising a needle safety device (PFS-NSD) which comprises 120 mg (for example 60 mg / 0.5 mL) of satralizumab for delivering 120 mg of satralizumab to the subject. In other embodiments, the subcutaneous administration device is an autoinjector (AI) which comprises 60 mg, 120 mg, or 180 mg of satralizumab.

[0061] In the present invention, the label or package insert indicates that the pharmaceutical composition or medicament is used for treating the condition of choice. Moreover, the article of manufacture may comprise (a) a first container with a composition contained therein, wherein the composition comprises an IL-6 inhibitor, preferably an anti-IL-6 receptor antibody, and more preferably satralizumab as described above; and (b) a second container with a composition contained therein, wherein the composition comprises a further therapeutic agent. The article of manufacture in this embodiment of the invention may further comprise a package insert indicating that the compositions can be used to treat a particular condition. Alternatively, or additionally, the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0062] The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and / or warnings concerning the use of such therapeutic products.

[0063] A pharmaceutical composition or a medicament of the present invention can be formulated to produce freeze-dried formulations or solution formulations by mixing, if necessary, with suitable pharmaceutically acceptable carriers, vehicles, and such. The suitable pharmaceutically acceptable carriers and vehicles include, for example, sterilized water, physiological saline, stabilizers, excipients, antioxidants (such as ascorbic acid), buffers (such as phosphate, citrate, histidine, and other organic acids), antiseptics, surfactants (such as PEG and Tween), chelating agents (such as EDTA), and binders. Other low-molecular-weight polypeptides, proteins such as serum albumin, gelatin, and immunoglobulins, amino acids such as glycine, glutamine, asparagine, glutamic acid, aspartic acid, methionine, arginine, and lysine, sugars and carbohydrates such as polysaccharides and monosaccharides, and sugar alcohols such as mannitol and sorbitol may also be contained in the formulation. When preparing an aqueous solution for injection, physiological saline and isotonic solutions comprising glucose and other adjuvants such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride may be used; and appropriate solubilizers such as alcohol (for example, ethanol), polyalcohols (such as propylene glycol and PEG), and nonionic surfactants (such as polysorbate 80, polysorbate 20, poloxamer 188, and HCO-50) may be used in combination. By mixing hyaluronidase into the formulation, a larger fluid volume can be administered subcutaneously (Expert Opin. Drug Deliv. 2007 Jul; 4(4): 427-40). Furthermore, syringes may be prefilled with the pharmaceutical composition of the present invention. Solution formulations can be prepared according to the method described in WO2011 / 090088.

[0064] If necessary, a pharmaceutical composition or a medicament of the present invention may be encapsulated in microcapsules (e.g., those made of hydroxymethylcellulose, gelatin, and poly(methylmethacrylate)), or incorporated into colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) (see, for example, "Remington's Pharmaceutical Science 16th edition", Oslo Ed. (1980)). Methods for preparing the pharmaceutical agents as controlled-release pharmaceutical agents are also known, and such methods may be applied to the pharmaceutical compositions of the present invention (Langer et al., J. Biomed. Mater. Res. 15: 267-277 (1981); Langer, Chemtech. 12: 98-105 (1982); U.S. Patent No. 3,773,919; European Patent Application Publication No. EP 58,481; Sidman et al., Biopolymers 22: 547-556 (1983); and EP 133,988).

[0065] An anti-IL-6 receptor antibody or antigen binding fragment thereof contained in a medicament or a composition of the present invention can be administered to a patient via any appropriate route. For example, it can be administered to a patient intravenously by bolus injection or by continuous infusion, intramuscularly, intraperitoneally, intracerebrospinally, transdermally, subcutaneously, intraarticularly, sublingually, intrasynovially, orally, by inhalation, locally, or externally, for a certain period of time. Intravenous administration or subcutaneous administration is preferred. In certain embodiments of the present invention, an anti-IL-6 receptor antibody or antigen binding fragment thereof contained in a medicament or a composition of the present invention is administered to a subject subcutaneously.

[0066] All prior art references cited herein are incorporated by reference into the present specification.

[0067] Herein below, the present invention will be specifically described with reference to the Examples, but it is not to be construed as being limited thereto.

[0068] Example 1: Preparation of satralizumab (SA237) An antibody with the generic name satralizumab (and a private name of SA237), which is an IL-6 receptor antibody described in the patent document WO 2010 / 035769 as comprising a heavy chain having the amino acid sequence of SEQ ID NO: 26 (SEQ ID NO: 3 in the present specification) and a light chain having the amino acid sequence of SEQ ID NO: 29 (SEQ ID NO: 4 in the present specification)), was prepared according to the description of that patent document. The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: 1, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO: 2. Using the prepared antibody, a subcutaneous administration preparation was prepared by the method described in the patent document WO 2011 / 090088.

[0069] Example 2: Phase 2 multicenter, open-label study to evaluate the safety, efficacy, pharmacokinetics and pharmacodynamics of satralizumab in pediatric patients with duchenne muscular dystrophy (DMD)

[0070] 1.INTRODUCTION 1.1 STUDY RATIONALE The purpose of this study is to assess the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of satralizumab (also known as RO5333787), a humanized anti-interleukin-6 receptor (aIL-6R) monoclonal antibody, in ambulatory and non-ambulatory patients with Duchenne muscular dystrophy (DMD) aged from 8 to less than 16 years old. A subset of non-ambulatory participants aged from 12 to less than 16 years of age will be initially treated to assess PK / PD before treating participants below 12 years of age.

[0071] Current treatment options for DMD aim to target the underlying myopathy caused by a lack of dystrophin production, mainly due to out-of-frame mutations in the DMD gene, including therapies available to a small proportion of patients (e.g., exon-skipping or gene transfer therapies). Systemic corticosteroids (either prednisone / prednisolone or deflazacort) are considered the standard of care in DMD (Sejerson et al. 2009), and while they confer limited benefit in extending ambulation (Gloss et al. 2016), they introduce significant unwanted side effects such as progressive osteotoxicity that leads to osteoporosis and fragility fractures. The mechanism of bone loss in DMD is thought to be mainly driven by two factors: the progressive loss of muscle strength with reduced mobility and glucocorticoid-induced osteotoxicity (Ward et al. 2018). Fractures are often reported in young DMD patients even prior to steroid treatment commencement (Perera et al. 2016), which highlights the critical role of muscle strength and mechanical load input into natural bone development, which is lacking in DMD. In addition, well known severe complications from recurrent fractures include permanent loss of ambulation (Tian et al. 2016; Crabtree et al. 2018, Suthar et al. 2021), spinal deformities, chronic back pain (Suthar et al. 2021), fat embolism syndrome and increased mortality (Feder et al. 2017). This debilitating progressive bone loss in DMD is in part mediated by a dysregulation of the IL-6 signaling pathway that over activates osteoclasts promoting bone resorption (Rufo et al. 2011), a mechanism already proven in rheumatoid arthritis (RA) patients and successfully treated through IL6R inhibition (Chen et al. 2017). The elevation of serum pro-inflammatory and fibrotic biomarkers due to muscle cell membrane damage and chronic activation of inflammatory processes, including interleukin-6 (IL-6), further exacerbates the progression of DMD (Starosta et al. 2021). This increased IL-6 signaling is thought to be promoting both the underlying muscle atrophy and the increased bone resorption reported in DMD patients (Rufo et al. 2011).

[0072] There are currently no approved treatments for DMD that specifically target progressive bone loss and recurrent fragility fractures. The 2018 Duchenne care guidelines recommend the use of bisphosphonates (anti-resorptive therapies not approved for DMD) once a certain level of bone fragility is reached, i.e., when osteoporosis manifests as bone fragility fractures, especially the compression vertebral fractures (VF) (Birnkrant et al 2018). Although bisphosphonates have been shown to increase bone mineral density (BMD) in glucocorticoid treated DMD patients, the uptake of bisphosphonates in DMD is overall low. This may be in part due to the high frequency of acute phase reactions and other harmful adverse events, inconsistent systemic effects between oral and intravenous routes of administration, and because they are not recommended before adolescence (Zhao 2022; Landfeldt 2024; Zoledronic acid USPI). In addition, they do not significantly reduce the incidence of fractures in DMD patients, despite increasing the BMD (Landfeldt et al 2024). Therefore, there is a high unmet medical need for the development of an efficacious treatment to prevent bone loss and the associated fragility fractures in all patients with DMD. The treatment with satralizumab has the potential to halt IL-6-mediated bone resorption observed in DMD patients to increase their BMD and reduce the risk of fractures and the associated complications over the course of their disease. In addition, by inhibiting IL-6 signaling, satralizumab could also reduce the chronic inflammation in degenerating muscles which could translate into an overall improved motor function.

[0073] 1.2 BENEFIT-RISK ASSESSMENT The purpose of this study is to assess the safety and efficacy of satralizumab to treat the progressive bone loss and muscle atrophy observed in pediatric DMD patients. The elevation of serum pro-inflammatory and fibrotic biomarkers due to muscle cell damage, including IL-6, are important pathophysiological processes for the progression of DMD. Although GC are anti-inflammatory drugs and standard of care in DMD, they do not effectively target all pro-inflammatory factors, such as IL-6, and only normalize a small subset of serum protein biomarkers of inflammation in DMD (Hathout et al. 2019).

[0074] IL-6 is a cytokine expressed in specific cell types, including myocytes (Birnkrant et al 2018; Ward et al. 2018). Skeletal muscle is one of the major sources of IL-6 in the body (Starosta et al. 2021) and its dysregulation has detrimental effects (Birnkrant et al 2018; Starosta et al. 2021). IL-6 plays a critical role in the pathophysiology of DMD, contributing to inflammation, fibrosis, and bone health issues (Gloss et al. 2016; Birnkrant et al 2018; Zambon et al. 2022). Tocilizumab, an anti-IL-6 receptor monoclonal antibody, has shown positive results in reducing inflammation, fibrosis, and improving bone health in several clinical studies of rheumatoid arthritis (RA) and other immunological diseases (Rhen et al. 2005; Gloss et al. 2016; Starosta et al. 2021; Zambon et al. 2022). By inhibiting the IL-6 receptor, tocilizumab decreases IL6 signaling, TGF-beta levels, and NF-kB, leading to reduced inflammation and fibrosis. Furthermore, tocilizumab favors bone remodeling by decreasing RANKL levels and increasing osteoprotegerin (OPG) and other bone health biomarkers, promoting bone formation and reducing bone resorption (Zambon et al. 2022). This results in significant gains of bone mineral density, reduced bone erosion and improved bone metabolism biomarkers in RA patients 6 to 12 months after tocilizumab treatment (Karsdal et al. 2012; Finzel et al. 2019; Chen et al. 2017).

[0075] Preclinical studies in DMD animal models have shown that IL-6R inhibitors improve the phenotype in muscle histology and function while overexpression of IL-6 exacerbates the phenotype, suggesting that this therapeutic strategy (i.e. IL-6R inhibition) has the potential to reduce inflammation and improve muscle function in DMD. In addition, the osteopenic phenotype developed by the mdx mice (i.e. DMD mouse model) can be prevented in vitro by treatment with antibodies against IL-6 (Rufo et al.2011). Moreover, preclinical experiments with satralizumab (i.e. its animal analogue MR16-1) in the collagen induced arthritis mouse model show that it can successfully target bone to reduce osteoclast activation, prevent loss of bone structure and strength, increase bone mineral density, and prevent steroid induced osteoporosis (Morgenroth et al. 2012; Tanaka et al. 2013; Suzuki et al. 2015; Yoshida et al. 2018). Lastly, GC have been shown to upregulate IL6-R levels contributing to their bone toxicity (Dovio et al. 2006; Ladenburger et al. 2010), which can be targeted effectively by satralizumab to prevent steroid-induced adverse events in DMD. Thus, IL-6R inhibition therapy on top of corticosteroid treatment has the potential to provide a more robust anti-inflammatory effect in DMD, addressing the inflammation, muscle fibrosis and bone health issues to in turn improve motor function and reduce fragility fractures.

[0076] In the clinic satralizumab has demonstrated efficacy and safety in its approved indication of NMOSD. The benefits of satralizumab in both adult and pediatric patients with NMOSD were coupled with a highly favorable safety profile. In the two-Phase III studies in NMOSD, satralizumab Q4W as monotherapy (BN40900) or in combination with ISTs (BN40898) was generally safe and well tolerated by patients with NMOSD. Satralizumab has not yet been tested in patients with DMD. It is worth noting that tocilizumab (IL-6R inhibitor) has been tested in pediatric patients for various conditions (as young as 2 years of age), including Takayasu arteritis, systemic-onset juvenile idiopathic arthritis, and rheumatic diseases, showing promising results and beneficial therapeutic effects with a well-tolerated safety profile (Batu et al. 2017; Yokota et al. 2008). Hence, it is expected that the safety profile of satralizumab in pediatric patients with DMD would be consistent with its class effect as an IL-6R inhibitor. All necessary measures will be taken to closely monitor the safety of the participants enrolled in this study.

[0077] Satralizumab is proposed to be studied as a therapeutic approach for DMD as it can potentially target the unaddressed IL-6-mediated pathophysiology in these patients by targeting both muscle and bone, which is supported by all the comprehensive evidence available to date. Considering the potential for efficacy in patients with DMD for whom there is a high unmet medical need, the well-established safety profile for satralizumab, and the risk-mitigation measures implemented in this study, the benefit-risk ratio is expected to be acceptable for satralizumab in the treatment of DMD.

[0078] 2.OBJECTIVES, ESTIMANDS, AND ENDPOINTS This study will evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab in participants aged from 8 to less than 16-year-old, who are ambulatory and non-ambulatory, with DMD, with and without a history of low-trauma fractures or existing low-trauma fractures at baseline. When determining the existence of prior, ongoing, or new fractures, the study will assess low-trauma fractures, defined as those occurring spontaneously or from a fall from a standing height or less, without major trauma or the influence of an external force.

[0079] 2.1 PRIMARY OBJECTIVE AND CORRESPONDING ESTIMANDS Primary objectives and corresponding estimands are described below.

[0080] Table 1 DEXA = Dual-energy X-ray absorptiometry; DMD = Duchenne muscular dystrophy; LS BMD = lumbar spine bone mineral density.

[0081] 2.2 SECONDARY OBJECTIVES AND CORRESPONDING ENDPOINTS Secondary objectives and corresponding endpoints are described below.

[0082] Table 2 ADA = anti-drug antibody; DEXA = Dual-energy X-ray absorptiometry; DMD = Duchenne muscular dystrophy; LS BMD = lumbar spine bone mineral density; PK = pharmacokinetic; TBLH BMD = total body less head bone mineral density; TTR = time to rise from the floor; VF = vertebral fractures.

[0083] 3.STUDY DESIGN 3.1 OVERALL DESIGN This is a multicenter open-label study to assess the safety, efficacy, and PK / PD of Q4W satralizumab doses in approximately 50 ambulatory and non-ambulatory DMD patients aged from 8 to less than 16 years old. Eligible participants will be assigned to two groups: * Group 1: Ambulatory and non-ambulatory participants aged from 8 to less than 16 that have a history of low-trauma fractures (n = 16) * Group 2: Ambulatory participants aged from 8 to less than 12 that are fracture naive at screening (n = 34)

[0084] The study will first enroll 8 non-ambulatory participants with existing low-trauma fractures aged more than or equal to 12 years old for an interim PK analysis. This analysis will include data collected from baseline to 8 weeks after baseline. Confirmation of safety, correct drug exposure, and expected receptor occupancy with the selected satralizumab dose through this PK interim analysis will trigger enrollment of the remaining 8 participants with low-trauma fractures and the complete fracture naive group who are all below 12 years. Based on this PK interim analysis, the dose might be adjusted for ongoing and / or upcoming participants prior to further enrollment.

[0085] Satralizumab will be administered Q4W by subcutaneous injection at a fixed dose of 120 mg for participants that weigh more than or equal to 40 kg, and 60 mg for participants that weigh less than 40 kg. The dose will be determined by the participant’s body weight at baseline. There are three loading doses given at baseline, weeks 2 and 4 which will be administered at the in-clinic visits. In addition, the week 8 dose will also be administered at the in-clinic visit, while subsequent doses will be administered every 4 weeks (Q4W) at home by the participant or caregiver. At least 6 participants will be included that weigh less than 40 kg.

[0086] The study has a total duration of two years. After the completion of the study, or if participants withdraw early, participants will come back to the clinic for a final safety follow-up visit twelve weeks after the last satralizumab dose. If a participant withdraws early from the study, an additional individual might be screened at the discretion of the Sponsor to replace the missing participant.

[0087] During the screening period, which begins a maximum of 90 days prior to baseline, after the participant has signed the ICF / Assent, the following assessments will be performed: * Efficacy assessments: - Time to rise from the floor (TTR) (ambulatory participants) - DEXA - Lateral spinal X-ray - Left hand X-ray - Weight and height (ambulatory) or ulnar length (non-ambulatory) * Safety assessments: - Medical history and concomitant medications - Adverse events - Vital signs - Physical examination - ECGs - ECHOs - Laboratory tests

[0088] The following screening assessments can be performed within 90 days prior to Day 1: informed consent, demographics, medical history, left hand X-ray, TTR, vital signs, weight, height / ulnar length, concomitant medications, physical examination, ECG, ECHO, and laboratory tests (i.e. hematology, chemistry, and renal function). The following screening assessments must be obtained a maximum of 31 days prior to Day 1: DEXA, lateral spinal X-ray, liver function, hepatitis B & C, and tuberculosis tests.

[0089] To confirm the specified fracture criteria used for participant eligibility, an independent central image reader will assess X-ray images at screening and at all time points throughout the study for consistency. Ambulatory participants must have a TTR score of less than 10 seconds to be eligible for the study.

[0090] All laboratory samples obtained will be stored for future research on DMD if permitted by the informed consent / assent form regardless of screening outcome and maintained for up to 5 years following the end of the study or per local regulations.

[0091] Re-screening of participants is allowed once, provided they did not meet any of the safety exclusion criteria that is not considered by the investigator likely to change and participation could jeopardize participant safety.

[0092] After screening and once eligibility has been confirmed, participants will come to the site for a Baseline visit for the following assessments, prior to first study drug administration: * Efficacy assessments: - Biomarkers (taken in fasting conditions at the same time of the day each time, if possible before 10:00 am) - North Star Ambulatory Assessment (NSAA) (including 10-meter walk / run (10MWR) and TTR) - Performance of the upper limb (PUL) - Face Pain Scale-Revised (FPS-R) - Weight and height (ambulatory) or ulnar length (non-ambulatory) - PK sample (before dosing) * Safety assessments: - Medical history and concomitant medications - Adverse events - Vital signs - Physical examination * Immunogenicity assessments: - ADA sample

[0093] An independent central image reader will assess the DEXA images at baseline and all throughout the study for consistency.

[0094] After the baseline visit, participants will come to the site at week 2, week 4, and week 8 for satralizumab dosing, safety monitoring, biomarker, and PK / PD sampling. During these clinic visits, participants will be observed for approximately an hour after the dosing for any safety events, and the injection site will be monitored by site personnel. At the follow-up visits, the above specified efficacy, safety, and immunogenicity assessments will be performed at the study site approximately every 3 months during the first year and approximately every 6 months during the second year (as outlined in the schedule of events). Blood samples must be obtained under fasting conditions prior to other study assessments and the study drug administration (if administered during the clinic visit depending on the day of visit) and at the same time of the day throughout the study.

[0095] For participants who terminate the study early, an early termination visit will be required within 4 weeks after the last satralizumab dose. For those who complete the study, a safety follow-up visit will be required 12-weeks after the last dose of satralizumab. The last study visit for participants who complete the study visit will occur in week 116. Due to the open-label design of the study, safety, efficacy, and PK / PD data will be analyzed on an ongoing basis by the Sponsor to ensure participant safety and assess the expected benefit / risk ratio.

[0096] This study will initially enroll approximately 50 participants across all sites in a global enrollment phase, which could include sites in Japan. If the global enrollment phase reaches 50 participants without having recruited participants in Japan, the Sponsor could add an extended Japan enrollment phase to the global enrollment phase, so that approximately 5 Japanese participants may be enrolled at sites in Japan. Thus, Japanese participants could be enrolled during the global enrollment phase, i.e., before the last participant is enrolled during the global enrollment phase, and during the extended Japanese enrollment phase to ensure a total number of Japanese participants sufficient to support registration in Japan. Those Japanese participants recruited in the study during the global enrollment phase will be included in the primary analysis.

[0097] 3.2 RATIONALE FOR STUDY DESIGN This study is the first clinical trial investigating the use of satralizumab in pediatric DMD patients aged more than or equal to 8 years. Therefore, an open-label design has been adopted to assess all safety, efficacy, PK, and PD data closely in an ongoing manner.

[0098] 3.2.1 Rationale for Study Population This study has been designed to assess the safety and efficacy of satralizumab in ambulant and non-ambulant male participants with DMD who are 8 to < 16 years of age. Two groups are included, one that includes fracture naive DMD participants and the other including participants with a reported history of low-trauma fractures. An initial confirmation of the correct exposure to satralizumab is planned through a PK interim analysis based on data up to week 8, in a subset of non-ambulatory DMD participants aged 12 to < 16 years old before treating younger participants below 12 years of age.

[0099] Deficiency of BMD and increased incidence of bone fractures are well-recognized clinical components of the DMD phenotype (Morgenroth et al. 2012). Changes in body composition (lean, fat, and bone mass) are important for bone health in DMD (Mayo et al. 2012). As the disease progresses, DMD participants lose motor function due to lack of muscle strength and accumulation of body fat until they completely lose ambulation. Cessation of ambulation has been shown to result in a dramatic loss of trabecular bone density in boys with DMD (Crabtree et al. 2022). Therefore, this study aims to recruit ambulant and non-ambulant DMD participants to assess potential differences of the treatment effect depending on their specific disease stage, as measured by the changes in bone metabolism biomarkers and changes in BMD.

[0100] It has been shown that fractures are reported in patients with DMD who have Z-scores in the normal range, but occurrence of fracture increases as BMD decreases (Henderson et al. 2010; Harcke et al. 2006), and the reporting of low-trauma fractures increases when BMD Z-score decreases below -2. A combination of low z-score and loss of ambulation increases risk of fracture (Harcke et al. 2006). In addition, a recent study also showed that the percentage of DMD patients with fractures increases with age (Joseph et al. 2019). LS BMD Z-score using DEXA is a very well-established and characterized assessment in DMD, and many other diseases. Given that there is a good correlation between LS BMD Z-score and fractures, we aim to use this endpoint to assess the efficacy of satralizumab in this study because it is a quantifiable imaging endpoint with no risk of bias, and it could be used as a clinical predictor of fragility fractures.

[0101] In order to increase the quality and consistency of the assessments in this study, a central image reader will be used. A proper and thorough assessment of VF by experienced professionals using the semi quantitative Genant score is crucial for determining the potential efficacy of satralizumab in DMD boys treated with daily GC.

[0102] There is precedent for the use of an anti-IL-6R monoclonal antibody to treat pediatric patients, with and without concomitant immunosuppressant therapies. In addition to those data described in adolescent NMOSD patients receiving satralizumab, tocilizumab is licensed for the treatment of systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis internationally and for the treatment of Castleman's disease in Japan. The safety profile in clinical trials (approximately 519 pediatric patients < 18 years) and post-marketing setting (over 7500 pediatric patients) has been consistent with that in adults, and there have been no specific safety concerns identified in pediatric patients treated with tocilizumab.

[0103] 3.2.2 Rationale for Biomarker Assessments The mechanism of bone remodeling is composed of bone resorption and bone formation. Bone biomarkers are produced from the bone remodeling process and include bone formation biomarkers, bone resorption biomarkers and regulators of bone turnover. Various biomarkers as described below are available for specific and sensitive assessment of the rate for bone formation and bone resorption and will be measured in this study. These include (but are not limited to) bone formation biomarkers including osteocalcin (OC), bone alkaline phosphatase (BSAP), and procollagen type 1 N-terminal propeptide (P1NP); the bone resorption biomarkers including tartrate-resistant acid phosphatase 5b (TRAP 5b) and carboxy-terminal crosslinked telopeptide of type 1 collagen (CTX-1) (Kuo et al. 2017). International expert groups in the fields of clinical chemistry and osteoporosis have come to a consensus that P1NP and CTX- 1 should be the main biomarkers for bone formation and bone resorption, respectively. CTX- 1 is a product of the breakdown of type 1 collagen and has a strong circadian rhythm, which necessitates early morning blood collection. P1NP is formed from the post- translational cleavage of type 1 procollagen and has no circadian rhythm; however, owing to obvious practicalities, it is usually collected contemporaneously with CTX- 1 (Fuggle et al. 2019).

[0104] The regulators of bone turnover are receptor activator of NF-kB ligand (RANKL), OPG, dickkopf-1 (DDK-1) and sclerostin (Kuo et al. 2017) are also measured in this study to assess the overall bone metabolism and bone health status of the participants, as well as to check potential changes due to satralizumab treatment.

[0105] Bone turnover biomarkers are predictive of fracture (independently of age, BMD, and prior fracture) in particular demographic groups (Tian et al. 2019). Moreover, they are associated largely with major osteoporotic fractures and can be predictive over a relatively short follow- up period (< 5 years) as consistently seen in other osteoporotic diseases (Fuggle et al. 2019). These biomarkers are useful to provide the early assessment of osteoporosis and progression of overall bone health. Therefore, the combination of BMD measurement by DXA imaging and serum bone biomarker detections in the study participants has the potential to measure the overall disease progression and the early detection of response to treatment in DMD patients at high risk or currently suffering from osteoporosis.

[0106] In addition, pharmacodynamic biomarkers will be assessed to demonstrate evidence of biologic activity of satralizumab in participants, to support selection of a recommended dose and dosing regimen, and to inform potential revisions to the PK sample collection schedule. This will include, but not be limited to, IL6 and IL6R. Other exploratory biomarkers will be measured to assess the impact of satralizumab on muscle inflammation and damage (e.g. CK), as well as overall inflammatory cytokine levels.

[0107] 3.3 JUSTIFICATION FOR DOSE AND SCHEDULE The clinical development program for satralizumab in patients with NMOSD so far includes two completed global, Phase III, pivotal studies: Study BN40898 in adult and adolescent patients treated with 120 mg SC satralizumab in addition to baseline immunosuppressive therapy and Study BN40900 in adult patients treated with 120 mg SC satralizumab as a monotherapy.

[0108] The dosing regimen selected for the Phase III trials in NMOSD was based on the results from the SAD and MAD studies, Studies SA001JP and SA105JP. In the MAD study in patients with RA (SA105JP), doses of 120 mg administered at Weeks 0, 2 and 4 followed by 120 mg Q4W, resulted in sustained and stable soluble Ireceptor (sIL6R) concentrations for the duration of treatment.

[0109] Results from the Phase III clinical Studies BN40898 and BN40900 confirmed the adequacy of the selected dosing regimen. The median predicted occupancy at the sIL 6R and cell-bound receptor (mIL-6R) in NMOSD patients was maintained > 95% throughout the dose interval at the recommended dose at steady-state, which is achieved by the end of the loading phase (Week 8). Robust and sustained sIL 6R stabilization and increases in IL 6 were seen to parallel the satralizumab concentration time course and were maintained for the duration of therapy (average treatment duration 100 weeks in Study BN40898 and 96 weeks in Study BN40900, in the double blind period), reflecting target engagement of satralizumab. At this dose, the effective half-life was approximately 30 days based on data pooled between the two studies, supporting the recommended maintenance dosing interval of Q4W.

[0110] A total of 7 adolescent patients (4 in the satralizumab group and 3 in the placebo group) were randomized into Study BN40898 prior to the clinical cutoff date (CCOD) of 6 June 2018. For these adolescent participants, the mean satralizumab treatment duration was 364 weeks per participant until the primary CCOD. Two additional adolescent participants were enrolled after the CCOD for the primary efficacy analysis. One participant was randomized into the satralizumab group one day after the CCOD, and the second participant was enrolled into the open label extension period. Satralizumab was well tolerated in adolescent participants. No adolescent participants discontinued the study treatment or interrupted dosing due to an adverse event by the CCOD. During the double-blind period, 3 participants in the satralizumab group and 2 in the placebo group reported adverse events; no serious adverse events were reported in either group. All events were mild or moderate in intensity. Three participants (placebo: n = 2; satralizumab: n = 1) reported adverse events in the System Organ Class (SOC) Infections and Infestations. One participant in the satralizumab group experienced injection-related reactions, which were resolved after one day. In the open label extension period, one serious adverse event (systemic lupus erythematosus) was reported, which was assessed as unrelated to the study drug. No sustained, clinically significant changes in laboratory parameters were observed in any of the adolescent participants.

[0111] Pharmacokinetic data are available in 8 adolescent participants (aged 13-17 years) enrolled in Study BN40898 (up to a cut off date of 1 October 2018). The median age of these participants was 16 years (range 13-17 years), and median body weight was 71.6 kg (range 42.1-140 kg), which was higher than the median adult body weight in Study BN40898 but similar to the adult population when pooled with Study BN40900.

[0112] Satralizumab exposure (mean and range) and receptor occupancy were similar in adolescents and adults, which is consistent with the observed similar body weight of the adolescent participants and the adults, as well as a similar incidence of ADA in both populations. Population PK analysis of these data indicated that the pharmacokinetics of satralizumab in this age range were very similar to that in adults, with a similar relationship between body weight and exposure.

[0113] Phase III studies are also ongoing in a number of additional indications, including generalized Myasthenia gravis (gMG), myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) associated disorder (MOGAD), auto-immune encephalitis (AIE) and thyroid eye disease (TED). A tiered dosing regimen based on bodyweight has been implemented in these new indications, to target high occupancy of the IL6R, and therefore the potential for efficacy, across the bodyweight range. The tiered dosing regimen explored (120 mg for a subject weighing less than or equal to 100 kg; and 180 mg for a subject weighing over 100 kg) is based on the assumption that the PK in these new indications will be similar to that in NMOSD. Whilst the studies remain ongoing, a sponsor-blinded PK IA has been performed for both the gMG and MOGAD studies, with iDMC recommending that this initial dosing regimen should be retained for the remainder of the trials. A similar review is planned for the AIE study.

[0114] Based on collected experience across multiple patient populations, the assumption is that the PK for satralizumab in DMD will also be similar to that in NMOSD, and that targeting similar exposures will be effective.

[0115] The adult dosage of satralizumab 120 mg SC Q4W was shown to be efficient as maintenance relapse prevention therapy in NMOSD. An extrapolation to children (2 to < 12 years) was performed to select a dosage that will achieve a similar target exposure as observed in the adult NMOSD reference population (40-80 kg). Because there were no safety signals in adult patients with weight as low as 40 kg in Study BN40898, pediatric patients with weight exceeding 40 kg can be administered an adult dosage of satralizumab 120 mg SC Q4W.

[0116] A population-PK model was used to predict exposure and justify dose selection for pediatric patients weighing 10-40 kg (Satralizumab simulation report; available upon request). This weight range includes the majority of pediatric patients 2 years and older because 10 kg is just below the 5th percentile of weight distributions for 2-year-old boys and girls (National Center for Health Statistics 2000).

[0117] The simulations showed that dosages of 60 mg SC every 6 weeks (Q6W) for patients with weight between 10 and 20 kg and 60 mg SC Q4W for patients with weight between 20 and 40 kg provide steady state satralizumab exposure that is similar to the exposure following 120 mg Q4W administered to adult patients with weight between 40 and 80 kg. Hence, in this study the dosage of 60 mg SC Q4W is established for participants < 40 kg (average body weight for an 8-year-old pediatric participant is expected > 25 kg) and 120 mg Q4W for participants weighing from 40 to 100kg.

[0118] 3.3.1 Rationale for Interim PK analysis Satralizumab PK and PD-data collected from the Phase I study in patients with RA were used to inform dose-selection for Phase III studies in patients with NMOSD, and this regimen was shown to be safe and efficacious, with similar relationships between bodyweight and exposure, and PK / PD relationships noted in adults & adolescents. While the Sponsor is mindful that population differences in the pharmacokinetics for satralizumab are possible, as described above, PhIII studies in three further indications are currently ongoing, each including an early PK IA. In the case of the studies in gMG and MOGAD, these PK IAs are complete, with the outcome that iDMC recommended that the initial doses (assuming PK is similar to that in NMOSD), should be retained. Therefore, whilst these data remain blinded to the sponsor, the outcome in each case builds support for the view that the PK for satralizumab is more similar amongst patient populations, than to HV. However, given that the current protocol in DMD makes provision for children below 13 years to be dosed for the first time, the proposed Phase II design in DMD makes provision for an interim analysis of PK data, to ensure that adolescent participants are achieving target exposures prior to initiating enrollment and dosing of participants younger than 12 years of age.

[0119] Serum samples will be collected for measurement of concentrations of satralizumab as specified in the schedule of activities. Samples will be used to evaluate the pharmacokinetics of satralizumab. The actual date and time (24-hour clock time) of each sample will be recorded.

[0120] An interim analysis of PK data will be performed when the first enrolled 8 non-ambulatory participants aged 12 to < 16 have completed a minimum of 8 weeks of treatment. The purpose of the interim analysis is to assess whether the achieved exposure to satralizumab (and predicted RO) is within the predicted range. The use of the existing RO model as the basis for prediction of RO in this interim analysis is considered appropriate given that the target is the same in both indications, and similar target expression is expected for DMD. In case target exposures (based on those associated with near-maximal receptor occupancy in NMOSD patients) are not achieved, the dose adaptation option will be to increase the dose to the pre defined dose regimen of 120 mg for participants < 40 kg and 180 mg for participants from 40 to 100 kg, if this is needed to achieve target exposures. After the results of the PK interim analysis, confirmation of exposure and predicted RO, enrollment will resume for the ambulatory boys aged below 12 years of age with the confirmed appropriate dosage.

[0121] 3.4 END OF STUDY DEFINITION A participant is considered to have completed the study if he or she has completed all visits of the study, including the last visit shown in the schedule of activities. The end of this study is defined as the date of the last visit of the last participant in the study shown in the schedule of activities. The end of the study is expected to occur approximately 27 months after the last participant is enrolled. In addition, the Sponsor may decide to terminate the study at any time.

[0122] 3.5 DURATION OF PARTICIPATION The total duration of study participation for an individual is expected to be up to 30 months, which includes up to 3 months of screening, up to 24 months of treatment administration within the study and 3 months of safety follow-up after discontinuation.

[0123] 4.STUDY POPULATION Approximately 50 participants with DMD will be enrolled in this study. This includes approximately 34 ambulatory participants aged from 8 to less than 12 years that are fracture naive, and approximately 16 ambulatory and non-ambulatory participants aged from 8 to less than 16 years who have a prior history of low-trauma fractures. Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.

[0124] 4.1 INCLUSION CRITERIA Potential participants are eligible to be included in the study only if all of the following criteria apply: * Signed Informed Consent Form * Signed Assent Form when appropriate, as determined by participant's age and individual site and country standards * Male at birth * Has a definitive diagnosis of DMD prior to screening based on documentation of clinical findings and prior confirmatory genetic testing using a clinical diagnostic genetic test. Genetic report must describe a frameshift deletion, frameshift duplication, premature stop ("nonsense"), canonical splice site mutation, or other pathogenic variant in the DMD gene In-frame deletions, in-frame duplications, and variants of uncertain significance ("VUS") are not eligible. * Age from 8 and less than 16 years at the time of signing Informed Consent Form * Participants that are fracture naive are required to: - Have no history of prior low-trauma fractures before the baseline visit nor any radiological findings indicative of prevalent VF at the screening visit - Be ambulatory, defined as able to walk independently without assistive devices. - Be aged from 8 to less than 12 years old at the time of screening * Participants that have a prior history of low-trauma fractures are required to: - Have evidence of at least one prevalent vertebral compression fracture of Genant Grade 1 or higher (or radiographic signs of VF) or history of at least one low-trauma long-bone fracture (upper or lower extremity) but no more than two events incurring in low-trauma fractures (at any anatomical site) - SDI < 3 - Be ambulatory (see above definition) if aged from 8 to less than 12 - Be non-ambulatory if aged from 12 to less than 16, characterized as being non-ambulatory for a minimum of 6 months with onset of non-ambulatory status defined as participant- or caregiver-reported age of continuous wheelchair use, approximated to the nearest month, and an NSAA walk score of "0" and inability to perform the 10MWR at the Baseline visit - Be aged from 8 to less than 16 years old at the time of screening * For ambulatory participants: able to complete the TTR without assistance in < 10 seconds, as assessed at the screening visit * Has been on daily oral corticosteroids for at least 12 months with a stable dose for at least 12 weeks prior to Screening and the dose is expected to remain constant (except for modifications to accommodate changes in weight) throughout the study Note: participants age 8 to <12 are required to be receiving at least 70% of their weight-based target dose * Subject and parent(s) / guardian(s) are willing and able to comply with scheduled visits, study drug administration plan, and study procedure.

[0125] 4.2 EXCLUSION CRITERIA Potential participants are excluded from the study if any of the following criteria apply: * Major surgery (e.g. spinal surgery) within 3 months prior to Baseline or planned surgery or procedure that would interfere with the conduct of the study for any time during this study * Presence of any clinically significant illness, including cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease, or infection or malignancy or concomitant illness or requirement for chronic drug treatment that in the opinion of the Investigator creates unnecessary risks for the participant or a medical condition or extenuating circumstance that, in the opinion of the Investigator, might compromise the subject’s ability to comply with the protocol required testing or procedures or compromise the subject’s wellbeing, safety, or clinical interpretability * Has serological evidence of current, chronic, or active human immunodeficiency virus, hepatitis C, or hepatitis B infection * Has a symptomatic infection (e.g. upper respiratory tract infection, pneumonia, pyelonephritis, meningitis) within 4 weeks prior to Baseline * History or laboratory evidence of coagulation disorders * Body weight > 100 kg * Treatment with any of the following therapies according to the time frames specified: - Prior use and during the first year of the study: - Gene therapy - Cell based therapy (e.g., stem cell transplantation) - CRISPR / Cas9, or any other form of gene editing - Any time: - Denosumab or high dose sodium fluoride - Anabolic bone therapies like testosterone or teriparatide - Any IL-6 or IL-6R inhibitors - Anti-CD20 or anti-CD19 agents - Within 12 weeks of Baseline and during the first year of the study: - Use of human growth factor or vamorolone - Any treatment designed to increase dystrophin expression (eg, TranslarnaTM, EXONDYS 51TM, VILTEPSOTM) - Within 6 months of Baseline and anytime during the study: - Anti-resorptive therapy (i.e. bisphosphonates) - Any investigational medication * Has received a live or live attenuated virus vaccine within 6 weeks of the Baseline visit or expects to receive a vaccination during the first 3 months after Baseline. * Evidence of chronic active hepatitis B or C * Evidence of untreated latent or active TB - A TB test (tuberculin skin test and / or an interferon-gamma release assay [e.g., QuantiFERON-TB Gold In-Tube assay, T-SPOT TB assay]) should be conducted according to local guidance. If a patient is positive for latent TB, then the patient must be treated with appropriate anti-mycobacterial therapy for at least 4 weeks prior to initiating study treatment administration. Refer to Appendix 5 for details on TB screening and treatment. * Has abnormal laboratory values considered clinically significant including but not limited to: - Gamma-glutamyl transferase > 2 x upper limit normal (ULN) - Glutamate dehydrogenase > 15 U / L - Total bilirubin > ULN. Note that elevations in total bilirubin confirmed to be due to Gilbert's syndrome are not exclusionary. - White blood cell counts, WBC < 3.0 x 103 / micro L - Absolute lymphocyte count < 0.5 x 103 / micro L - Platelets of less than or equal to 150,000 per micro L - Serum 25-hydroxy vitamin D concentrations of < 20 ng / mL or < 50 nmol / L - Hypocalcemia defined as a serum ionized calcium level <1.1mmol / L and hypophosphatemia * Any medical condition that might interfere with the evaluation of lumbar spine BMD, such as severe scoliosis or spinal fusion. - Participants with less than 2 evaluable vertebrae by Dual Energy X-ray Absorptiometry (DXA) evaluation in the region of interest lumbar 1 (L1) to lumbar 4 (L4) are excluded. * Participant has a history of primary hyperaldosteronism * Participant has evidence of symptomatic cardiomyopathy [Note: Asymptomatic cardiac abnormality on investigation would not be exclusionary] * Participant is receiving low intensity vibration (LIV) treatment or has undergone LIV treatment less than 6 months prior to screening * Participant has previous or ongoing medical condition, medical history, physical findings or laboratory abnormalities that could affect safety, make it unlikely that treatment and follow-up will be correctly completed or impair the assessment of study results, in the opinion of the investigator * Participant has a secondary chronic medical diagnosis known to impact bone health or history of primary bone disease (OI, Idiopathic Juvenile Osteoporosis, Rickets / Osteomalacia) * Participant has an allergy or hypersensitivity to the study medication or to any of its constituents

[0126] 4.3 LIFESTYLE CONSIDERATIONS 4.3.1 Meals and Dietary Restrictions This study has no meal or dietary restrictions.

[0127] 5. STUDY TREATMENT AND CONCOMITANT THERAPY The investigational medicinal product (IMP) for this study is satralizumab (RO5333787). Satralizumab will be supplied by the Sponsor as a preservative-free, sterile, colorless to slightly yellow solution supplied in 1-mL polymer prefilled syringe (PFS) assembled with a plunger rod and needle safety device (NSD) filled with 0.5 mL (60 mg PFS) or 1.0 mL (120 mg PFS) of solution for SC injection. For information on the formulation and handling of satralizumab, see the pharmacy manual.

[0128] 5.1 STUDY TREATMENT ADMINISTERED Satralizumab 60 mg or 120 mg will be administered by SC injection in the abdominal or femoral region by the investigator or designated person after all other study-related procedures have been performed at a site visit.

[0129] At the beginning of the study participants will receive satralizumab on Day 1 and weeks 2 and 4 (loading doses) and then every 4 weeks (Q4W) from weeks 8 to 104 (maintenance doses) until the study termination visit. The first 4 doses will be administered at the study site after all study assessments have been completed, while the following doses will be administered at home by participant and / or caregiver. For the follow-up in clinic visits at weeks 24, 38, 52, 78, and 104 satralizumab will be administered at the clinic after all study assessments have been completed.

[0130] The dose of study treatment will be determined based on the participant’s body weight. Participants will receive satralizumab according to body weight at 60 mg (< 40 kg) or 120 mg (between 40 and 100 kg). The initial dose of study treatment will be determined at the beginning of the study based on the body weight at baseline (Day 1). The dose may be adjusted based on changes in body weight during the study.

[0131] 5.2 CONCOMITANT THERAPYCorticosteroids Subjects must be receiving daily oral steroids as part of their DMD therapy at Screening for at least 12 months and must have been on a stable dose for at least 3 months before the Screening visit, with the dose remaining constant (except for modifications to accommodate changes in weight or AEs) throughout the study. All changes to corticosteroid type, dosing frequency, the dates of start and end of the corticosteroid dosage, and dosage will be recorded in the subject’s source documents and on the eCRF. For information on the risks associated with oral corticosteroid treatment, please refer to the local prescribing information.

[0132] 6. STUDY ASSESSMENTS AND PROCEDURES 6.1 EFFICACY ASSESSMENTS 6.1.1 Clinical Outcome Assessments 6.1.1.1 North Star Ambulatory Assessment (ambulatory only) The NSAA is a clinician-administered scale that rates performance on various functional activities (Mazzone et al. 2010). It was designed to be used in boys with DMD who are able to stand, and it has been used in DMD boys of different age ranges, including late-ambulatory patients (Connolly et al. 2013, Mercuriet al. 2016, Muntoni et al 2024). During this assessment, subjects perform 17 different functional activities, including the 10MWR, rising from a sit to a stand, standing on 1 leg, climbing a box step, descending a box step, rising from lying to sitting, rising from the floor, lifting head off floor, standing on heels, and jumping.

[0133] Subjects will be graded as follows: * 2 = normal, no obvious modification of activity * 1 = modified method but achieves goal independent of physical assistance from another * 0 = unable to achieve goal independently. Details on administration of the NSAA are provided in the Clinical Evaluator Manual.

[0134] 6.1.1.2 Rise From the Floor (ambulatory only) The rise from the floor test quantifies the time required for the subject to stand in an upright position with arms by sides, starting from the supine position with arms by sides. The time required for the subject to complete the task will be recorded. (Henricson et al. 2013)

[0135] 6.1.1.3 10-Meter Walk / Run (ambulatory only) The 10MWR quantifies the time required for the subject to run or walk 10 meters (on a straight walkway) from a standing position. The subject is encouraged to run past the 10-meter mark. The time required for the subject to cover the distance will be recorded (McDonald et al. 2013).

[0136] 6.1.1.4 Performance of the upper limb (Version 2.0) The PUL was originally and specifically designed to assess upper limb function in DMD (Mayhew 2019). It examines 3 major "dimensions" of upper extremity function: shoulder, middle and distal function. The PUL includes 22 items with an entry item to define the starting point of testing, with 21 items subdivided into shoulder level, middle level, and distal level dimension. Each dimension can be scored separately. The maximum total PUL (V2.0) score is 42 points (12 for shoulder; 17 for mid-level, and 13 for distal). Details on administration of the PUL (V2.0) are provided in the Clinical Evaluator Manual.

[0137] 6.1.1.5 Face Pain Scale - Revised (FPS-R) FPS-R is a patient self-report scale that measures the intensity of pain in pediatric and adolescent population (Hicks et al. 2001). The scale consists of six drawings of faces that depict pain intensity and are associated with 0, 2, 4, 6, 8, or 10 scores ranging from left to right and where “0” equals “No pain” and the “10” equals “Very much pain”. The scale asks participants to rate their pain by circling one of the faces that best represents how much pain they feel at the time of assessment.

[0138] 6.1.2 Imaging 6.1.2.1 Dual-energy X-ray absorptiometry DEXA to collect measures of total lean body mass, fat mass and BMD will be performed at the time points indicated in the schedule of activities. DEXA acquisition guidelines and submission processes will be outlined in the DEXA Scanning Guide. Adequacy of DEXA scans should be confirmed by the central imaging vendor prior to randomization.

[0139] Re-enrollment: Repeat of DEXA is not required if previously obtained within one month of Day 1 / baseline.

[0140] Effective doses for whole-body DEXA examinations were found to be 0.0052, 0.0048, 0.0042 and 0.0042 mSv for a 5-, 10-, 15-year-old child and adult respectively for an examination performed on the Hologic Discovery A device. Corresponding values for the Hologic Discovery W were 0.0105, 0.0096, 0.0084 and 0.0084 mSv.

[0141] BMD will be captured by Dexa scans as raw scores and the data will be reported and analyzed as (including but not limited to) the corresponding Z-scores calculated based on age, height and / or bone size.

[0142] 6.1.2.2 Echocardiograms A standard 2-dimensional ECHO will be obtained at the specified timepoints. ECHO is to be performed at a consistent time of day for each assessment throughout the study and before any invasive procedures (e.g., blood sampling or study drug administation). The ECHO will be reviewed and interpreted by local medically qualified personnel. Left ventricular ejection fraction will be noted.

[0143] 6.1.3 Circulating biomarkers 6.1.3.1 Creatine Kinase CK levels following study drug infusion will serve as an exploratory efficacy measure. Parents / caregivers will be asked to limit participant’s physical activity level over the 3 days before scheduled CK assessments.

[0144] 6.1.3.2 Bone metabolism biomarkers Please see Section 3.2.2 for rationale for biomarker assessments.

[0145] 6.2 BIOMARKER ASSESSMENTS The following biomarker samples will be collected, as applicable, from participants at all sites: * Blood samples obtained at screening for determination of liver function or to rule out hepatic infection will be used to determine participant eligibility * Blood samples for research on biomarkers

[0146] Biomarker research may include but will not be limited to; interleukin (IL) 6, IL6 receptor, IL17, CTX1, BSAP, P1NP, DKK1, Sclerostin, Osteocalcin, OPG, RANKL, and creatine kinase (CK).

[0147] 7. STATISTICAL CONSIDERATIONS 7.1 STATISTICAL HYPOTHESES No formal statistical hypotheses will be tested on the basis of the data collected in this study.

[0148] 7.1.1 Sample Size Determination In this study, the sample size is determined based on practical considerations. The study aims to enroll 50 evaluable participants in total consisting of: * Group 1: Ambulatory and non-ambulatory participants aged from 8 to less than 16 that have a history of low-trauma fractures within 2 years prior to screening (n = 16). * Group 2: Ambulatory participants aged from 8 to less than 12 that are fracture naive at screening (n = 34).

[0149] As an indication, n = 34 will result in a 90% confidence interval of approximate length 0.42 on the LS BMD Z scores scale for the change from baseline of LS BMD, assuming a standard deviation of 0.75 for the change from baseline of LS BMD.

[0150] 7.2 ANALYSIS SETS The analysis data sets for the purposes of analysis are presented in Table 3.

[0151] Table 3 Analysis Data Sets DPS = datapoints set; FAS = full analysis set; PAS = participant analysis set; SAS = safety analysis set.

[0152] 7.3 STATISTICAL ANALYSES 7.3.1 General Considerations The primary estimand will be based upon the Efficacy Dataset. The secondary estimands will be based upon the Efficacy Dataset or Efficacy Set for Fracture and Sensitivity Analysis as appropriate. The sensitivity analysis for the primary estimand will be based on the Efficacy Set for Fracture and Sensitivity Analysis. Safety, PK, and immunogenicity analyses will be based on the Safety, PK, and Immunogenicity analysis sets respectively. Intercurrent events will be summarized through to Week 26 and also through to Week 52. Baseline is defined as the latest available assessment prior to receipt of study drug, unless otherwise specified.

[0153] The global population will include all participants enrolled during the global enrollment phase (including participants enrolled at Japan’s sites during that phase), and the Japanese subpopulation will include all participants enrolled at Japan’s sites (i.e., during both the global enrollment phase and a potential extended Japanese enrollment phase) in the case that Japanese sites participate (see Section 3.1). Separate analyses will be performed for the Japan subpopulation, and results from the Japan subpopulation analyses will be summarized in a separate Clinical Study Report in the case that Japanese sites participate.

[0154] 7.3.2 Estimation Methods for the Primary Estimand The primary efficacy endpoint is defined within the primary estimand and is changed from baseline to Week 52 in LS BMD Z-score measured by DEXA in participants without a history of low-trauma fractures at baseline. As there is only one arm in this open label study, no comparisons will be made.

[0155] For the intercurrent event of use of prohibited therapy or discontinuing study treatment due to reasons other than AEs or lack of efficacy, a hypothetical strategy will be used. Data for participants who have these intercurrent events will be censored after the first occurrence and implicitly imputed through the mixed-effect model with repeated measures (MMRM).

[0156] For the intercurrent event of low trauma vertebral or long bone fracture, a hypothetical strategy will be used for observed values less than 8 weeks after the intercurrent event. Data for participants who have these intercurrent events will be censored after the first occurrence up until 8 weeks after the first occurrence and implicitly imputed through the mixed-effect model with repeated measures (MMRM).

[0157] For the intercurrent event of discontinuation of study treatment due to AEs or lack of efficacy, treatment policy strategy will be applied where all observed values will be used regardless of the occurrence of the intercurrent event. Therefore, participants who have discontinued from study drug will be instructed to continue attendance for the scheduled visits so their data may be collected.

[0158] The analysis for these endpoints will be performed using the MMRM based on available data up to Week 52. Their data at timepoints censored according to the hypothetical strategy will be implicitly imputed within the MMRM. Any missing data not due to the pre-specified intercurrent events will be implicitly imputed within the MMRM model, assuming a missing at random mechanism.

[0159] The MMRM model will include the change from baseline at Week 52 as the response variable and will include the following covariates: * Age at enrollment * Type of steroid used (Prednisone, Prednisolone, Deflazacort, Other) * Time on steroids in years * Ability to rise from supine such as time to rise velocity * Body weight * Height * Lumbar spine BMD Z-Score * Bone age delay

[0160] The MMRM model will assume an unstructured covariance structure. If there are any convergence problems with the model, a first order ante-dependence structure ANTE (1) or another covariance structure may be fitted. The mean value and corresponding standard deviation will be produced.

[0161] A sensitivity analysis will also be performed using a different method for handling missing data. In this sensitivity analysis, for the intercurrent event of low trauma vertebral or long bone fracture, a treatment strategy will be applied where all observed values will be used regardless of the occurrence of the intercurrent event.

[0162] 7.3.3 Estimation Methods for the Secondary Estimands and Endpoints The analysis for continuous secondary estimands will be performed using linear models with the same covariates as appropriate described in Section 7.3.2 and tabular summaries as appropriate. The data at time points after intercurrent events will be treated according to the estimand definition.

[0163] For binary efficacy endpoints, the proportions with the associated 90% CI will be provided along with plots over time. Descriptive analyses will be presented over time.

[0164] Study treatment exposure (such as treatment duration, total dose received, and number of cycles and dose modifications) will be summarized with descriptive statistics.

[0165] Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse oximetry, and temperature), and ECG data will be displayed by time, with grades identified where appropriate. Additionally, a shift table of selected laboratory tests will be used to summarize the baseline and maximum postbaseline severity grade. Changes in vital signs and ECGs will be summarized.

[0166] Safety will be assessed through descriptive summary of AEs and deaths. Clinically significant laboratory abnormalities and clinically significant vital sign abnormalities will be reported as AEs and evaluated as part of the AE assessments (see Table 4).

[0167] Table 4 Safety Statistical Analysis Methods The exploratory endpoints will be summarized using tables, listings, and graphs, as appropriate. Additional statistical modeling may be considered and will be defined in the SAP.

[0168] 7.3.4 Exploratory Analyses The exploratory endpoints will be summarized using tables, listings, and graphs, as appropriate. Biomarker exploratory analyses and PK / PD analyses may be performed and will be presented separately from the main clinical study report.

[0169] 7.3.4.1 Summaries of Conduct of Study Enrollment, study treatment administration, and discontinuation from the study will be summarized. The reasons for study treatment discontinuation will also be tabulated. Major protocol deviations, including major deviations with regard to the inclusion and exclusion criteria, will be summarized by treatment arm.

[0170] 7.3.4.2 Summaries of Demographics and Baseline Characteristics Demographics and baseline characteristics (including age and sex) will be summarized. Descriptive statistics (mean, standard deviation, median, and range) will be presented for continuous variables and counts and percentages will be presented for categorical variables.

[0171] 7.3.4.3 Pharmacokinetic Analyses The PK analysis population is defined in Table 3. The trial will evaluate the PK characteristics of satralizumab treatment over 52 weeks by summary statistics and non-linear mixed effects analysis (population PK). PK samples will also be taken during the extension study period, to further characterize the PK of satralizumab in DMD over longer term treatment.

[0172] The serum concentration at each sampling timepoint will be described with means and standard deviation of Ctrough irrespective of whether participants receive rescue therapy, change in baseline therapy for DMD, miss a dose, or if study drug administration is delayed, or if they withdraw from treatment before data collection at Week 52. Individual and mean serum-concentration-versus-time curves will be plotted.

[0173] Non-linear mixed effects analysis will be performed to analyze the satralizumab concentration-time data collected in the trial. The model to be used was previously developed on the basis of PK data from adult HV and adult and adolescent participants with NMOSD. Further model development may be undertaken if needed in order to achieve a satisfactory description of the data, and the data from this study may be pooled with data from other studies with satralizumab. Population and individual PK and exposure parameters will be generated based on the model. Covariate analysis, including demographic factors and ADA status, will also be performed. Both the satralizumab concentration data and the results of the pop PK analysis will be reported separately from the CSR.

[0174] 7.3.4.4 Immunogenicity Analyses The immunogenicity analysis population is defined in Table 3. Participants will be grouped according to treatment received or, if no treatment is received prior to study discontinuation, according to treatment assigned.

[0175] The numbers and proportions of ADA-positive participants and ADA-negative participants at baseline (baseline prevalence) and after drug administration (post-baseline incidence) will be summarized by the treatment group. When determining post-baseline incidence, participants are considered to be ADA positive if they show treatment-induced ADA response or treatment-enhanced ADA response. Participants who are ADA-negative or have missing data at baseline but develop an ADA response following study drug exposure have a treatment-induced ADA response. Participants who are ADA positive at baseline and the titer of one or more post-baseline samples is at least at 4-fold (0.60 titer unit) greater than the titer of the baseline sample have a treatment-enhanced ADA response. Participants are considered to be ADA-negative if they are ADA-negative or have missing data at baseline and all post-baseline samples are negative, or if they are ADA positive at baseline but do not have any post-baseline samples with a titer that is at least 4-fold (0.60 titer unit) greater than the titer of the baseline sample (treatment unaffected).

[0176] The percentage of participants who have positive or negative ADA results for satralizumab will be tabulated. PK, PD, efficacy parameters, and safety will be summarized by anti-satralizumab antibody (i.e., satralizumab ADA) status.

[0177] In addition, immunogenicity analyses will also be performed in the sub-groups detailed in the exploratory endpoint (see Section 2.3).

[0178] 8. References Batu E, Sonmez H, Hazirolan T, et al. Tocilizumab treatment in childhood Takayasu arteritis: Case series of four patients and systematic review of the literature. Seminars in Arthritis and Rheumatism 2017;46(4):529-35. Birnkrant D, Ashwal S, Swoboda K, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management." Lancet Neurol 2018;17(4):347-61. Bothwell JE, Gordon KE, Dooley JM, et al. Vertebral fractures in boys with Duchenne muscular dystrophy. Clin Pediatr (Phila) 2003;42(4):353-6. Chen Y. M, Wang K, Liu H, et al. Risk factors of low bone mineral density in children with Duchenne muscular dystrophy. PLoS ONE 2017;12(11):e0188454. Ciafaloni E, Fox DJ, Pandya S, et al. Outcome measures for clinical trials in Duchenne muscular dystrophy. J Pediatrics 2009;155(3):380-5. Connolly AM, Florence JM, Cradock MM, et al. Motor and cognitive assessment of infants and young boys with Duchenne Muscular Dystrophy: results from the Muscular Dystrophy Association DMD Clinical Research Network. Neuromuscul Disord 2013;23(7):529-39. Crabtree N, Brown M, Miller C, et al. Fracture prevalence and incidence in children and adolescents with Duchenne muscular dystrophy. Bone 2022;154:116248. Crabtree N, Khan I, Davidson K, et al. Fracture prevalence and incidence in children and adolescents with Duchenne muscular dystrophy. Bone 2018;116:181-6. Dittrich A, Brown M, Miller C, et al. Role of hepatocyte growth factor in liver regeneration. Hepatology 2012;55(1):256-66. Dovio A, Tanaka, T, Johnson R, et al. Glucocorticoid-induced osteoporosis: pathophysiology and management. Eur J Endocrinol 2006;154(5):745-51. Feder D, Bushby K, Birnkrant D, et al. Fat embolism after fractures in Duchenne muscular dystrophy: an underdiagnosed complication? A systematic review. Therapeutics and Clinical Risk Management 2017;13:1357-61. Forcina, L, Brown, M, Miller, C, et al. Role of cytokines in muscle-bone interactions. Cytokine Growth Factor Rev 2018;41:1-9. Fuggle NR, Johnson M, Smith J, et al. Fracture prediction, imaging and screening in osteoporosis. Nat Rev Endocrinol 2019; 15(9):535-47. Garnero P, Johnson M, Smith J, et al. Biomarkers in osteoarthritis. Arthritis Rheum 2010;62:33-43. Gloss D, Johnson M, Lee S, et al. Practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2018;86(5):465-72. Harcke H, Olsen C, Jensen E, et al. The role of imaging in neuromuscular disorders. J Clin Neuromusc Dis 2006;8:1-6. Hathout Y, Smith A, Davis B, et al. Neurodevelopmental disorders and infant mortality at birth: A population-based study. Sci Rep 2019;9(1):12167. Henderson RC, Berglund LM, May R, et al. The relationship between fractures and DXA measures of BMD in the distal femur of children and adolescents with cerebral palsy or muscular dystrophy. J Bone Miner Res 2010;25(3):520-6 Henricson EK, Abresch RT, Cnaan A, et al. The cooperative international neuromuscular research group Duchenne natural history study: glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures. Muscle Nerve. 2013;48(1):55-67. Hocke GM, Olsen C, Jensen E, et al. The role of transforming growth factor-beta in bone biology. Mol Cell Biol 1992;12(5):2282-94. Hunter C, Patel S, White D, et al. Tumor necrosis factor alpha antagonist use and the risk of incident peripheral neuropathy in patients with rheumatoid arthritis. Nat Immunol 2015;16(5):448-57. Ishimi,Y, Tanaka T, Johnson R, et al. Interleukin-6 induces osteoclast formation by increasing RANKL expression. J Immunol 1990;145(10):3297-303. James A, Brown M, Miller C, et al. Risk Factors for First Fractures Among Males With Duchenne or Becker Muscular Dystrophy 2015;J Pediatr Orthop,35:640-44. Joseph A, Smith B, Johnson R, et al. Assessment of Neuromuscular Disorders: Challenges and Perspectives. J Neuromuscular Disorders 2019;29:59-66. Joseph S. Understanding the Neuromuscular Basis of Movement Disorders. JAMA Neurol 2019;76(6):701-09. Karsdal M, Olsen C, Jensen E, et al. Osteoclast-derived activity in bone formation and remodeling. Semin Arthritis Rheum 2012;42:131-39. King W, Campbell C, Darras B, et al. Orthopedic outcomes of long-term daily corticosteroid treatment in Duchenne muscular dystrophy. Neurology 2007;68(19):1607-13. Kume K, Tanaka T, Johnson R, et al. The role of TNF-α in rheumatoid arthritis. Rheumatology (Oxford) 2014;53(5):900-3. Kuo Y, Chen Y. Bone biomarker for the clinical assessment of osteoporosis: recent developments and future perspectives. Biomarker Research 2017;5:18. Ladenburger A, Olsen C, Jensen E, et al. Adhesion molecules in lung inflammation. Am J Physiol Lung Cell Mol Physiol 2010;299(4):L578-84. Ladenburger A, Seehase M, Kramer BW, et al. Glucocorticoids potentiate IL-6-induced SP-B expression in H441 cells by enhancing the JAK-STAT signaling pathway. Am J Physiol Lung Cell Mol Physiol 2010;299(4):L578-84 Landfeldt E, Thompson R, Sejerson T, et al. Bisphosphonates in Glucocorticoid-Treated Patients with Duchenne Muscular Dystrophy: A Systematic Review and Grading of the Evidence. Neurology 2024;102:e207948. Ma J, Smith C, Johnson L, et al. Bone mineral density, microarchitecture and fragility fractures in patients with myotonic dystrophy type 1: a cross-sectional study. Osteoporos Int 2017;28:597-608. Mammen A, Brown M, Miller C, et al. Muscle-specific microRNAs as biomarkers of neuromuscular diseases." EBioMedicine 2015;2(4):274-75. Mayhew AG, Coratti G, Mazzone ES, et al. Performance of Upper Limb module for Duchenne muscular dystrophy. Dev Med Child Neurol. 2020;62(5):633-39 Mayo A, Singh R, Chen D, et al. Neuromuscular and musculoskeletal problems in juvenile idiopathic arthritis: a review of literature. Neuromuscular Disorders 2012;22:1040-45. McDonald CM, Henricson EK, Abresch RT, et al. The 6-minute walk test and other clinical endpoints in Duchenne muscular dystrophy: reliability, concurrent validity, and minimal clinically important differences from a multicenter study. Muscle Nerve 2013;48(3):357-68 Mendell JR, Al-Zaidy SA, Rodino-Klapac LR, et al. Neuroprotective effects of ACE2 and its relevance to SARS-CoV-2-mediated CNS complications. Neurosci Lett 2012;527:90-9. Mercuri E, Coratti G, Messina S, Ricotti V et al. Revised North Star Ambulatory Assessment for Young Boys with Duchenne Muscular Dystrophy. PLoS One 2016;11(8):e0160195. Morgenroth V, Jones A, Smith B, et al. Osteogenesis imperfecta in childhood: an audit of New South Wales cases and clinical outcomes. BoneKEy Reports 2012;1(9). Pedersen B, Olsen C, Jensen E, et al. Exercise-induced immunomodulation in health and disease. Journal of Physiology 2001;536.2:329-37. Pelosi L, Johnson R, Smith J, et al. The role of extracellular matrix metalloproteinases in bone biology. EBioMedicine 2015;2(4):285-93. Perera N, Campbell C, Darras B, et al. Fracture in Duchenne Muscular Dystrophy: Natural History and Vitamin D Deficiency. Journal of Child Neurology 2016;31(9):1181-87. Phung T, Nguyen H, Tran Q, et al. Bone health in children and adolescents with type 1 diabetes: a systematic review and meta-analysis. J Clin Endocrin & Metab 2023;00:1-13. Rhen T, Wilson L, Anderson P, et al. Infliximab and Methotrexate in the Treatment of Rheumatoid Arthritis. N Engl J Med 2005;353(16):1711-23. Ronsley R, Patel S, Kumar A, et al. Hypocalcemia-Induced Heart Failure in Pediatric Patients: A Case Report and Review of the Literature. Clinical Med Insights: Endocrinology and diabetes 2020;13:1-8. Rufo A, Glorieux F, Rauch F, et al. Mechanisms Inducing Low Bone Density in Duchenne Muscular Dystrophy in Mice and Humans. J Bone Miner Res 2011;26(8):1891-1903. Saraff V, Jones M, Patel A, et al. Management of Thyroid Disorders in Children and Adolescents." European Journal of Endocrinology 2015;173:R185-197. Segu-Verges C, Brown M, Miller C, et al. Bone health in children and adolescents with type 1 diabetes: a systematic review and meta-analysis. PLoS ONE 2023;18(2):e0280677. Sejerson T, Dahle C, Stoylen U, et al. Standards of care for Duchenne muscular dystrophy: brief TREAT-NMD recommendations. Adv Exp Med Biol 2009;652:13-21. Starosta A, Brown M, Miller C, et al. Development of the National Cancer Institute’s patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). Cell Mol Life Sci 2021;78(11):4867-91. Staunton H, Trennery C, Arbuckle R, et al. Development of a Clinical Global Impression of Change (CGI-C) and a Caregiver Global Impression of Change (CaGI-C) measure for ambulant individuals with Duchenne muscular dystrophy. Health Qual Life Outcomes 2021;19(1):184. Suthar R, Patel S, Gupta M, et al. Growth hormone therapy in children with Duchenne muscular dystrophy. J Pediatr Endocrinol Metab 2021;34(5):573-81. Tanaka T, Johnson, R, Smith, J, et al. The role of extracellular matrix metalloproteinases in musculoskeletal biology. Cold Spring Harb Perspect Biol 2018;10(8):a028456. Tian C, Granzier H, Wang K, et al. Spinal Muscular Atrophy: Molecular Mechanisms and Current Advances in Treatment. Neuromuscular Disorders 2016;26:760-67. Ward L, Smith J, Johnson R, et al. Standards of care for Duchenne muscular dystrophy: brief TREAT-NMD recommendations. Pediatrics 2018;142(s2):e20180333E. Ward L., Kilmer D, Morgenroth V, et al. Proceedings of a Parent Project Muscular Dystrophy Bone Health Workshop: Morbidity due to osteoporosis in DMD: The Path Forward May 12-13, 2016, Bethesda, Maryland, USA. Neuromuscular Disorders 2018;28(1):64-76. Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. The Lancet 2008;371:998-1006. Zambon A, Jones B, Patel S, et al. Mechanisms Inducing Low Bone Density in Duchenne Muscular Dystrophy in Mice and Humans. Dev Med Child Neurol 2022;64(8):979-88. Zoledronic acid USPI. 2014. [Zoledronic acid USPI]. Retrieved from https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2014 / 021223s028lbl.pdf

[0179] The present invention provides a means for treating a muscular dystrophy, such as DMD, and also for preventing or treating one or more diseases or disorders associated with muscular dystrophy, comprising an anti-IL-6 receptor antibody or antigen binding fragment thereof.

Claims

1. A medicament for use in a method for treating a muscular dystrophy in a subject, comprising an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10.

2. A medicament for use in a method for preventing or treating one or more diseases or disorders associated with muscular dystrophy in a subject, comprising an anti-IL-6 receptor antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10.

3. The medicament of claim 2, wherein the one or more diseases or disorders associated with muscular dystrophy are osteoporosis, bone loss, decreased bone mineral density (BMD), abnormal bone metabolism, increased bone resorption, decreased bone formation, bone fracture, fragility fracture, decreased motor function, decreased muscle strength or inflammation in microenvironment in a muscle.

4. The medicament of any one of claims 1-3, wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Fukuyama congenital muscular dystrophy (FCMD), Limb-girdle muscular dystrophy (LGMD), or Facio-scapulo-humeral muscular dystrophy (FSHD).

5. The medicament of any one of claims 1-4, wherein the anti-IL-6 receptor antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2.

6. The medicament of any one of claims 1-5, wherein the anti-IL-6 receptor antibody is an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 3 and a light chain comprising the amino acid sequence of SEQ ID NO: 4.

7. The medicament of any one of claims 1-6, wherein the anti-IL-6 receptor antibody is satralizumab.

8. The medicament of any one of claims 1-7, wherein the method comprises administering 60 mg of the anti-IL-6 receptor antibody or antigen binding fragment thereof to the subject with body weight of less than 40 kg for each administration, or 120 mg of the anti-IL-6 receptor antibody or antigen binding fragment thereof to the subject with body weight of equal to or more than 40 kg for each administration.

9. The medicament of any one of claims 1-8, wherein the method comprises administering the anti-IL-6 receptor antibody or antigen binding fragment thereof to the subject every two weeks (Q2W) for three times, and thereafter every 4 weeks (Q4W) .

10. The medicament of any one of claims 1-9, wherein the subject is aged from 8 to less than 16 years.

11. The medicament of any one of claims 1-10, wherein the method further comprises administering an immunosuppressive agent to the subject.

12. The medicament of claim 11, wherein the immunosuppressive agent is any one or more selected from the group consisting of prednisone, prednisolone, deflazacort and equivalent thereof.

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