Use of myostatin inhibitors to treat spinal muscular atrophy

Abstract

Administration of apitegromab leads to improvements in motor function and / or quality of life in subjects with spinal muscular atrophy.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of and priority to U.S. Provisional Patent Application Nos. 63 / 364,188, filed May 4, 2022; 63 / 366,447, filed June 15, 2022; 63 / 366,662, filed June 20, 2022; and 63 / 378,987, filed October 10, 2022, each entitled "USE OF ANTI-PRO / LATENT MYOSTATIN ANTIBODY FOR TREATING SPINAL MUSCULAR ATROPHY," the contents of which are expressly incorporated herein by reference in their entireties.

[0002] The present disclosure relates to therapeutic methods, uses, and compositions comprising anti-promyostatin / anti-latent myostatin antibodies for treating spinal muscular atrophy (SMA) in human patients. [Background technology]

[0003] Myostatin, also known as growth differentiation factor 8 (GDF-8) or GDF8, is a regulator of muscle homeostasis. Mutations that result in loss of myostatin and pharmacological inhibition of myostatin activity have been shown to increase muscle growth in several species, including humans. Over the past 15 years, at least 15 different myostatin inhibitor drug candidates, including small molecules and biologics, have been evaluated in human patients for the treatment of various muscle disorders; however, to date, none have achieved clinical success (Hanna et al. (2019) Lancet Neurol. 18(9):834-844; Rooks et al. (2020) JAMA Network Open. 3(10):e2020836). Furthermore, most of these inhibitors lacked selectivity, antagonizing other related growth factors, such as activin A, and raising toxicity concerns. Most of these projects have now been discontinued. Thus, in many cases, satisfactory preclinical results have not been successfully translated into safe and effective drugs.

[0004] In most cases of SMA, deletion mutations on chromosome 5q13.2 cause SMA; however, in a minority of cases, SMA is unrelated to 5q13.2 mutations (Peeters et al. (2014) Brain 137:2879-2896). Non-5q13.2 mutations can result in early- or late-onset SMA with a variety of clinical phenotypes. Sequencing methods can detect various genes associated with spinal muscular atrophy, which can manifest as conditions such as, but not limited to, early-onset scapuloperoneal spinal muscular atrophy and Farber disease (Teoh et al. (2017) Neural Plasticity 2017;2017:6509493. doi:10.1155 / 2017 / 6509493. Epub 2017 May 28; Axente et al. (2021) J. Medicine and Life 14(3):424-427).

[0005] The SMN1 gene, which is deleted or mutated in SMA, is responsible for the majority of SMN protein production. A second gene (SMN2), located near SMN1, is responsible for producing a small amount of SMN protein. Because SMN protein is critical for the function and survival of motor neurons that control muscle function, the lack of SMN protein caused by deletion or mutation of the SMN1 gene in SMA leads to the loss of a large number of motor neurons in the anterior horn of the spinal cord, but not complete loss, thereby ensuring at least some intact innervation. This partial denervation causes substantial atrophy of fast-twitch muscle fibers, which in turn leads to motor dysfunction and subsequent debilitating muscle atrophy and weakness. Patients' muscles can become so weak that moving, breathing, and eating become difficult.

[0006] In some countries, SPINRAZA® (nusinersen) is approved for the treatment of pediatric and adult SMA patients, and ZOLGENSMA® (onasemnogene abeparvovec) is approved for the treatment of pediatric SMA patients under the age of 2 with biallelic mutations in the SMN1 gene. EVRYSDI™ (risdiplam), a small molecule SMN therapy, is also approved in the United States and Europe. Nusinersen is an SMN2-directed antisense oligonucleotide (ASO) designed to treat SMA caused by mutations that lead to SMN protein deficiency. Risdiplam works in a similar way, being a pyridazine derivative that modifies the splicing of SMN2 messenger RNA. Onasemnogene abeparvovec is a recombinant adeno-associated virus vector type 9-based gene therapy designed to deliver a copy of the gene encoding the human SMN protein.

[0007] SMN therapies (e.g., SMN-directed or SMN-targeted therapies), such as nusinersen, risdiplam, onasemnogene abeparvovec, and others in development, primarily act on motor neurons to prevent further loss. Consistent with this concept, clinical data reported from extended SMN-targeted therapy indicate that after the first 15 months of treatment with nusinersen, improvement as measured by the mean change from baseline in HFMSE scores, efficacy appears to plateau. Limited further gains in motor function are observed over the next 3 years or more (Darras et al. (2019) Neurology 92(21):e2492-e2506). Similarly, a long-term evaluation of risdiplam showed only stabilization or minor / uncertain improvements in primary and secondary endpoints after 12 months (Oskoui et al., “SUNFISH Part 2: 24-month efficacy and safety of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA).” Presented at the MDA Clinical and Scientific Conference 2021; March 15–18. Poster 80). Therefore, while SMN therapy can help maintain motor function over time, its ability to confer long-term motor function enhancement is limited. SMN therapy approved for the treatment of SMA has been shown to significantly improve clinical outcomes by providing incremental improvements in motor and developmental milestones and preventing symptom progression in SMA. However, because SMN therapy focuses on motor neurons within the motor unit and does not target existing muscle atrophy, patients may continue to experience substantial motor impairment. Regardless of when SMN therapy is initiated, there remains a high unmet medical need for patients who receive such disease-stabilizing therapy after the onset of symptoms, and for example, may not see continued benefit over multiple years of treatment.Such patients may benefit from therapies such as the myostatin inhibition methods disclosed herein, which unexpectedly provide sustained improvement over the long term. Summary of the Invention [Problem to be solved by the invention]

[0008] Currently, there are no muscle-targeted therapies (i.e., muscle-directed or muscle-enhancing therapies) approved for the treatment of SMA. Consequently, there remains an unmet need for effective and durable muscle-targeted therapies that can address muscle atrophy and motor dysfunction in patients with SMA (Day et al. (2022) BMC Pediatrics 22:632). [Means for solving the problem]

[0009] The present disclosure includes, inter alia, therapeutic methods, uses, and compositions for treating SMA patients using muscle-enhancing agents (i.e., muscle-directing or muscle-targeting agents), such as apitegromab, also known as SRK-015. In various embodiments, apitegromab or compositions comprising apitegromab are used in the treatment of late-onset SMA in human subjects, either as monotherapy or as an adjunct to motor neuron-directed therapy, such as SMN upregulator / modifier therapy (i.e., SMN therapy). The data provided herein represent evidence of long-lasting benefits of muscle-enhancing agents administered over a 24-month period to patients with SMA type 2 and type 3. Provided herein is apitegromab therapy for treating subjects with SMA.

[0010] Further, disclosed herein is the selection of certain subpopulations of SMA patients who are particularly likely to benefit from muscle-building agents, such as myostatin inhibitors. In some embodiments, the myostatin inhibitor is a myostatin-selective inhibitor, optionally an antibody that binds to latent myostatin and thereby inhibits its activation, such as apiteglomab. In some embodiments, the myostatin inhibitor binds to myostatin and GDF11, but not activin A.

[0011] According to the present disclosure, certain SMA patient subpopulations likely to benefit from muscle-building agents include patients suffering from muscle weakness and / or stiffness. In some embodiments, patients suffer from fatigue; difficulty or impairment of bulbar function (e.g., difficulty coughing, swallowing, and / or eating); and / or difficulty or impairment of elimination (e.g., urinary urgency and frequency, bowel changes, etc.).

[0012] In some embodiments, the patient has Type 2 or Type 2-like SMA, where optionally the patient is 2 years of age or older. In some embodiments, the patient has non-ambulatory Type 3 or Type 3-like SMA, where optionally the patient is 2 years of age or older. In some embodiments, the patient has ambulatory SMA. In some embodiments, the patient has non-ambulatory SMA. In some embodiments, the patient is under 2 years of age. In some embodiments, the patient is 13-21 years of age, where optionally the patient has non-ambulatory Type 2 or Type 3 SMA.

[0013] According to the present specification and the data presented herein, in some embodiments, the therapeutic dose is greater than 2 mg / kg and less than or equal to 20 mg / kg of apitegromab when administered every four weeks (i.e., Q4W) or monthly. In some embodiments, therapeutic doses less than 20 mg / kg may be used, such as 2 mg / kg, 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12 mg / kg, and 15 mg / kg. In some embodiments, the therapeutic dose is 10 mg / kg. In some embodiments, the therapeutic dose is 20 mg / kg. In some embodiments, the therapeutic dose is 10 mg / kg administered once every four weeks (i.e., Q4W) or once monthly. In some embodiments, the therapeutic dose is 20 mg / kg administered once every four weeks (i.e., Q4W) or once monthly. In various embodiments, apitegromab therapy can improve motor function in patients with late-onset SMA.

[0014] Pharmacokinetic (PK) analysis provides the relationship between dosage (e.g., therapeutic dose) and bioavailability (serum exposure) of a therapeutic drug. In some embodiments, a therapeutic dose is determined by measuring serum concentrations of apitegromab at steady state as measured at trough (C trough ), a dose that achieves or results in a serum exposure of about 25-250 μg / mL of apitegromab. Doses that achieve this result may be administered by any suitable route, for example, intravenously or subcutaneously. In some embodiments, the doses described herein are achieved by intravenous administration.

[0015] In some embodiments, a therapeutic dose is determined as a peak serum concentration of apitegromab measured within about 2 hours of administration (C max ), a dose that achieves or produces a serum exposure of about 1100 μg / mL or less, e.g., about 25-1100 μg / mL. Doses that achieve this result may be administered by any suitable route, e.g., intravenously or subcutaneously.

[0016] In some embodiments, pharmacodynamic (PD) analysis allows for determination of target engagement as measured by serum concentrations of latent myostatin (LM), i.e., determination of therapeutic antibody binding to pro / latent myostatin. In some embodiments, a therapeutic dose is preferably a dose that achieves or produces a serum concentration of latent myostatin in a subject of at least about 100, or preferably at least about 250 ng / mL, measured at steady state, e.g., 14 days or more after administration of apitegromab. A dose that achieves this result may be administered by any suitable route, e.g., intravenously or subcutaneously. For example, the serum concentration of latent myostatin may be about 250 ng / mL or greater, greater than 400 ng / mL, or 550 ng / mL, or greater than 700 ng / mL, or greater than 950 ng / mL, or greater than 1100 ng / mL, etc.

[0017] In some embodiments, PD analysis that enables determination of target engagement includes measuring serum creatinine levels. In some embodiments, a therapeutic dose of a treatment comprising apitegromab is a dose that achieves or causes an increase in serum creatinine levels in a subject of at least 10% (e.g., at least 20%, at least 25%, at least 30%, or more) compared to the level before treatment begins. In some embodiments, the serum creatinine level is measured at steady state, e.g., at least 2 weeks (e.g., at least 3 weeks, at least 4 weeks, or at least 1 month) after treatment begins. In some embodiments, treatment with apitegromab includes administering an amount and / or titration regimen sufficient to achieve an increase in serum creatinine of 10% or more (e.g., at least 20%, at least 25%, at least 30%, or more) when measured before and after treatment, e.g., at steady state before treatment and after treatment begins.

[0018] Apitegromab or another selective myostatin inhibitor may be used alone (e.g., monotherapy) to treat SMA, or in conjunction with another therapy, such as an SMN-targeted therapy, including SMN therapy or an SMN-upregulator or corrector therapy (e.g., add-on / adjuvant therapy or concurrent therapy). In some embodiments, the subject is treated with an SMN-upregulator therapy, such as nusinersen (SPINRAZA®) or risdiplam (EVRYSDI®). In some embodiments, the subject is treated with an SMN-modifying drug therapy, such as an SMN gene therapy, e.g., onasemnogene abeparvovec (ZOLGENSMA®). In some embodiments, the subject initiated SMN therapy at age 5 or later. In some embodiments, this neuron-directed therapy increases progranulin and maintains neuronal viability.

[0019] In some embodiments, SMN therapy (e.g., an SMN-targeted therapy, e.g., an SMN-upregulator / modifier therapy) and apitegromab therapy (e.g., a muscle-targeted therapy) are used as a combination therapy, or additional therapy, or adjunctive therapy. Thus, SMN therapy and apitegromab may be used in treating SMA in a patient, wherein the treatment comprises administration of SMN therapy and apitegromab in amounts sufficient to treat SMA, wherein the apitegromab therapy is administered intravenously to the patient at a dose of greater than 2 mg / kg and less than or equal to 20 mg / kg every four weeks or monthly. In some embodiments, the SMN therapy is an SMN1-directed gene therapy. In some embodiments, the SMN therapy is an SMN-upregulator therapy, such as an SMN2-directed therapy, wherein optionally the SMN2-directed therapy is a splicing modifier. In some embodiments, the SMN-modifying drug may be administered orally, intrathecally, or intravenously. In some embodiments, the patient has late-onset SMA.

[0020] In some embodiments, the disclosure provides a therapy comprising apitegromab and an SMN therapy (e.g., an SMN upregulator or modifying drug therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec) for use in the treatment of SMA in patients 2 years of age or older with SMA Type 2 or Type 3, wherein the therapy comprises administration of the SMN therapy and apitegromab in amounts sufficient to treat SMA, wherein the apitegromab therapy is administered intravenously to the patient every four weeks or monthly at a dose of greater than 2 mg / kg and less than or equal to 20 mg / kg.

[0021] In some embodiments, the disclosure provides a therapy comprising apitegromab and an SMN therapy (e.g., an SMN upregulator or modifying drug therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec) for use in the treatment of SMA in ambulatory SMA patients, wherein the therapy comprises administration of the SMN therapy and apitegromab in amounts sufficient to treat SMA, wherein the apitegromab therapy is administered intravenously to the patient every four weeks or monthly at a dose of greater than 2 mg / kg and less than or equal to 20 mg / kg.

[0022] In some embodiments, the disclosure provides a therapy comprising apitegromab and an SMN therapy (e.g., an SMN upregulator or modifying drug therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec) for use in the treatment of SMA in non-ambulatory Type 2 or Type 3 SMA patients aged 13 to 21 years, wherein the therapy comprises administration of the SMN therapy and apitegromab in amounts sufficient to treat SMA, wherein the apitegromab therapy is administered intravenously to the patient every four weeks or monthly at a dose of greater than 2 mg / kg and less than or equal to 20 mg / kg.

[0023] In some embodiments, the disclosure provides a therapy comprising apitegromab and an SMN therapy (e.g., an SMN upregulator or modifying drug therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec) for use in the treatment of SMA in patients under the age of 2, wherein the therapy comprises administration of the SMN therapy and apitegromab in amounts sufficient to treat SMA, wherein the apitegromab therapy is administered intravenously to the patient every four weeks or monthly at a dose of greater than 2 mg / kg and less than or equal to 20 mg / kg.

[0024] In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, the patient has three copies of the SMA2 gene. In some embodiments, the patient has four copies of the SMA2 gene. In some embodiments, the patient has five copies of the SMA2 gene. In some embodiments, the patient has six copies of the SMN2 gene.

[0025] In some embodiments, the patient begins the combination therapy at age 5 or older. In some embodiments, the patient begins the combination therapy at age less than 5 years. In some embodiments, the patient begins the combination therapy at age less than 2 years. In some embodiments, the patient begins the combination therapy at age less than 6 weeks. In some embodiments, the patient is diagnosed with SMA by genetic screening (e.g., identified as a carrier of an SMN1 mutation), optionally wherein the genetic screening is, for example, newborn screening or in utero screening for one or more SMN1 mutations. In some embodiments, the patient is presymptomatic.

[0026] In some embodiments, apitegromab therapy is used as an additional or adjunctive therapy in the treatment of SMA. Thus, a composition comprising apitegromab may be used in the treatment of a patient with late-onset SMA, wherein the treatment comprises intravenous administration of a therapeutic dose of a composition comprising apitegromab, wherein the therapeutic dose is greater than 2 mg / kg and less than or equal to 20 mg / kg every four weeks or monthly, and wherein the patient is treated with SMN therapy. In some embodiments, the SMN therapy is an SMN1-directed therapy, optionally, wherein the SMN1-directed therapy is gene therapy. In some embodiments, the SMN therapy is an SMN2-directed therapy, optionally, wherein the SMN2-directed therapy is an SMN-upregulator therapy, e.g., a splicing modifier. In some embodiments, either SMN therapy may be administered orally, intrathecally, or intravenously. In some embodiments, the patient has type 2 or type 2-like SMA. In some embodiments, the patient has non-ambulatory type 3 or type 3-like SMA. In some embodiments, the patient has ambulatory type 3 or type 3-like SMA. In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, the patient has three copies of the SMN2 gene. In some embodiments, the patient has four copies of the SMN2 gene. In some embodiments, the patient has five copies of the SMN2 gene. In some embodiments, the patient has six copies of the SMN2 gene. In some embodiments, the patient begins SMN-modifying drug therapy at age less than 5 years. In some embodiments, the patient begins SMN-modifying drug therapy at age 5 years or older. In some embodiments, the patient is diagnosed with SMA by genetic screening (e.g., identified as a carrier of an SMN1 mutation), optionally wherein the genetic screening is newborn screening or in utero screening. In some embodiments, the patient is a fetus diagnosed with SMA. In some embodiments, the patient is a fetus treated in utero with apitegromab. In some embodiments, the patient is presymptomatic. In some embodiments, the patient is treated with an SMN-modifying drug prior to apitegromab therapy. In some embodiments, the patient is treated with apitegromab prior to receiving SMN-modifying drug therapy.

[0027] SMA patients who may benefit from apitegromab therapy include those who meet one or more of the following criteria: a documented diagnosis of 5q SMA and late-onset (and / or type 2, type 2-like, type 3, or type 3-like) SMA prior to receiving therapy for SMA; have SMA not due to a 5q mutation; non-ambulatory subjects who are able to sit unaided according to the WHO motor milestone definition; ambulatory subjects who can walk 10 meters unaided in 30 seconds or less; a Revised Hammersmith Scale (RHS) score of 63 or less and / or a Hammersmith Functional Motor Scale-Extended score of 10 or more. Subjects with a HFSME (Expanded, HFSME) score; subjects who have not used tracheostomy positive pressure ventilation or chronic daytime noninvasive ventilatory support for more than 16 consecutive hours per day within 2 weeks prior to treatment; subjects who have no acute or coexisting medical conditions that interfere with their well-being within 2 weeks prior to treatment; subjects who have no severe scoliosis or contractures; and / or subjects who have not used systemic corticosteroids, valproic acid, or any therapy with potential muscle or neuromuscular effects within 60 days other than approved SMN-targeted therapies, such as SMN-upregulator (also known as SMN-modifying) therapy. Therapies with potential muscle or neuromuscular effects include androgens, insulin-like growth factors, growth hormones, systemic beta-agonists, botulinum toxin, muscle relaxants, muscle-enhancing supplements, or acetylcholinesterase inhibitors. In some embodiments, the patient has a documented diagnosis of 5q SMA and late-onset (and / or Type 2, Type 2-like, Type 3, or Type 3-like) SMA prior to receiving therapy for SMA and meets one or more of the additional criteria listed above. In various embodiments, the methods disclosed herein include selecting one or more such patients or patient populations for treatment with apitegromab, e.g., according to the dosages or regimens disclosed herein.

[0028] SMA patients who may benefit from apitegromab therapy include those who meet one or more of the following criteria: have one, two, three, or four copies of the smn2 gene and achieve one or more gross motor milestones based on the World Health Organization (WHO) Motor Development Scale: 1) sit unsupported (e.g., hold head upright for at least 10 seconds; balance without using arms or hands); 2) crawl on hands and knees (e.g., do not touch abdomen to ground surface for at least three consecutive movements); 3) stand with assistance (e.g., stand upright on both feet for at least 10 seconds without leaning against anything); 4) walk with assistance (e.g., take at least five steps while holding on to a stable object); 5) stand unsupported (e.g., stand for at least 10 seconds without touching a person or object); and 6) walk unsupported (e.g., take at least five steps independently).

[0029] SMA patients who may benefit from apitegromab therapy include those who meet one or more of the following criteria: have one, two, three, or four copies of the smn2 gene and achieve one or more gross motor milestones based on the HFMSE: 1) neck stability (e.g., able to hold or lift head while supine); 2) roll over; 3) sit in tripod position (e.g., use hands for support while sitting); 4) sit unsupported; 5) support Standing with support; 6) Crawling / crawling; 7) Standing with support (e.g., standing with support and crawling along furniture); 8) Standing without support; 9) Taking a few steps on one's own but falling over; 10) Walking independently (e.g., walking independently, walking unsupported); 11) Crouching to pick up an object (e.g., a toy); 12) Walking / crawling up and down stairs; 13) Jumping; 14) Climbing stairs with alternating feet; 15) Hopping on one foot; 16) Descending stairs with alternating feet.

[0030] In some embodiments, patients treated with apitegromab as disclosed herein have received or are being treated with an SMN-targeted therapy (also called an SMN-upregulator or corrector), such as nusinersen, risdiplam, or onasemnogene abeparvovec. In some embodiments, patients initiate SMN-upregulator (corrector) therapy at age less than 5 years. In some embodiments, patients initiate SMN-upregulator (corrector) therapy at age 5 years or older. In some embodiments, the SMN-modifying drug therapy is an SMN2-upregulator therapy. In some embodiments, the SMN-modifying drug therapy is SMN1 gene therapy.

[0031] In some embodiments, the patient receives apitegromab therapy for at least 6 months (e.g., 6 months, 12 months, 24 months, or more) at a therapeutic dose sufficient to achieve a clinical benefit characterized by improved motor function, disease stabilization, and / or delay in disease progression.

[0032] In some embodiments, patients receiving apitegromab therapy may achieve improvement in motor function. The improvement in motor function may correspond to an increase in HFMSE score or RHS score. For example, patients may achieve an increase in HFMSE score of at least 1, 2, 3, 4, 5, or more points relative to baseline after 6, 12, or 24 months of apitegromab treatment (i.e., apitegromab therapy). In some embodiments, 12 months of apitegromab therapy may produce an increase in HFMSE score of 3 or more points relative to baseline (e.g., at least 3 points, at least 5 points, at least 10 points, about 20 points or less) in HFMSE score relative to baseline in patients who initiated background SMN-targeted therapy at an early age. In some embodiments, the improvement in HFMSE score may be additive and synergistic with background therapy, e.g., background SMN-upregulator / modifier therapy. In some embodiments, 24 months of apitegromab therapy may produce an increase in HFMSE score of 3 or more points (e.g., at least 3 points, at least 5 points, at least 10 points, up to about 20 points) over baseline in patients who initiated background SMN therapy at an early age (e.g., less than 2 years of age). In some embodiments, the improvement in HFMSE score may be additive and even synergistic with background therapy, e.g., background SMN upregulator / modifier therapy.

[0033] In some embodiments, patients receiving apitegromab therapy may exhibit disease stabilization. Disease stabilization may correspond, for example, to a net zero (e.g., at least no change or an increase) or near-zero change in HFMSE or RHS score relative to baseline for at least 24 months. In some embodiments, this is a clinically meaningful outcome, as opposed to an expected gradual deterioration in motor function in an untreated patient population (e.g., natural history) or a patient population treated with prior art methods (e.g., background therapy).

[0034] In some embodiments, patients receiving apitegromab therapy may exhibit delayed disease progression. Delayed disease progression may include, for example, a slower rate of decline in HFMSE scores over time, for example, after at least 12 or 24 months of treatment, when compared to suitable controls (e.g., untreated patients exhibiting the natural history of a particular patient population). In some embodiments, delay may include a delay in the transition from ambulatory SMA to non-ambulatory SMA.

[0035] In some embodiments, apitegromab can increase the therapeutic response rate in a patient population compared to controls not receiving apitegromab.

[0036] In any embodiment, the therapeutically effective amount of apitegromab does not cause any serious adverse events in the patient after 12 months of treatment or after 24 months of treatment.

[0037] The present disclosure is based, at least in part, on the discovery that anti-promyostatin / anti-latent myostatin antibodies capable of selectively inhibiting activation of latent myostatin can improve muscle function in human patients with SMA, including SMA patients who may or may not be on background SMN-upregulating drug therapy (e.g., nusinersen, risdiplam, or onasemnogene abeparvovec), and in some cases can do so to an unexpected degree not typically expected or observed in certain patient populations, while avoiding adverse events (see, e.g., Mercuri et al. (2018) New Engl J Med 378(7):625-635). Accordingly, the present disclosure provides various embodiments of methods, uses, and compositions comprising anti-promyostatin / anti-latent myostatin antibodies for treating SMA in human subjects. Furthermore, based on the data presented herein demonstrating the clinical benefit of selective myostatin inhibition for the treatment of neuromuscular diseases, the present disclosure also encompasses the concept that other selective myostatin inhibitors may be used as well, including, for example, neutralizing antibodies capable of selectively inhibiting myostatin but sparing other related growth factors, such as activin A, and ligand traps engineered to preferentially bind myostatin.

[0038] In some embodiments, a therapeutically effective amount of apitegromab of greater than 2 and less than or equal to 20 mg / kg achieves one or more of the following in a subject: preserving motor function compared to deterioration in controls, delaying disease progression, delaying or preventing ambulatory loss in ambulatory patients with type 3 SMA, delaying or preventing the need for respiratory support or intervention, reducing the rate of deterioration of one or more motor function scores compared to controls, and / or maintaining at least a zero net change in one or more motor function scores compared to baseline. In some embodiments, this amount is a dose of apitegromab of greater than 2 and less than or equal to 20 mg / kg administered intravenously every four weeks or monthly. In some embodiments, although average deterioration from baseline may be observed in this patient population, the majority of patients demonstrate disease stabilization (no change or increase in RHS). In some embodiments, a portion of the patient population (e.g., 10% or more, e.g., 15% or more, 20% or more) achieves an increase of 3 or more points on the RHS after 12 months of treatment with apitegromab as monotherapy. In some embodiments, a portion of patients in a patient population (e.g., 10% or more, e.g., 15% or more, 20% or more) achieves an increase of 3 or more points on the RHS after 24 months of treatment with apitegromab as monotherapy.

[0039] In some embodiments, the disclosure provides a method of treating SMA in a human subject, the method comprising administering to the subject a composition comprising apitegromab and a composition comprising an SMN-targeted therapy (e.g., an SMN-upregulating agent), wherein the subject is administered apitegromab by intravenous infusion every four weeks or monthly for at least six or twelve months in an amount greater than 2 and less than or equal to 20 (mg / kg) sufficient to produce a mean increase in HFMSE score of at least one point compared to the pre-treatment baseline score, e.g., in a cohort of at least 14 subjects.

[0040] In some embodiments, the disclosure provides a composition comprising apitegromab for use in treating SMA in a human subject receiving an SMN-upregulating drug, wherein the subject is administered apitegromab by intravenous infusion every four weeks or monthly for at least six months in an amount greater than 2 and less than or equal to 20 (mg / kg) sufficient to produce a mean increase in HFMSE score of at least 1 point compared to the pre-treatment baseline score, e.g., in a cohort of at least 14 subjects.

[0041] In some embodiments, a composition comprising apitegromab for use in treating SMA in a human subject receiving SMN therapy is administered intravenously at a medical facility. In some embodiments, a composition comprising apitegromab for use in treating SMA in a human subject receiving SMN therapy is administered intravenously at a location other than a medical facility, for example, at the subject's home. In some embodiments, a composition comprising apitegromab for use in treating SMA in a human subject receiving SMN therapy is administered intravenously at the subject's home by a medical professional, for example, a medical specialist. In some embodiments, a composition comprising apitegromab for use in treating SMA in a human subject receiving an SMN upregulatory drug is administered subcutaneously at the subject's home, for example, by a medical professional, for example, a medical specialist. In some embodiments, a composition comprising apitegromab is administered subcutaneously by the patient.

[0042] In some embodiments, the disclosure provides the use of apitegromab in the manufacture of a composition for the treatment of SMA in a human subject receiving an SMN-upregulating drug, wherein the subject is administered apitegromab by intravenous infusion every four weeks or monthly for at least six months in an amount greater than 2 mg / kg and less than or equal to 20 mg / kg (e.g., 10 mg / kg or 20 mg / kg) sufficient to produce a mean increase in HFMSE score of at least one point compared to the pre-treatment baseline score, for example, in a cohort of at least 14 subjects.

[0043] In some embodiments, the SMA is late-onset SMA. In some embodiments, the SMA is Type 2 SMA or Type 2-like SMA. In some embodiments, the SMA is non-ambulatory Type 3 SMA or Type 3-like SMA. In some embodiments, the subject is 5 to 21 years old. In some embodiments, the SMN-upregulator therapy is nusinersen, risdiplam, and / or onasemnogene abeparvovec. In some embodiments, the SMN-upregulator therapy is nusinersen. In some embodiments, the SMN-upregulator therapy is risdiplam. In some embodiments, the sufficient amount is an intravenous dose of greater than 2 and less than or equal to 20 mg / kg (mg / kg), optionally about 5, 7.5, 10, 15, or 20 mg / kg. In some embodiments, the therapeutic dose of apitegromab is sufficient to cause a majority (e.g., greater than 50%, greater than 60%, etc.) of patients, e.g., a patient population, to increase their HFMSE by 1 or more points, and / or is sufficient to cause at least 20% (e.g., at least 25%) of patients, e.g., a patient population, to increase their HFMSE by 3 or more points.

[0044] In some embodiments, the SMA is late-onset SMA, and the late-onset SMA is type 2 SMA or type 2-like SMA, and the patient initiated background SMN-modifying drug therapy at an early age (e.g., less than 5 years of age). Apitegromab therapy can achieve significant motor function improvement in this patient population (e.g., a 5-point or greater increase in HFMSE score). In some embodiments, the patient achieves a 3-point or greater increase, a 5-point or greater increase, or a 10-point or greater increase in HFMSE score relative to baseline after 12 months of apitegromab therapy, where baseline is measured before or at the time of the first administration of apitegromab. In some embodiments, the patient achieves a 3-point or greater increase, a 5-point or greater increase, or a 10-point or greater increase in HFMSE score relative to baseline after 24 months of apitegromab therapy, where baseline is measured before or at the time of the first administration of apitegromab. In some embodiments, the patient achieves a greater increase in HFMSE over baseline at 24 months of apitegromab treatment compared to 12 months of apitegromab treatment.

[0045] In some embodiments, the subject is a patient who has not achieved the ability to sit unaided at 4-9 months of age based on the WHO motor development milestone classification. In some embodiments, the subject is a patient who has the ability to sit unaided at 4-9 months of age. In some embodiments, the subject is a patient who has not achieved the ability to stand unaided at 5-11 months of age. In some embodiments, the subject is a patient who has the ability to stand unaided at 5-11 months of age. In some embodiments, the subject is a patient who has the ability to stand unaided at 5-11 months of age. In some embodiments, the subject is a patient who has not achieved the ability to crawl on hands and knees at 5-13 months of age. In some embodiments, the subject is a patient who has the ability to crawl on hands and knees at 5-13 months of age. In some embodiments, the subject is a patient who has not achieved the ability to walk unaided at 6-14 months of age. In some embodiments, the subject is a patient who has the ability to walk unaided at 6-14 months of age. In some embodiments, the subject is a patient who has not achieved the ability to stand unaided at 7-14 months of age. In some embodiments, the subject is a patient who is able to stand without support at age 7-14 months. In some embodiments, the subject is a patient who has not achieved the ability to walk without support at age 8-18 months. In some embodiments, any of the above patients who are unable to walk can also be characterized as having Type 2, Type 2-like, Type 3, or Type 3-like SMA. In some embodiments, any of the above patients who are able to walk (with or without assistance) can also be characterized as having Type 3 or Type 3-like SMA. In some embodiments, the subject initiated SMN upregulator / modifier therapy at age less than 5 years. In some embodiments, the subject initiated SMN upregulator / modifier therapy at age 5 years or older. In some embodiments, any of the above patients can achieve one or more new milestones according to the WHO Motor Development Milestones after 6-12 months of treatment with a myostatin inhibitor (e.g., apitegromab).In some embodiments, any of the above patients may achieve one, two, or three new milestones according to the WHO Motor Development Milestones, such as one or more of the following: the ability to walk independently, the ability to stand independently, standing with assistance, crawling on hands and knees, and / or walking with assistance, after 6 to 24 months of treatment with a myostatin inhibitor (e.g., apitegromab).

[0046] In some embodiments, the disclosure provides a method of treating SMA in a patient, comprising administering to the patient a therapeutically effective amount of a myostatin inhibitor, e.g., apitegromab, wherein the therapeutically effective amount is sufficient to achieve one or more WHO motor milestones after 12, 24, or 36 months of treatment, where the patient is unable to achieve the one or more WHO motor milestones at baseline.

[0047] In some embodiments, the target patient population to be treated with apitegromab includes those 12 years of age or younger at the time of initiation of myostatin inhibitor (e.g., apitegromab) therapy. In some embodiments, the target patient population includes those 2 years of age or older. In some embodiments, the target patient population includes those 2 to 12 years of age. In some embodiments, the target patient population includes those 2 to 5 years of age.

[0048] In some embodiments, apitegromab is administered as monotherapy to SMA patients. In some embodiments, apitegromab is administered as monotherapy to SMA patients who are unable to undergo the intrathecal injections required for SMN-upregulator therapy (e.g., due to spinal fusion) or who choose not to receive SMN-upregulator therapy.

[0049] In some embodiments, the present disclosure provides the use of apitegromab in the manufacture of a pharmaceutical composition (e.g., a medicament) for treating late-onset SMA in a human subject. The medicament is intended to be administered to the subject every four weeks or monthly at a dose of greater than 2 mg / kg and less than or equal to 20 mg / kg of apitegromab, optionally wherein the subject has initiated a motor neuron-directed therapy for SMA at less than five years of age, and wherein the motor neuron-directed therapy increases SMN1 or SMN2 expression. The manufacturing method can include providing a cell line comprising one or more vectors carrying nucleic acid sequences for the heavy and light chains of an apitegromab immunoglobulin polypeptide, capable of producing a recombinant antibody corresponding to apitegromab, or an antigen-binding fragment thereof. Such a cell line can be used to produce apitegromab in mammalian cell culture, such as CHO cells. In some embodiments, the production of apitegromab may utilize large-scale (e.g., 250 L, 1000 L, 2000 L, 3000 L, 4000 L, etc.) bioreactors. The recombinant antibody molecule may then be purified from the cell culture, and the purified antibody may be formulated into a pharmaceutical composition comprising apitegromab and one or more excipients. This process typically includes a sterile filtration step. In some embodiments, the pharmaceutical composition is a liquid formulation containing about 50 mg / mL apitegromab, suitable for intravenous administration.

[0050] In some embodiments, apitegromab is contained in a multi-dose vial, such as a glass vial. In some embodiments, a container (such as a glass vial) containing apitegromab is part of a kit. In some embodiments, apitegromab is contained in a pre-filled syringe. [Brief explanation of the drawings]

[0051] [Figure 1] HFMSE scores after 15 months of nusinersen treatment are shown. [Figure 2A] The mean change (95% CI) from baseline in HFSME over 24 months is shown. [Figure 2B]The mean change (95% CI) in RULM over 24 months is shown. [Figure 3A] Correlation between HFSME and RULM at 12 months of apitegromab treatment. [Figure 3B] Correlation between HFSME and RULM at 24 months of apitegromab treatment. [Figure 4] The mean change in HFMSE score (left panel) and RULM score (right panel) over 24 months of apitegromab treatment is shown. [Figure 5] 1 shows the relationship between change from baseline in HFMSE score and baseline age in type 2 and non-ambulatory type 3 SMA patients. [Figure 6A] The correlation between the change in HFMSE from baseline and the age ratio of latent myostatin concentration is shown. [Figure 6B] Correlation between change in HFMSE from baseline and age ratio of latent myostatin fold change is shown. [Figure 7] PEDI-CAT scores for type 2 and non-ambulatory type 3 SMA patients are shown. [Figure 8] 1 shows PROMIS scores in type 2 and non-ambulatory type 3 SMA patients. [Figure 9A] Figure 1 shows the severity of muscle function in patients with SMA type 2 and type 3. [Figure 9B] Figure 1 shows fatigue severity in patients with SMA type 2 and type 3. [Figure 9C] Figure 1 shows the severity of bulbar function in patients with SMA type 2 and type 3. [Figure 9D] Figure 1 shows the severity of excretion in patients with SMA type 2 and type 3. [Figure 9E] This shows the severity of daily life problems in patients with SMA type 2 and type 3. [Figure 9F] Figure 1 shows the severity of social impact in patients with SMA type 2 and type 3. [Figure 10A] 1 shows the relationship between changes in muscle mass and changes in serum creatinine in non-human primates treated with apitegromab. [Figure 10B]1 shows the percent change in serum creatinine in healthy human volunteers treated with apitegromab. DETAILED DESCRIPTION OF THE INVENTION

[0052] definition In order that this disclosure may be more readily understood, certain terms are first defined. These definitions should be read in light of the remainder of the disclosure and as understood by one of ordinary skill in the art. Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Additional definitions are set forth throughout this detailed description.

[0053] Administer: The terms "administer," "administering," and "administration" include any method of delivering a therapeutic agent (e.g., an anti-promyostatin / anti-latent myostatin antibody, e.g., apitegromab) to a subject's systemic system or to a specific area within or on a subject's body (systemic administration and local administration, respectively). In some embodiments, the therapeutic agent is apitegromab. In some embodiments, apitegromab is formulated for administration as a composition, e.g., a pharmaceutical composition. In some embodiments, apitegromab is formulated for intravenous administration. For example, in some embodiments, apitegromab is administered by intravenous injection / infusion, e.g., by intravenous infusion. In some embodiments, apitegromab is administered by intravenous infusion, e.g., over approximately 1-2 hours. In some embodiments, apitegromab is administered by intravenous infusion over approximately 2 hours. In some embodiments, the infusion time is less than 2 hours and greater than 1 hour.

[0054] Antibody: As used herein, the term "antibody" includes any naturally occurring, recombinant, modified, or engineered immunoglobulin or immunoglobulin-like structure, or antigen-binding fragment or portion thereof, or derivatives thereof. Thus, the term refers to immunoglobulin molecules that specifically bind to a target antigen, including, for example, chimeric antibodies, humanized antibodies, fully human antibodies, and multispecific antibodies (including bispecific antibodies). Intact antibodies will generally contain at least two full-length heavy chains and two full-length light chains, although in some cases fewer chains may be included, such as antibodies naturally occurring in camelids, which may contain only heavy chains. Antibodies may be derived entirely from a single source or may be "chimeric," i.e., different portions of the antibody may be derived from two different antibodies. Antibodies, or antigen-binding portions thereof, may be produced in hybridomas, by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. The term antibody, as used herein, includes monoclonal antibodies, multispecific antibodies such as bispecific antibodies, minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as "antibody mimetics"), chimeric antibodies, humanized antibodies, human antibodies, and antibody fusions (sometimes referred to herein as "antibody conjugates"). The term "antigen-binding fragment" encompasses adnectins. In various embodiments of the therapeutic methods, uses, and compositions disclosed herein, the antibody is a promyostatin / latent myostatin antibody (e.g., apitegromab).

[0055] Apitegromab: Apitegromab (also known as "SRK-015") is a clinical trial fully human monoclonal antibody that inhibits myostatin activation by binding specifically with high affinity to the proform of myostatin, i.e., the inactive precursor form of myostatin—i.e., promyostatin and latent myostatin. See, e.g., CAS Registry Number 2278276-46-1; International Nonproprietary Names (INN) (2020) WHO Drug Information, Vol. 34, No. 2, pp. 272-273; also see GtoPdb Ligand ID: 11180; GtoPdb PubChem SID: 434122240; IMGT / mAb-DB Database ID: 829; NIH ChemIDplus Database: RN: 2278276-46-1; UNII: UZ54216N0Y. Apitegromab is a human immunoglobulin G4 (IgG4) / λ isotype. It binds to latent myostatin in a manner that prevents it from becoming its active form via tolloid-mediated cleavage, thereby preventing the activation and release of mature myostatin growth factor, which inhibits muscle growth. Apitegromab is a selective myostatin inhibitor (selective myostatin activation inhibitor). See, for example, International Publication No. WO 2017 / 049011. The term "selective myostatin inhibitor" (or "myostatin-selective inhibitor") refers to an agent capable of blocking, inhibiting, or otherwise antagonizing the activation or activity of myostatin / GDF-8 without affecting structurally related growth factors, such as activin A.Apitegromab comprises the CDR regions of SEQ ID NO:1 (HCDR1), SEQ ID NO:2 (HCDR2), SEQ ID NO:3 (HCDR3), SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3), as defined by the Kabat numbering system; or the CDR regions of SEQ ID NO:7 (HCDR1), SEQ ID NO:8 (HCDR2), SEQ ID NO:9 (HCDR3), SEQ ID NO:10 (LCDR1), SEQ ID NO:11 (LCDR2), and SEQ ID NO:12 (LCDR3), as defined by the IMGT numbering system; a heavy chain variable region of SEQ ID NO:13 and a light chain variable region of SEQ ID NO:14; and a heavy chain amino acid sequence of SEQ ID NO:15 and a light chain amino acid sequence of SEQ ID NO:16. Apitegromab is being developed for the treatment of SMA in pediatric and adult patients.

[0056] Baseline: As used herein, the term "baseline" or "baseline score," in the context of an SMA-related parameter, refers to the numerical value of a patient's SMA-related parameter at the start of treatment or prior to treatment (e.g., within 6 months prior to initiation of treatment) with an SMA therapy of the present disclosure (e.g., at the time of the first administration of apitegromab alone or as an adjunct to background therapy, including SMN therapy). Examples of SMA-related parameters include scores on motor assessment scales, such as the Revised Upper Limb Module (RULM) score, the Hammersmith Functional Motor Scale Expanded (HFMSE) score, and / or the Revised Hammersmith Scale (RHS) score.

[0057] In other embodiments, a patient (e.g., a patient with late-onset SMA, e.g., a patient with a non-ambulatory form of SMA, such as type 2 or non-ambulatory type 3 SMA) who will be treated with apitegromab, e.g., apitegromab as an adjunct to background SMN therapy, has a baseline RULM, RHS, or HFMSE score measured. In some embodiments, the baseline score is measured at or before the start of treatment with apitegromab (i.e., apitegromab therapy). In some embodiments, the patient is being treated with SMN therapy at the time of the baseline measurement. In some embodiments, the patient has been treated with SMN therapy for at least 6 months prior to the baseline measurement. In some embodiments, the patient has been treated with SMN therapy for at least 2 years at the time of initiation of apitegromab therapy, at which time the baseline measurement is taken. Thus, in some embodiments, the baseline score used to assess the therapeutic effect of apitegromab therapy is in addition to the therapeutic effect, if any, resulting from background therapy. In some embodiments, patients respond to background therapy alone with an increase in motor function score, e.g., 1 to 7 points, measured compared to pre-treatment, demonstrating the therapeutic ability of apitegromab to improve the effect of SMN background therapy alone.

[0058] Both the RHS (Ramsey et al. (2022) PLOS ONE https: / / doi.org / 10.1371 / journal.pone.0278996) and the HFMSE (Main et al. (2003). Eur J Paediatr Neurol. 7(4):155-9) have been validated for assessing physical performance in patients with SMA types 2 and 3. The RULM has also been used to assess upper limb function in ambulatory and non-ambulatory patients with SMA (Mazzone et al. (2017) Muscle Nerve. 55(6):869-874).

[0059] In some embodiments, the HFMSE is used to assess the physical performance of patients with SMA types 2 and 3 (O'Hagen et al. (2007) Neuromuscul Disord. 17(9-10):693-697; Glanzman et al. (2011) J Child Neurol. 26(12):1499-1507). In some embodiments, the HFMSE is used to evaluate non-ambulatory SMA patients. The HFMSE consists of 33 items to assess an individual's ability to perform various movements. The quality and feasibility of each movement for the parameters listed above is rated on a scale of 0, 1, or 2, where 0 represents inability, 1 represents performed with modification or alteration, and 2 represents no modification or alteration. The maximum achievable score is 66.

[0060] In another embodiment, a baseline Hammersmith Infant Neurological Exam (HINE) score is measured in patients to be treated with apitegromab, e.g., apitegromab as an adjunct to background SMN therapy. The HINE assesses seven different motor milestone developmental domains, e.g., kicking, head control, rolling over, sitting, crawling, standing, or walking, with a maximum score of 2 to 4 for each developmental motor milestone (Day et al. (2022) BMC Pediatrics 22:632). The HINE may be used as a whole, or a developmental module, HINE-2, may be used independently to assess developing motor milestones. In another embodiment, a Hammersmith Neonatal Neurological Examination (HNNE) is measured in infant patients to be treated with apitegromab, e.g., apitegromab as an adjunct to background SMN therapy. The HNNE assesses 34 items divided into the categories of posture and tone, tone patterns, reflexes, movement, abnormal findings / patterns, and orientation / behavior (Pane et al. (2022) Eur. J Pediatr 181:2821-29).

[0061] The RULM is based on 19 scoreable items reflecting different functional domains, rated on a 3-point scale with scores of 0 (unable to do), 1 (able with modification), and a maximum of 2 (able without difficulty), with one additional item scored as an able / unable score (with 1 being the highest score). The maximum RULM total score is 37 (Mazzone et al. (2017) Muscle Nerve. 55(6):869-874).

[0062] The RHS is a clinician-determined SMA-specific outcome measure that includes 36 items assessing physical motor performance. The motor functions assessed include sitting, lying down, rolling over, lying down, moving and rising from the floor, balance, standing, running / walking, climbing stairs and steps, and jumping. The 33 items are rated on a 0-1-2 ordinal scale, with 0 representing minimal physical performance or function and 2 representing the highest performance. Three items are rated on a 0-1 scale, with 0 representing inability to complete the item and 1 representing achievement. This scale includes two timed tests, which may also lead to the completion of WHO motor milestones. (Ramsey et al. (2022) PLOS ONE https: / / doi.org / 10.1371 / journal.pone.0278996)

[0063] Cohort: As used herein, the term "cohort" or "cohort population" refers to a group or population of human subjects sharing factors or influences, such as age, SMA disease severity (e.g., SMA Type 2 and / or SMA Type 3), concomitant treatment (e.g., SMN therapy), etc. In some embodiments, as used herein, "cohort" refers to a group of human subjects sharing age, SMA disease severity, and / or concomitant treatment.

[0064] Control: The term "control" or "control sample," as used herein, refers to any clinically or scientifically relevant comparison sample, population, or counterpart, including, for example, a sample from a healthy subject, a sample from a subject with a deficiency that may cause or predispose the subject to a certain disease or condition, a subject with the disease or condition of interest, a sample from a placebo-treated subject, a sample from a subject before treatment, a sham- or buffer-treated subject or sample, an untreated subject or sample, etc.

[0065] Inhibit or inhibition of: The terms "inhibit" or "inhibition of," as used herein, mean to reduce by a measurable amount and can, but does not necessarily, include complete prevention or inhibition.

[0066] Effective amount: The terms "effective amount" and "therapeutically effective amount" refer to the ability or amount to achieve its intended purpose or purposes, i.e., to achieve a desired biological or pharmaceutical response in a subject and / or realize a statistically significant clinical benefit (e.g., efficacy) in a patient population. An "effective amount" may refer to a therapeutically effective amount or therapeutic dose, and may be a dosage or titration regimen sufficient to produce a detectable change in a disease parameter, e.g., a slowing, cessation, reversal, reduction, or improvement of a disease parameter, symptom, or downstream effect. This term encompasses, but does not require, the use of an amount that completely cures the disease. As used herein, a dose of an anti-promyostatin / anti-latent myostatin antibody (e.g., a dose of apitegromab) may refer to a therapeutically effective dose as described herein. In some embodiments, efficacy may be measured by well-known motor function assessments and / or one or more surrogate biomarkers, e.g., serum latent TGF-β concentration and / or serum creatinine concentration. For example, in certain embodiments of the present disclosure, the intended goal may be to inhibit myostatin activation in vivo to achieve clinically meaningful outcomes associated with myostatin inhibition.

[0067] Measurement of the relevant intended goal may be objective (i.e., measurable by some assay or marker) or subjective (i.e., the subject provides an indication or perception of effect). In some embodiments, a therapeutically effective amount is an amount that, when administered to a patient population who meets certain clinical criteria for SMA (e.g., as determined by presenting symptoms, disease progression / stage, genetic profile, etc.), results in a statistically significant therapeutic response in that population.

[0068] An effective amount may refer to an amount that, when administered according to a particular regimen, produces a positive clinical outcome with reasonably acceptable levels of adverse effects (e.g., toxicity), if any, that are sufficiently tolerable for the patient to continue with the treatment regimen and that the benefits of the therapy outweigh the risks of toxicity. One of skill in the art will understand that in some embodiments of the present disclosure, a dosage may be considered to contain an effective amount if it contains an amount appropriate for administration in the context of a dosage regimen that correlates with a positive outcome.

[0069] Latent myostatin: As used herein, the term "latent myostatin" refers to an inactive precursor of mature myostatin comprising disulfide-bonded homodimers, each molecule of which contains an amino-terminal prodomain noncovalently bound to a carboxyl-terminal mature myostatin domain. In some embodiments, latent myostatin is generated from promyostatin that has been cleaved by proprotein convertases but not yet cleaved by BMP / tolloid family proteases. In some embodiments, latent myostatin may be generated by combining the prodomain and the carboxy-terminal mature myostatin domain in vitro and allowing them to fold properly. See, e.g., Sengle et al. (2011) J. Biol. Chem., 286(7):5087-5099.

[0070] Late-onset SMA: As used herein, unless otherwise expressly defined, the term late-onset SMA refers to patients who do not exhibit the onset of SMA symptoms until six months of age (e.g., no symptoms are detected at the six-month checkup), regardless of genotype, and regardless of whether and when they received SMN treatment. Late-onset SMA patients can also be patients who can be characterized as having SMA type 2, type 3, or type 4 based on conventional disease classifications known in the art. Late-onset SMA patients typically have at least two copies (e.g., two copies, three copies, four copies, or more, e.g., two to four copies) of the SMN2 gene. In some embodiments, late-onset SMA patients are being treated with or have received a motor neuron-directed therapy, such as an SMN-targeted therapy, e.g., an SMN-upregulating agent (e.g., have received such therapy at age less than five years). In contrast to late-onset SMA, "early-onset SMA" or "infantile-onset SMA" refers to SMA in which symptoms appear at or before the age of 6 months (including patients who may also be classified as type 1 SMA using conventional classifications known in the art). By comparison, patients with early- or infantile-onset SMA typically have one or two copies of the SMN2 gene. In some embodiments, a patient has late-onset SMA because they have received early intervention, e.g., one or more SMN therapies, where it is believed that if the patient had not received such early intervention, the patient would have had early-onset SMA.

[0071] In some embodiments, late-onset SMA patients have 2-4 copies of the SMN2 gene. In some embodiments, late-onset SMA patients have 1-2 copies of the SMN2 gene. In some embodiments, late-onset SMA patients with early therapeutic intervention (i.e., patients who would have developed symptoms before 6 months of age without the intervention) may also be referred to as "emerging" or "treatment-emerged" late-onset SMA patients or patient populations. In some embodiments, treatment-emergent late-onset SMA patients may differ in genotype (e.g., 1-2 copies of the SMN2 gene), phenotype (e.g., gait), and / or disease course and response to myostatin treatment compared to non-treatment-emergent late-onset SMA patients. In some embodiments, patients with late-onset SMA who would not have been able to walk and / or sit unaided (e.g., would have type 1 and / or non-ambulatory type 2 SMA) without treatment, e.g., SMN-targeted therapy, are able to do so thanks to the treatment. In some embodiments, a late-onset SMA patient who emerges from treatment, e.g., a treatment that would have resulted in non-ambulatory type 3 SMA, e.g., would have lost the ability to walk by 18 months of age without SMN-targeted therapy, retains the ability to walk at 18 months of age thanks to the treatment. When considering treatment of ambulatory type 3 SMA patients, in some embodiments, any ambulatory patient is treated. In some embodiments, a type 3 patient is one who would have retained the ability to walk by 18 months of age without intervention. In some embodiments, a type 3 patient is one who would have lost the ability to walk without intervention. In some embodiments, patients are identified through newborn screening or in utero, and treatment, e.g., SMN-targeted therapy, is initiated before disease onset. In some embodiments, the onset of SMA symptoms is not observed thanks to early initiation of treatment after newborn screening. In some embodiments, the treated patient has type 4 SMA (e.g., a patient with four or more copies of the SMN2 gene and who has a much later onset of symptoms, e.g., after the age of 18).

[0072] Mature myostatin: As used herein, the term "mature myostatin" refers to the mature, biologically active form of myostatin. In some embodiments, mature myostatin has the ability to bind and / or activate myostatin receptors. Activation and release of mature myostatin from its promyostatin form in vivo is achieved by several distinct protease cleavage events. First, "promyostatin" is cleaved by a proprotein convertase to yield "latent myostatin," in which mature myostatin is shielded from binding to its receptor by a portion of the prodomain. Activation and release of mature myostatin is achieved after latent myostatin is cleaved by an additional protease from the BMP / tolloid family, such as mTLL-2. As used herein, the term "mature myostatin" can refer to both full-length mature myostatin and fragments of full-length mature myostatin that retain biological activity. So-called neutralizing antibodies bind to mature myostatin, thereby preventing the ability of mature myostatin to bind to and activate its cellular receptor.

[0073] Motor neuron therapy: "Motor neuron therapy" refers to any therapy that can partially or completely restore motor neuron function. Examples include, but are not limited to, agents that affect neurotransmitter signaling, agents that reduce oxidative stress on neurons, and neuroprotective stem cell therapies. Motor neuron therapy includes SMN therapy.

[0074] Motor Skill: As used herein, "motor skill," "motor skills," or "motor function" refers to a subject's ability to perform one or more tasks designed to measure muscle function. Motor skill can be measured by a test designed to assess certain physical activities, which produces a score that is indicative of the patient's level of muscle function. For example, a subject's motor skill can be assessed using the Hammersmith Functional Motor Scale-Expanded (HFMSE) test; the Revised Upper Limb Module (RULM) test; the Revised Hammersmith Scale (RHS) test; Motor Function Measure (MFM) tests (e.g., MFM-D1, MFM-D2, MFM-32); the WHO Motor Development Milestones; or any other known muscle function test.

[0075] Muscle-directed therapy: As used herein, the term "muscle-directed therapy" or "muscle-targeted therapy" refers to any therapy that restores muscle function. Examples of muscle-targeted therapies include myostatin inhibitors.

[0076] Promyostatin / Latent Myostatin: As used herein, the term "promyostatin / latent myostatin" refers to promyostatin, latent myostatin, or both. In some embodiments, an anti-promyostatin / anti-latent myostatin antibody specifically binds to promyostatin. In some embodiments, an anti-promyostatin / anti-latent myostatin antibody specifically binds to latent myostatin. In some embodiments, an anti-promyostatin / anti-latent myostatin antibody specifically binds to both latent myostatin and promyostatin. In some embodiments, the anti-promyostatin / anti-latent myostatin is apitegromab, which specifically binds to both latent myostatin and promyostatin. The term "pro myostatin" (or "promyostatin") refers to an inactive precursor of mature myostatin comprising a disulfide-bonded homodimer, each molecule of which contains an amino-terminal prodomain covalently linked to a carboxyl-terminal mature myostatin domain. In some embodiments, "promyostatin" has not yet been cleaved by either a proprotein convertase or a BMP / tholoide family protease. Promyostatin and latent myostatin (see below) are proforms of myostatin / GDF-8. As used herein, the term "proform of myostatin" refers to the inactive (e.g., precursor or latent) form of myostatin growth factor that is associated with the N-terminal latency-associated peptide (LAP) domain. The proform of myostatin is composed of a dimer. This term encompasses both "promyostatin" and "latent myostatin." This term excludes mature growth factors (GDF8) that are not associated with the LAP domain.

[0077] Natural history: The natural history of SMA refers to the untreated progression of a person's SMA over time.

[0078] Progression: Disease (e.g., SMA) progression is the process of increasing symptoms or worsening of the condition over a period of time. Absent pharmacological intervention (e.g., therapy), progression is reflected by or corresponds to the natural history of the disease observed in a particular patient population. Disease progression may be determined by the rate at which the condition worsens and / or the extent to which the condition worsens. Accordingly, efficacy may include the ability of a drug or therapy to delay or slow the progression of the disease. For example, a patient may show a worsening of motor function scores over time, but at a slower rate than would be expected based on the natural history. Efficacy may include the ability of a drug or therapy to reduce the extent of deterioration. Efficacy may include disease stabilization, i.e., at least a net zero change over time in one or more functional parameters.

[0079] Quality of Life (QoL): As used herein, QoL is defined by outcomes that are meaningful from the patient's perspective and measure the impact of therapy on dimensions of life other than determining significant changes in survival or motor milestones, such as activities of daily living, work productivity, and fatigue.

[0080] SMN therapy / SMN-targeted therapy: In the context of this disclosure, the terms "SMN therapy," "SMN-targeted therapy," or "SMN-directed therapy" (used interchangeably herein) refer to pharmacological agents (drugs, biologics) aimed at increasing the amount or availability of functional SMN protein in a patient for the purpose of treating SMA.

[0081] As used herein, other synonymous terms include "SMN upregulator" or "SMN upregulator therapy" or "SMN-directed therapy" or "SMN-modifying agent" or "SMN-modifying agent therapy" or "SMN-enhancing therapy" or "SMN-enhancing agent." These agents encompass any therapy or compound that can be used to increase or improve SMN gene expression (e.g., SMN1 gene expression and / or SMN2 gene expression), SMN protein production, and / or functional SMN activity. For example, SMN1-directed therapy can include gene therapy intended to supplement or replace a deleted or mutated SMN1 gene. SMN2-directed therapy can include splicing modifiers that target certain exons or exons of the SMN2 backup gene to increase the availability of at least partially functional SMN protein to the body. Non-limiting examples of SMN therapies include nusinersen, onasemnogene abeparvovec, and risdiplam. SMN upregulators can be centrally modifying or systemically modifying agents. Centrally modifying agents may be administered directly to the central nervous system (CNS) via an intrathecal route. In contrast, systemic upregulators may be administered by any route, for example, orally, and may affect not only the CNS but also other tissues throughout the body. Systemically delivered SMN splicing modifiers may also affect SMN splicing in other (i.e., non-neuronal) tissues where SMN is expressed. In some embodiments, a "functional SMN protein" has the ability to promote motor neuron function and / or survival, or partially or completely restore motor neuron function in a cell (e.g., in a cell within a subject's body). In some embodiments, the functional SMN protein is capable of restoring at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more of motor neuron function in a cell (e.g., in a cell within a subject's body). In some embodiments, the full-length SMN protein is the result of protein translation (e.g., in a cell) of a correctly spliced ​​SMN mRNA.In some embodiments, the functional SMN protein is encoded from an SMN2 mRNA having exon 7.

[0082] Specific binding: As used herein, the terms "specific binding" or "specifically binds" mean that an antibody or antigen-binding portion thereof exhibits a particular affinity (e.g., KD as measured by Biacore®) for a particular structure on an antigen (e.g., antigenic determinant or epitope). In some embodiments, an antibody or antigen-binding portion thereof exhibits a particular affinity (e.g., KD as measured by Biacore®) for a target, e.g., promyostatin / latent myostatin, such that the antibody binds to its target with at least about 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 In the context of this disclosure, an "antibody that specifically binds to an antigen with high affinity" generally has a KD of 1.0 x 10 M or less. -8 In some embodiments, an antibody or antigen-binding portion thereof may also "selectively" (i.e., "preferentially") bind to a target antigen if it binds to its target with a strength relatively greater than the strength of binding shown to other antigens, for example, if it binds to the target antigen (e.g., promyostatin / latent myostatin) with a comparative affinity that is 10-fold, 100-fold, 1000-fold, or more than its affinity to a non-target antigen (e.g., mature myostatin (GDF-8), GDF-11, and / or other members of the TGFβ growth factor superfamily).

[0083] Steady state: As used herein, the term "steady state" refers to a situation in which the total uptake of a molecule (e.g., apitegromab) is in complete dynamic equilibrium with its elimination. In some embodiments, the steady state serum concentration of apitegromab is the maximum serum concentration (i.e., C) of apitegromab after administration, e.g., to a human subject or a cohort of human subjects. max ) or minimum (trough) serum concentration (i.e., C min or C trough) for example, the steady state of apitegromab can be determined using the maximum serum concentration of apitegromab or the minimum serum concentration of apitegromab in a PK analysis. In some embodiments, the pharmacodynamic (PD) target is latent myostatin. In some embodiments, the PD profile of apitegromab is assessed by measuring the concentration of latent myostatin in serum. In some embodiments, the serum latent myostatin concentration is a steady-state concentration. In some embodiments, the serum latent myostatin concentration is measured as the pre-dose or trough concentration (i.e., C) in, for example, a human subject or cohort of human subjects. min or C trough )

[0084] Subject: The term "subject," in the context of therapeutic applications, refers to an individual receiving or in need of clinical care or intervention, such as treatment, diagnosis, etc. Suitable subjects include vertebrates, including, but not limited to, mammals (e.g., humans and non-human mammals). When the subject is a human subject, the term "patient" may be used interchangeably. In clinical contexts, the term "patient population" or "patient subpopulation" is used to refer to a group of individuals who fall within a set of criteria, such as clinical criteria, medical history, health status, sex, age group, genetic criteria, and / or lifestyle factors. As used herein, a human subject, patient, or patient population refers to an SMA patient or patient population, unless the context dictates otherwise.

[0085] Target engagement: As used herein, the term "target engagement" refers to the ability of a molecule (e.g., apitegromab) to bind to its intended target (e.g., latent myostatin) in vivo, such as in skeletal muscle. As used herein, saturation of target association indicates a dosage sufficient to achieve a certain therapeutic effect (e.g., efficacy), although it may be possible to achieve efficacy without saturation.

[0086] Therapeutic dose: The term "therapeutic dose" refers to an amount (e.g., an amount of apitegromab) sufficient to achieve efficacy as determined by a clinical endpoint measuring therapeutic effect (e.g., by one or more of the clinical endpoint measurements discussed herein) when administered to a patient in a particular manner (e.g., using a particular titration regimen). For example, a therapeutic dose of apitegromab can be greater than 2 mg / kg and less than or equal to 20 mg / kg when administered intravenously every four weeks. In certain embodiments, a therapeutic dose of apitegromab is 10 mg / kg or 20 mg / kg when administered intravenously every four weeks.

[0087] Treatment: As used herein, the term "treating" or "treatment" of a disease or disorder (e.g., SMA) means slowing, delaying, or preventing the onset of such disease or disorder, or reversing, alleviating, ameliorating, inhibiting, slowing, stabilizing, or halting the progression, worsening, progression, or severity of the conditions associated with such disease or disorder, e.g., when compared to a baseline without treatment (e.g., where treatment halts disease progression observed in the absence of treatment). The term includes, but does not necessarily require, complete treatment or prevention of the disease or disorder. As used herein, "treating" or "treatment" refers to the administration of one or more active agents (concurrently or sequentially), or one or more compositions comprising one or more active agents, to a subject, e.g., with SMA, for the purpose of eradicating, curing, alleviating, mitigating, altering, repairing, ameliorating, improving, or affecting the disorder, the symptoms of the disease, or the predisposition to a disease, e.g., SMA.

[0088] Treatment-Emergent Patient Populations: Traditional classifications or types of SMA patient populations (e.g., type 0, type 1, type 2, nonambulatory type 3, ambulatory type 3, type 4, etc.) are primarily based on the natural history of disease manifestations, which strongly correlate with SMN2 gene copy number. Based on traditional classifications, type 0 is the most severe form with in utero onset, characterized by reduced or no mobility, and requires mechanical ventilation at birth. With the recent availability of approved SMN-targeted therapies (e.g., SMN2 upregulators, SMN1 gene therapy, etc.) and newborn screening, further classification may be necessary to describe emerging patient populations, referred to herein as "emerging" or "treatment-emergent" patient populations. In these populations, if patients begin SMN-targeted therapy at an early age, the expected SMA manifestations based on natural history and / or genetic analysis may be altered. In other words, regardless of disease genotype, early intervention may impact the course of disease progression predicted by the natural history. For example, early SMN therapy for infants with a confirmed SMN1 deletion and one copy of the SMN2 gene may enable them to sit unsupported at 12 months of age, an infant who would otherwise be predicted to develop SMA type 1. While SMA patients with two copies of the SMN2 gene may be predicted to develop a severe form of the disease (e.g., type 2) without SMN-targeted therapy, SMN-targeted therapy, particularly with early intervention, can shift the clinical appearance of such patients to resemble milder forms of the disease. As a result of such therapy, non-ambulatory type 3 SMA patients (those who have lost the ability to walk) may regain the ability to walk, or type 2 SMA patients may walk for the first time. Similarly, patients predicted to develop non-ambulatory type 3 SMA at age 18 months or later may exhibit preserved walking ability at older ages with early SMN-targeted therapy and may exhibit distinct phenotypes (e.g., gait) and / or responses to SMA treatment (Mercuri et al. (2020) Nature Reviews Neurology, 16:706-715). To accommodate medical advances in SMA therapy, the field continues to evolve, including certain nomenclature / terminology adjustments, aiming to better describe various disorders.

[0089] Type 1 SMA: Children with type 1 SMA typically deteriorate rapidly due to the natural history of the disease (Cances et al. (2022) Orphanet J Rare Dis 17:300). Early symptoms include hypotonia, small or weak muscles, difficulty breathing, difficulty swallowing, a weak cough or cry, and an inability to sit. Infants with type 1 are extremely fragile and unable to sit. By 5-6 months of age, patients typically require respiratory and / or nutritional support. More than 90% of patients die before their second birthday. These patients typically have one to two copies of the SMN2 gene.

[0090] Type 2 SMA: Children with type 2 SMA are nonambulatory without intervention, often have three copies of the SMN2 gene, and become symptomatic between the ages of 6 and 18 months. Muscle weakness is very common, affecting the ability to stand or walk unassisted and typically requiring a wheelchair. These children generally begin to lose abilities before the age of 2 years. However, these children can sit, hold their head, and roll over independently.

[0091] Type 3 SMA: In patients with type 3 SMA, symptoms may begin after 18 months of age, usually in early childhood, based on, for example, clinical classification and / or physical milestones such as sitting or walking. These patients often have three, four, or more copies of the SMN2 gene; the more severe form of non-ambulatory type 3 SMA is typically associated with three copies of the SMN2 gene (type 3a), while the less severe form of non-ambulatory type 3 SMA is typically associated with four copies (type 3b). Typically, patients with type 3 SMA can walk and climb with assistance, at least initially, feed themselves using utensils, and dress themselves, but generally cannot run, jump, or climb unaided. As these patients grow older, they lose many motor functions, including the ability to walk and climb. Patients with type 3 SMA who are able to walk are referred to as ambulatory type 3 SMA, while those who have lost the ability to walk are referred to as non-ambulatory type 3 SMA. Patients with type 3 often lose their ability to walk by the age of 4 to 16, with an average age of about 10 years.

[0092] SMA Type 4: SMA Type 4 is a rare adult-onset form of SMA. Patients usually have four or more copies of the SMN2 gene and usually experience only mild muscle weakness, which can begin around age 18, but often at an older age (e.g., in their 20s or 30s).

[0093] As more patients receive treatment, e.g., SMA therapy, patients diagnosed with SMA Type 1, Type 2, Type 3, or Type 4 may demonstrate clinical improvement such that their phenotype more closely resembles another SMA type. For example, a patient who would be classified as a Type 1 SMA patient without treatment may exhibit characteristics of a Type 2 patient and thus become "Type 2-like;" a Type 2 patient may exhibit characteristics of a Type 3 patient and thus become "Type 3-like;" and a Type 3 patient may exhibit characteristics of a Type 4 patient and thus become "Type 4-like." As used herein, the terms "Type 1-like," "Type 2-like," "Type 3-like," and "Type 4-like" with respect to SMA classification refer to a patient's clinical findings, measurements, or behavior, regardless of genotype or the natural history of the disease in the absence of intervention.

[0094] Wearable Medical Devices: Wearable medical devices are autonomous, non-invasive devices that perform a specific medical function, such as monitoring or assisting, and are attached to the body or clothing. Examples include, but are not limited to, wearable sensor devices, wearable devices that measure upper limb muscle activity, such as electromyography patches, including Acti-Myo® and AUTOMA.

[0095] Except in the operating examples or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood to be modified in all instances by the term "about," which, when used in connection with percentages, can mean ±1%.

[0096] The indefinite articles "a" and "an," as used herein in the specification and claims, unless expressly indicated otherwise, should be understood to mean "at least one."

[0097] The term "and / or," as used herein in the specification and claims, should be understood to mean "either or both" of the elements so conjunctivly connected, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Unless expressly indicated otherwise, other elements may optionally be present other than the elements specifically identified by the "and / or" clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, the phrase "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer in some embodiments to A without B (optionally including elements other than B); in other embodiments to B without A (optionally including elements other than A); in yet other embodiments to both A and B (optionally including other elements), etc.

[0098] As used herein in the specification and claims, the phrase "at least one," referring to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in that list of elements, but not necessarily including at least one of each and every element specifically listed in that list of elements, and not excluding any combination of elements in that list of elements. This definition also allows that, optionally, there may be elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically listed. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B" or, equivalently, "at least one of A and / or B") may refer in some embodiments to at least one A and no B (and optionally including elements other than B), optionally including more than one; in other embodiments to at least one B and no A (and optionally including elements other than A); in still other embodiments to at least one A, optionally including more than one, and at least one B (and optionally including other elements), optionally including more than one; etc.

[0099] The use of ordinal numbers such as "first," "second," "third," etc. in the claims to modify claim elements does not, in itself, imply any priority, precedence, or order of one claim element over another, or any chronological order in which acts of a method are performed, but is merely used as a marker to distinguish a particular designated claim element from other elements of the same designation (other than the use of ordinal numbers) and to distinguish those claim elements.

[0100] Ranges provided herein are understood to be shorthand for all values ​​within that range. For example, a range of 1 to 10 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 2 to 8, 1 to 5, etc.

[0101] All references cited herein are incorporated by reference for all purposes. In the event of a conflict between a reference and the present specification, the present specification shall control. It should be understood that certain features of the compositions and methods of the present disclosure that are described herein in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the compositions and methods of the present disclosure that are described herein in the context of a single embodiment for brevity may also be provided separately or in any subcombination.

[0102] Spinal Muscular Atrophy (SMA) Spinal muscular atrophy (SMA) is a debilitating, often fatal neuromuscular disease and the most common genetic cause of infant death (Awano et al. (2014) Neurotherapeutics 11:786-795). SMA is an autosomal recessive genetic disorder associated with mutations or deletions in the survival motor neuron 1 (SMN1) gene. Specifically, SMA is caused by reduced levels of the SMN protein, sufficient amounts of which are required to promote the survival of anterior horn cells in the spinal cord. Loss of motor neurons results in severe muscle atrophy, often leading to death due to respiratory failure (Monani (2005) Neuron 48:885-896). SMA muscle pathology is characterized by the presence of small, atrophic fibers thought to represent denervated or partially denervated muscle fibers. The presence of atrophic fibers is a classic indicator of motor neuron denervation caused by motor neuron loss or dysfunction. Unlike patients with Duchenne muscular dystrophy (DMD), patients with SMA, even in the most severe cases, do not exhibit the necrotic and inflammatory changes characteristic of the disease (Le Verche V. et al. Spinal Muscular Atrophy; Disease Mechanisms and Therapy 2017; Ch. 21: 341-356).

[0103] SMA patients typically lack a functional SMN1 gene, while the paralogous gene, SMN2, produces low levels of functional SMN protein due to alternative splicing that truncates the transcript. Advances in molecular medicine have advanced the diagnosis of SMA patients based on genotyping of both SMN1 and SMN2 copy number. SMA patients are also diagnosed based on clinical findings and phenotypes are classified based on maximal motor milestones achieved and age at symptom onset. Disease-modifying drugs are partially transforming traditional diagnosis and classification. In some embodiments, classification can be based on one or more of age at therapy initiation, age at symptom onset, and / or SMN2 copy number, for example, separately, or to refine clinical SMA phenotype definition beyond traditional classifications defined solely by age at onset and severity (Jedrzejowska M. et al. Degener Neurol Neuromuscul Dis. 2020;10:39-47).

[0104] In some embodiments, the late-onset SMA patient is being treated with or has received a motor neuron-directed therapy, such as SMN therapy (e.g., received such therapy at age less than 5 years). In some embodiments, the late-onset SMA patient has at least two copies of the SMN2 gene (e.g., at least three copies or at least four copies of SMN2). In some embodiments, the late-onset SMA patient develops diagnosable symptoms of SMA at age 6 months or later. Subjects with SMA can be treated before they exhibit symptoms of the disease or after diagnosable symptoms have developed.

[0105] In some embodiments, the infantile-onset SMA patient is being treated with or has received a motor neuron-directed therapy, such as SMN therapy. In some embodiments, the infantile-onset SMA patient has one copy of SMN2. In some embodiments, the infantile-onset SMA patient develops diagnosable symptoms of SMA at age less than 6 months of age. In some embodiments, the infantile-onset SMA patient could have developed diagnosable symptoms at age less than 6 months of age, but has not developed the symptoms, e.g., due to treatment with SMN therapy. In some embodiments, such subjects are diagnosed with infantile-onset SMA based, e.g., on SMN2 copy number, and are distinguished from later-onset SMA patients based on other factors besides age of disease onset, e.g., genotype (e.g., SMN2 copy number), phenotype (e.g., gait or other observed motor traits), and / or response to SMA therapy.

[0106] A summary of SMA classification and disease characteristics is provided below.

[0107] [Table 1]

[0108] Genotype-based SMA classification The clinical heterogeneity of SMA is due in part to the complex genetics of the disease. Mutations in the SMN1 gene cause SMA (Lefebvre et al. (1995) Cell 80:155-165); however, in humans, a nearly identical gene, SMN2, is located very close to SMN1 (Monani et al. (1999) Hum Mol Genet 8:1177-1183). The main difference between these genes is a C-to-T transition, which creates an exon splicing silencer, resulting in the removal of exon 7 from the final mRNA transcript. This truncated SMN protein is unstable and rapidly degraded. Nevertheless, approximately 10% of the mRNA produced by SMN2 is correctly spliced ​​to produce the full-length SMN protein, but this amount is insufficient to completely compensate for the loss of SMN1.

[0109] The copy number of SMN2 varies from individual to individual and is strongly correlated with SMA disease severity. Higher copy numbers (e.g., 3 or 4 copies) are generally associated with milder forms of SMA. Although SMA patients with a single SMN2 copy are rare, this copy number is highly predictive of the severe type 1 phenotype, which has a poor prognosis. The majority of patients with type 1 SMA have one or two copies of SMN2; most type 2 patients have three copies of SMN2; and most type 3 patients have three or four copies of SMN2. For example, according to Calucho et al. ((2018) Neuromuscular Disorders. 28:208-215 at Table 2), approximately 80% of patients with type 1 SMA carry one or two copies of SMN2, approximately 94% of patients with type 2 carry two or three copies, approximately 93% of patients with type 3 carry three or four copies, and nearly 100% of patients with type 4 carry four to six copies of SMN2.

[0110] Traditional SMA classifications include, in order of increasing severity, types 1, 2, 3, and sometimes 4. Type 1 SMA is typically diagnosed between birth and 6 months of age, and without early intervention, patients never gain enough muscle strength to sit independently. Without intervention, most type 1 patients do not survive beyond the age of 2 years without respiratory support. Types 2 and 3 individuals produce higher amounts of SMN protein and are less severe, but still life-altering, forms of SMA. Type 2 patients are generally diagnosed between 6 and 18 months of age. These patients are able to sit unaided but are unable to walk unaided. In type 3 SMA, patients are typically diagnosed after 18 months of age and are able to sit and walk unaided, but may become wheelchair-dependent later in life. Thus, type 3 SMA includes both ambulatory and nonambulatory subpopulations. Many ambulatory type 3 SMA patients become nonambulatory at some point as the disease progresses. Type 4 SMA is an adult-onset, mildly phenotypically severe form that is extremely rare.

[0111] Although stratification of SMA by type is a useful clinical paradigm, disease phenotypes exist along a continuum rather than discrete categories. For example, patients who carry SMA gene mutations can be presymptomatic (without manifesting an overt disease phenotype).

[0112] In some cases, patients carrying a genetic mutation in an SMN gene (such as SMN1) have a presymptomatic phenotype and can be identified for treatment based on genetic screening. In some embodiments, delayed disease manifestation can be due, at least in part, to early intervention, such as SMN upregulator therapy (e.g., SMN2 upregulator therapy and SMN1 gene therapy). Early intervention generally means that treatment is initiated before age 5, e.g., before age 4, 3, 2, or 1, or shortly after birth. In recent years, newborn genetic screening has become widely available, allowing for the identification of individuals born with genetic disorders such as SMA. For example, in the United States, many states have included SMA, among other known genetic disorders, in their routine newborn screening panels, which are typically performed within the first few days of life. Thus, infants carrying a mutation in the SMN gene (SMN1) who are likely to develop disease can be identified early, often while they are asymptomatic (presymptomatic). Early detection and diagnosis, for example, even before the child begins to develop symptoms, can lead to early therapeutic intervention, which can help prevent certain clinical manifestations and / or delay the onset or progression of SMA.

[0113] Genetic screening can be performed on newborn / infant subjects and can also be performed in utero (e.g., fetuses). In some embodiments, the subject is identified, or has been identified, as a carrier of an SMN mutation, e.g., by genetic screening either in utero or as a newborn / infant. In some embodiments, genetic screening is performed as a newborn / infant (e.g., within 24 hours of birth). In other embodiments, genetic screening is performed in utero.

[0114] SMA classification based on onset Severe forms of SMA typically present with early symptoms, e.g., before 6 months of age. This can be referred to as infantile-onset SMA, in contrast to late-onset SMA. When SMA symptoms are present at birth or by 6 months of age, the disease is also SMA type 1 (also called infantile-onset or Werdnig-Hoffmann disease). Infants typically have generalized muscle weakness, a weak cry, and difficulty breathing.

[0115] Recently, with the availability of approved SMN-upregulator therapies, such as nusinersen, risdiplam, or onasemnogene abeparvovec, early intervention has been shown to be particularly effective in delaying the onset and / or reducing the severity of SMA with more severe phenotypes based on a particular patient's genotype. For example, some patients diagnosed with type 1 SMA (or at risk for developing it due to a low copy number of the SMN2 gene) may be able to convert their phenotype to one more consistent with later-onset SMA with early intervention with SMN-upregulator therapy.

[0116] In some embodiments, definitions based on symptom occurrence are useful for classifying certain patient populations for early intervention that would alter the usual course or timeline of disease progression.

[0117] Improving muscle function by targeting myostatin - myostatin inhibition In some embodiments, the disclosure encompasses the use of agents that inhibit myostatin activation, regardless of mechanism of action. In some embodiments, the inhibitor is a small molecule. In some embodiments, the inhibitor is an antibody or antigen-binding fragment (e.g., an Adnectin such as taldef globep alfa). In some embodiments, the antibody is a myostatin-selective antibody, e.g., a promyostatin / latent myostatin-selective antibody.

[0118] In some embodiments, the present specification discloses antibodies capable of binding to promyostatin and / or latent myostatin, thereby inhibiting myostatin activity, and their use to treat diseases and disorders associated with muscle wasting, such as SMA.

[0119] In some embodiments, the disclosure provides methods that include the use of apitegromab or antibodies having the CDR sequences, variable domain sequences, or full-length antibody sequences provided in Tables 1-10 below.

[0120] [Table 2]

[0121] [Table 3]

[0122] [Table 4]

[0123] [Table 5]

[0124] Inhibition of myostatin activation by apitegromab can lead to the accumulation of promyostatin and latent myostatin. Because promyostatin is found primarily in skeletal muscle and latent myostatin is found primarily in serum, in some embodiments, serum latent myostatin levels can serve as a marker of apitegromab target engagement, e.g., target engagement with apitegromab in skeletal muscle. In some embodiments, serum latent myostatin levels and / or serum creatinine levels may be relatively low at baseline (i.e., before treatment) and increase after treatment with apitegromab. In some embodiments, increased serum latent myostatin and / or serum creatinine levels indicate target engagement by apitegromab, e.g., in skeletal muscle. In some embodiments, low baseline serum levels of latent myostatin and / or serum creatinine compared to elevated levels after treatment indicate that the majority of the drug target is in skeletal muscle rather than circulating systemically. Similarly, in some embodiments, serum latent myostatin levels can serve as a target engagement marker for other pro-myostatin / latent myostatin antibodies, such as, for example, GYM329, or antibodies or antigen-binding fragments that compete with apitegromab or GYM329 for binding in a similar manner. In some embodiments, serum latent myostatin levels can be relatively low at baseline (i.e., before treatment) and increase after treatment with apitegromab. In some embodiments, an increase in serum latent myostatin levels indicates target engagement by apitegromab, e.g., target engagement by apitegromab in skeletal muscle. In some embodiments, low baseline serum levels of latent myostatin compared to high levels after treatment indicates that the majority of the drug target is in skeletal muscle, rather than circulating systemically.

[0125] In some embodiments, serum creatinine levels can serve as a target engagement marker for apitegromab. In some embodiments, serum creatinine levels can be relatively low at baseline (i.e., before treatment) and increase after treatment with apitegromab.

[0126] In some embodiments, an increase in serum creatinine levels indicates target engagement by apitegromab, e.g., target engagement by apitegromab in skeletal muscle. In some embodiments, serum creatinine levels can serve as a target engagement marker for another promyostatin / latent myostatin antibody, such as GYM329 (RO7204239) or an antibody or antigen-binding fragment that competes with apitegromab or GYM329 for antigen binding. Circulating creatine, i.e., 2-[carbamimidoyl(methyl)amino]acetic acid, is transported from the circulation into muscle, where it serves as an energy storage buffer. Serum creatinine is derived from these muscle stores of creatine; creatine is converted to creatinine and released into the circulation at a constant rate of approximately 1.7% per day. It is known that serum creatinine levels correlate with muscle mass and inversely correlate with disease severity in spinal muscular atrophy (Alves et al (2019) Neurology 94:e921).

[0127] In some embodiments, saturation of target association indicates a dosage sufficient to achieve some therapeutic effect (e.g., efficacy), although it may be possible to achieve efficacy without saturation.

[0128] In certain embodiments, the present disclosure encompasses the use of alternative anti-myostatin antibodies or antigen-binding fragments, such as anti-promyostatin / anti-latent myostatin antibodies or antigen-binding fragments, e.g., selective anti-promyostatin / anti-latent myostatin antibodies, such as any one of the antibodies or antigen-binding fragments disclosed in PCT / JP2015 / 006323 (International Application No. 2016098357), the contents of which are hereby incorporated by reference in their entirety. A myostatin selective inhibitor as used herein may be an alternative anti-promyostatin / anti-latent myostatin antibody or antigen-binding fragment as described herein, such as GYM329. In certain embodiments, the present disclosure encompasses anti-promyostatin / anti-latent myostatin antibodies or antigen-binding fragments that are humanized variants of MST1032-G1m as disclosed in PCT / JP2015 / 006323. In certain embodiments, the present disclosure encompasses anti-promyostatin / anti-latent myostatin antibodies or antigen-binding fragments comprising a heavy chain variable domain comprising three CDR sequences, HCDR1, HCDR2, and HCDR3, and a light chain variable domain comprising three CDR sequences, LCDR1, LCDR2, and LCDR3, wherein the heavy chain CDRs comprise the amino acid sequences X1X2DIS (HCDR1; SEQ ID NO: 17); IISYAGSTYYASWAKG (HCDR2; SEQ ID NO: 18); GVPAYSX3GGDL (HCDR3; SEQ ID NO: 19), respectively; and the light chain CDRs comprise the amino acid sequences X4X5SQSVYX6X7NWLS (LCDR1; SEQ ID NO: 20); WASTLAX8 (LCDR2; SEQ ID NO: 21); and AGGYGGGX9YA (LCDR3; SEQ ID NO: 22), respectively (wherein each of X1 to X9 is any amino acid residue). In certain embodiments, X1 is S or H; X2 is Y, T, or D; X3 is T or H; X4 is Q or T; X5 is S or T; X6 is D or H; X7 is N or E; X8 is S or Y; and X9 is L or R. In certain embodiments, the antibody or antigen-binding fragment comprises six CDR sequences of SEQ ID NOs: 23-28; 29-34; 35-40; or 41-46.In certain embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 47 to 50. In certain embodiments, the antibody or antigen-binding fragment comprises a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 51 to 54. In some embodiments, the antibody or antigen-binding fragment comprises a set of six CDRs (e.g., from the same MST1032 mutant antibody) or a pair of VH / VL (e.g., from the same MST1032 mutant antibody) from those listed in the table below.

[0129] [Table 6]

[0130] [Table 7]

[0131] [Table 8]

[0132] [Table 9]

[0133] [Table 10]

[0134] [Table 11]

[0135] In certain embodiments, the disclosure encompasses the use of GYM329 or an antibody comprising any of the sequences from Tables 5-10 above (e.g., a set of six CDRs or a pair of variable domains) as an alternative anti-promyostatin / anti-latent myostatin antibody for treating subjects with SMA. In certain embodiments, GYM329 or an antibody comprising any of the sequences from Tables 5-10 above is used in conjunction with SMN therapy (e.g., risdiplam, nusinersen, and / or onasemnogene abeparvovec) for the treatment of SMA. In certain embodiments, GYM329 or an antibody comprising any of the sequences from Tables 5-10 above is used to treat SMA subjects who are ambulatory or have the ability to walk unaided. In certain embodiments, the subject has late-onset SMA. In certain embodiments, the subject has early-onset SMA. In certain embodiments, the patient has Type 2 or Type 3 SMA. In certain embodiments, the patient has ambulatory SMA. In certain embodiments, the patient has non-ambulatory SMA, e.g., non-ambulatory Type 2 and Type 3 SMA. In certain embodiments, the patient has non-ambulatory SMA. In certain embodiments, the subject is 2-10 years of age. In certain embodiments, the subject is 13-21 years of age. In certain embodiments, the subject is less than 2 years of age. In certain embodiments, the subject has previously been treated with an SMN-upregulating drug. In certain embodiments, the subject has previously been treated with SMN, e.g., risdiplam, nusinersen, and / or onasemnogene abeparvovec. In certain embodiments, the subject has not previously been treated with an SMN-upregulating drug. In certain embodiments, GYM329 is used to treat SMA in subjects who are ambulatory or capable of walking independently, preferably subjects 2-10 years of age, wherein the use comprises administering GYM329 to the subject in conjunction with SMN treatment, wherein the subject has previously been administered at least one dose of SMN treatment, e.g., risdiplam, nusinersen, or onasemnogene abeparvovec. In some embodiments, the subject is able to walk or run 10 meters in under 30 seconds and / or has a confirmed genetic diagnosis of 5q autosomal recessive SMA and syndromic disease.In some embodiments, the use of GYM329 or an antibody comprising any of the sequences from Tables 5-10 above, alone or in combination with an SMN-upregulating agent, may lead to improvement compared to no treatment. Improvement may be measured by RHS and / or Motor Function Measure-32 (MFM32) score. Improvement may be improvement in muscle mass as measured by MRI and / or dual-energy X-ray absorptiometry (DXA) scan. Improvement in muscle strength as measured by dynamometer may be improvement in upper limb muscle strength as measured by MyoGrip or MyoPinch. Improvement may be improvement in muscle strength as measured by dynamometer. Improvement may be as determined by the SMA Independence Scale (SMAIS). Improvement may be seen in two or more of the aforementioned metrics.

[0136] In some embodiments, a composition comprising an anti-myostatin antibody, e.g., an anti-promyostatin / anti-latent myostatin antibody such as GYM329 or apitegromab, is used to treat SMA in patients 2 months of age or older, where optionally the treatment further comprises risdiplam (EVRYSDI®). In some embodiments, GYM329 or apitegromab and risdiplam are administered to the patient as a combination therapy. In some embodiments, GYM329 or apitegromab is administered in conjunction with an SMN therapy, e.g., nusinersen, e.g., administered to the patient as a combination therapy. In some embodiments, GYM329 or apitegromab is administered in conjunction with onasemnogene abeparvovec, e.g., administered to the patient as a combination therapy. In some embodiments, GYM329 or apitegromab is administered as an add-on or adjunctive therapy to patients being treated with (i.e., receiving) SMN therapy (e.g., risdiplam, nusinersen, or onasemnogene abeparvovec). In some embodiments, SMN therapy is administered as an add-on or adjunctive therapy to patients being treated with (i.e., receiving) GYM329 or apitegromab. In some embodiments, patients have been receiving SMN therapy for at least 8 weeks prior to receiving GYM329. In some embodiments, patients receiving SMN therapy receive GYM329 for at least 18 weeks, at least 24 weeks, at least 54 weeks, or at least 72 weeks. In some embodiments, GYM329 or apitegromab is administered intravenously. In some embodiments, GYM329 or apitegromab is administered subcutaneously. In some embodiments, the patient is 2-7 months old, optionally having or suspected of having SMA Type 1. In some embodiments, the patient is 2-25 years old, optionally having SMA Type 2 or 3. In some embodiments, the patient is 5-10 years old. In some embodiments, the patient is 2-4 years old. In some embodiments, the patient is under 2 years old. In some embodiments, the patient is of any age (e.g., infant, child, or adult) and has SMA Type 1, 2, or 3.In some embodiments, the patient is of any age and has ambulatory SMA. In some embodiments, the patient is of any age and has non-ambulatory SMA. In some embodiments, the patient's motor performance is monitored by a wearable device. In certain embodiments, the wearable device is one or more insole-type measurement devices. In some embodiments, motor function is measured as change from baseline in RHS, MFM D1, MFM D2, MFM32, or SMA Independence Score (SMAIS) score. In some embodiments, muscle strength is measured by a dynamometer. In some embodiments, muscle wasting is monitored by MRI. In some embodiments, circulating myostatin levels are measured. In some embodiments, immune responses are monitored.

[0137] In certain embodiments, the disclosure encompasses the use of tardef globep alfa as an alternative to anti-promyostatin / anti-latent myostatin antibodies in treating subjects with SMA. Tardef globep alfa, also known as BHV2000 or BMS-986089, is an IgG (human Fc fragment) fusion protein with the sequence CAS 1580565-26-5, INN 10661, and comprising a peptide (synthetic 17 aa linker) and an Adnectin (anti-(human GDF-8) human clone BMS-986089 derived from fibronectin type III domain 10 dimer). In certain embodiments, tardef globep alfa is used in conjunction with an SMN-upregulator therapy (e.g., risdiplam, nusinersen, and / or onasemnogene abeparvovec) to treat SMA. In certain embodiments, taldef globep alfa is used to treat SMA subjects who are ambulatory or have the ability to walk independently. In certain embodiments, the subject has late-onset SMA. In certain embodiments, the subject has early-onset SMA. In certain embodiments, the patient has Type 2 or Type 3 SMA. In certain embodiments, the patient has ambulatory SMA. In certain embodiments, the patient has non-ambulatory SMA, e.g., non-ambulatory Type 2 and Type 3 SMA. In certain embodiments, the subject is 2-10 years of age. In certain embodiments, the subject is 13-21 years of age. In certain embodiments, the subject is under 2 years of age. In certain embodiments, the subject has previously been treated with an SMN-upregulating drug. In certain embodiments, the subject has previously been treated with risdiplam, nusinersen, and / or onasemnogene abeparvovec. In certain embodiments, the subject has not previously been treated with an SMN-upregulating drug. In certain embodiments, tardef globep alfa is used to treat SMA in subjects who are ambulatory or capable of walking independently, preferably subjects between the ages of 2 and 10, wherein the use comprises administering tardef globep alfa in combination with risdiplam to the subject, wherein the subject has previously received at least one dose of risdiplam, nusinersen, or onasemnogene abeparvovec.In some embodiments, the subject can walk or run 10 meters in 30 seconds or less and / or has a confirmed genetic diagnosis of 5q autosomal recessive SMA and symptomatic disease. In some embodiments, the use of taldef globep alfa alone or in combination with an SMN-upregulating drug can lead to improvement compared to no treatment. Improvement can be measured by RHS and / or Motor Function Measure-32 (MFM32) score. Improvement can be an improvement in muscle mass as measured by MRI and / or dual-energy X-ray absorptiometry (DXA) scan. Improvement can be an improvement in muscle strength as measured by dynamometer. Improvement in muscle strength as measured by dynamometer can be an improvement in upper limb muscle strength as measured by MyoGrip or MyoPinch. Improvement can be measured by the SMA Independence Scale (SMAIS). Improvement can be seen in two or more of the aforementioned measures.

[0138] In some embodiments, a composition comprising an anti-myostatin antibody or antigen-binding fragment thereof, e.g., apitegromab or taldef globebep alfa, is used in the treatment of SMA in patients 2 months of age or older, where the treatment optionally further comprises SMN therapy, e.g., nusinersen, risdiplam, or onasemnogene abeparvovec. In some embodiments, tardef globebep alfa or apitegromab and SMN therapy are administered to the patient as a combination therapy. In some embodiments, tardef globebep alfa or apitegromab is administered as an add-on or adjunctive therapy to a patient being treated with (i.e., receiving) SMN therapy. In some embodiments, SMN therapy is administered as an add-on or adjunctive therapy to a patient being treated with (i.e., receiving) taldef globebep alfa or apitegromab. In some embodiments, the patient has been receiving SMN therapy for at least 8 weeks prior to receiving tardef globebep alfa. In some embodiments, the patient receiving risdiplam receives tardef globep alfa for at least 18 weeks, at least 24 weeks, at least 12 months, or at least 24 months. In some embodiments, tardef globep alfa or apitegromab is administered intravenously. In some embodiments, tardef globep alfa or apitegromab is administered subcutaneously. In some embodiments, the patient is 2-7 months old, optionally having or suspected of having SMA Type 1. In some embodiments, the patient is 2-25 years old, optionally having SMA Type 2 or SMA Type 3. In some embodiments, the patient is 5-10 years old. In some embodiments, the patient is 2-4 years old. In some embodiments, the patient is under 2 years old. In some embodiments, the patient is of any age (e.g., infant, child, or adult) and has SMA Type 1, 2, or 3. In some embodiments, the patient is of any age and has ambulatory SMA. In some embodiments, the patient is of any age and has non-ambulatory SMA. In some embodiments, the patient's athletic performance is monitored by a wearable device.In some embodiments, the wearable device is one or more insole-type measuring devices. In some embodiments, motor function is measured as change from baseline in RHS, MFM D1, MFM D2, MFM32, or SMA Independence Score (SMAIS) score. In some embodiments, muscle strength is measured by a dynamometer. In some embodiments, muscle wasting is monitored by MRI. In some embodiments, circulating myostatin levels are measured. In some embodiments, immune responses are monitored.

[0139] Motor Neuron-Directed Therapy In some embodiments, motor neuron-directed therapies may be contemplated for use in the combination therapies disclosed herein.

[0140] As used herein, the term "motor neuron-directed therapy" refers to an agent that aims to improve (e.g., enhance or restore) nerve function. Such therapies are useful in treating conditions involving impaired signaling between motor neurons and their target muscles. Specifically, motor neuron-directed therapies may be particularly useful in treating conditions involving partial, but not complete, loss of neurons that innervate muscles. In some embodiments, the motor neuron-directed therapy is a gene therapy, a small molecule, or an antisense oligonucleotide. In some embodiments, the motor neuron-directed therapy is an "SMN-upregulating agent." In some embodiments, the motor neuron-directed therapy is an agent capable of fully restoring motor neuron function in a cell (e.g., a cell within a subject's body). In some embodiments, the motor neuron-directed therapy is an agent capable of partially restoring motor neuron function in a cell (e.g., a cell within a subject's body). In some embodiments, a motor neuron-directed therapy is an agent capable of restoring at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more of motor neuron function of a cell (e.g., a cell within a subject's body). Those skilled in the art will understand that motor neuron function typically includes membrane excitability, axonal transport, vesicle transport, neurotransmitter release, mitochondrial function, and / or mitochondrial availability, and that such function is measured using assays known to those skilled in the art.

[0141] In some embodiments, motor neuron-targeted therapy includes therapy that slows or stops neurodegeneration. Such therapies are known in the context of Parkinson's disease and Huntington's disease. Such therapies may improve neuronal mitochondrial function, prevent protein deregulation, or reduce apoptosis. In certain embodiments, therapy that slows or stops neurodegeneration may include providing progranulin (Chitramuthu et al. (2010) Molec Neurodegen 5:41) in combination with muscle-directed therapy, for example, by providing progranulin gene therapy with, for example, ALPHA-0602.

[0142] In some embodiments, the motor neuron targeted therapy comprises transcutaneous spinal cord stimulation. In some embodiments, the transcutaneous spinal cord stimulation is combined with another motor neuron targeted therapy, e.g., as in NCT05430113. In some embodiments, the motor neuron targeted therapy comprises a therapy that affects neurotransmitter signaling. In some embodiments, the motor neuron targeted therapy comprises a therapy that reduces oxidative stress to neurons. In some embodiments, the motor neuron targeted therapy comprises a neuroprotective stem cell therapy.

[0143] Exemplary motor neuron-directed therapies suitable for use in conjunction with apitegromab according to the present disclosure include, but are not limited to, SMN upregulator therapy (also referred to as SMN corrector therapy). Exemplary motor neuron-directed therapies include "SMN upregulators," such as splicing modifiers, SMN gene replacement or gene therapy, SMN transcription enhancers, SMN protein translation enhancers, and SMN protein stabilizers, as discussed further below. The terms "splice corrector," "splice regulator," and "splice modifier" as used herein are synonymous and refer to agents that correct aberrant splicing of RNA transcripts, such as those encoded by the SMN2 gene, and / or agents that modulate the expression of SMN protein. In some embodiments, an SMN2 splice corrector increases the inclusion of exon 7 in the SMN2 pre-mRNA. In some embodiments, increased inclusion of exon 7 in the SMN2 pre-mRNA leads to increased expression of functional SMN protein (e.g., from the SMN2 gene) in a cell or subject, such as an SMN protein capable of promoting neuronal function and / or survival.

[0144] In some embodiments, the SMN upregulator is an agent, e.g., a small molecule or oligonucleotide (e.g., an antisense oligonucleotide), that increases expression of functional SMN protein, e.g., by promoting inclusion of exon 7 in SMN2 mRNA transcripts. In some embodiments, the cell is a cell within a subject, e.g., a subject to whom the SMN upregulator is administered. In some embodiments, the SMN upregulator increases the relative amount of SMN2 mRNA that includes exon 7 compared to SMN2 mRNA that does not include exon 7 in a cell, e.g., a cell of a subject. In some embodiments, an "effective amount" of an SMN upregulatory agent is one that increases the amount of correctly spliced ​​SMN2 mRNA in a cell (e.g., a cell in a subject's body) such that at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more of the SMN2 mRNA in the cell contains exon 7. In some embodiments, an "effective amount" of an SMN upregulator increases the level of SMN2 mRNA that includes exon 7 in a subject by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or more. In some embodiments, an "effective amount" of an SMN upregulator increases the level of functional SMN protein in a subject by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or more.

[0145] Novartis and PTC Therapeutics / Roche have both developed small molecules that selectively enhance SMN2 exon 7 inclusion, resulting in increased full-length SMN protein levels and therapeutic efficacy in mouse SMA models (Calder et al. (2016) J Med Chem 59:10067-10083; Naryshkin et al. (2014) Science 345:688-693; Palacino et al. (2015) Nat Chem Biol 11:511-517; Ratni et al. (2016) J Med Chem 59:6086-6100). For example, risdiplam (formerly RO7034067, CAS number 1825352-65-5), sold by Roche under the trademark EVRYSDI®, was the first oral medication approved for the treatment of SMA. Branapram (formerly known as LMI070 and NVS-SM1) is being studied in a Phase 1 / 2 multi-part, first-in-human, open-label clinical trial in infants with Type 1 SMA (see Clinical Trial NCT02268552, Novartis).

[0146] Oral administration of SMN-C2 (an analog of risdiplam, CAS No. 1446311-56-3) and SMN-C3 (CAS No. 1449597-34-5) in preclinical models of mild and severe SMA showed that these compounds increased SMN protein levels in both brain and muscle tissue in treated mice compared with vehicle. These molecules also efficiently crossed the blood-brain barrier (BBB). Both compounds showed early promise in mouse models of severe SMA, but clinical programs were discontinued.

[0147] Additional small molecule-based SMN2 splicing modifiers are described, for example, in U.S. Patent Application Publication No. 2009 / 0031435; and U.S. Patent No. 8,399,437 (the contents of each of which are incorporated herein by reference in their entirety). However, it should be understood that SMN2 splicing modifiers known in the art, including, for example, risdiplam, and other small molecule splicing modifiers that would be apparent to one of ordinary skill in the art, are within the scope of this disclosure.

[0148] In some embodiments, the SMN upregulator is an oligonucleotide molecule. In some embodiments, the SMN upregulator is an antisense molecule. In some embodiments, the SMN upregulator is an antisense molecule that increases expression of the SMN2 gene. In some embodiments, the SMN upregulator is an antisense molecule that increases expression of an SMN2 mRNA that includes exon 7. In some embodiments, the SMN upregulator is an antisense molecule that increases expression of a functional SMN protein, for example, an SMN protein encoded by an SMN2 mRNA that includes exon 7. For example, an antisense oligonucleotide directed to inhibiting the intron splicing silencer site (ISS) in intron 7 of the SMN2 gene can modulate pre-mRNA processing, leading to an increased probability of exon 7 inclusion in the mature SMN2 mRNA transcript, and therefore increased production of functional SMN protein.

[0149] In some embodiments, antisense oligonucleotides (ASOs) block the SMN2 intron splicing silencer, thereby increasing exon 7 inclusion, again rescuing disease in mouse SMA models (Hua et al. (2010) Genes Dev 24:1634-1644; Hua et al. (2011) Nature 478:123-126; Passini et al. (2011) Sci Transl Med 3:72ra18). Biogen / Ionis is developing nusinersen, an ASO splicing modifier, which has shown clinical efficacy and received FDA approval for the treatment of SMA in infants and adults, marketed as Spinraza™ (Chiriboga et al. (2016) Neurology 86:890-897; Finkel et al. (2016) Lancet 388:3017-3026; FDA, Nusinersen; Office of Drug Evaluation Decision Memorandum (2016)). However, nusinersen requires intrathecal delivery under general anesthesia for each dose. Additionally, the antisense corrective agent nusinersen has proven promising, but its clinical efficacy appears to be modest: among infantile-onset SMA (Type 1), 60% of patients have been reported to be non-responders, and 43% of nusinersen-treated patients did not achieve a 3-point or greater increase in HFMSE score compared with placebo, while the mean increase in treated patients was less than 6 points. Thus, only partial improvement is achieved with nusinersen treatment.

[0150] Although these ASO treatments have demonstrated efficacy in preclinical and clinical trials, none have resulted in a complete cure for the disease. In mouse models, both small molecule and ASO splicing modifiers significantly reduced disease severity, but treated animals still exhibit deficits in longevity, body weight, muscle mass, and muscle function compared with healthy controls (Hua et al. (2011) Nature 478:123-126; Feng et al. (2016) Hum Mol Genet 25:964-975). In a double-blind clinical trial in infantile-onset SMA, nusinersen provided clinically meaningful benefits at the interim analysis (41% of treated patients showed improvement in motor milestones using the Hammersmith Infant Neurological Examination compared with 0% of placebo patients). The motor milestones achieved were impressive for Type 1 patients, with 5 of 81 treated patients able to sit unaided (a milestone that is almost never reached in these patients). Nevertheless, these patients did not achieve the full range of developmental milestones, milestones that would be considered disappointing in normal individuals. In a second placebo-controlled study in Type 2 SMA, nusinersen again demonstrated clinically meaningful improvements, with HFMSE scores increasing by 5.9 points compared with the placebo group. Note that the maximum HFMSE score is 66 points, and most Type 2 patients achieve scores below 20 points (Glanzman et al. (2011) J Child Neurol 26:1499-1507; Kaufmann et al. (2011) Arch Neurol 68:779-786). Nevertheless, 43% of patients in this study failed to achieve at least a 3-point improvement in motor function. These results indicate that SMN2 splicing modulators have the potential to have significant effects on the SMA disease course, but additional gain-of-function is needed for further refinement to reduce disease burden.

[0151] In some embodiments, the SMN-upregulating agent is a gene therapy. As used herein, the term "gene therapy" refers to any procedure that uses nucleic acids to cure, eradicate, or otherwise improve a condition in a subject. In gene therapy, nucleic acids are delivered to specific cells. Delivery methods include viral and non-viral means, which are known in the art. See, for example, Patil et al. (2005) AAPS J. 7(1):E61-E77; Gascon et al., Non-Viral Delivery Systems in Gene Therapy (2013); Somiari et al. (2000) Molecular Therapy, 2(3):178-187; Herweijer and Wolff (2003) Gene Therapy 10(6):453-458; Nayerossadat et al. (2012) Advanced Biomedical Research 1(2):1-11. Viral gene therapy delivery involves the use of viral vectors. Viral vectors are genetically modified viruses that have been reprogrammed to carry a therapeutic gene payload and achieve infection and subsequent delivery of the payload to specific tissues without the side effects typically associated with wild-type viral infection. Several viruses can be used as viral vectors, including retroviruses, adenoviruses, herpes simplex viruses, lentiviruses, poxviruses, and Epstein-Barr viruses. While safer than wild-type viruses, viral vectors can induce immune responses, making non-viral delivery methods sometimes necessary. In some embodiments, the viral vector is an AAV viral vector. Non-viral delivery methods include physical methods, such as, but not limited to, naked DNA injection, electroporation, gene gun bombardment, and ultrasound, as well as biochemical methods. Magnetofection, another delivery technique, combines physical and biochemical components.

[0152] SMN1 gene replacement therapy using adeno-associated viral vectors (AAV) has shown benefit in the treatment of SMA; ZOLGENSMA® (onasemnogene abeparvovec, formerly AVXS-101), an AAV9-SMN1 vector from Novartis Gene Therapies (formerly AveXis), is approved by the FDA in the United States for the treatment of pediatric patients under the age of 2 with spinal muscular atrophy (SMA) who have biallelic mutations in the survival motor neuron 1 (SMN1) gene. ANB-004, an AAV9-SMN1 vector from Biocad (WO 2022 / 164351), is in Phase 1 / 2 clinical trials in symptomatic infants under the age of 6 months with SMA.

[0153] In some embodiments, gene therapy involves the introduction of one or more transgenes into a patient. In some embodiments, gene transfer is achieved through the use of a suitable vector, such as a viral vector or lipid-based carrier. For viral vector-mediated gene delivery, gene therapy may involve the use of a specific serotype for initial treatment, followed by a different serotype for subsequent treatments, to minimize adverse immune responses in the subject. In some embodiments, gene therapy involves targeted genome editing, such as CRISPR / Cas9 technology or modifications thereof. Non-limiting examples of SMN-upregulating drugs suitable for use in conjunction with apitegromab of the present disclosure include, but are not limited to: nusinersen; risdiplam; and onasemnogene abeparvovec. Nusinersen is an SMN2-directed antisense oligonucleotide (ASO) designed to treat SMA caused by mutations leading to SMN protein deficiency. See, for example, Darras et al. (2019) Neurology. 92(21) e2492-e2506; Mercuri et al. (2018) N Engl J Med. 378:625-635. Risdiplam is a pyridazine derivative that works in a similar way, modifying the splicing of SMN2 messenger RNA. See, for example, Oskoui et al. “SUNFISH Part 2: 24-month efficacy and safety of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA).” Presented at MDA Clinical and Scientific Conference 2021; March 15-18. Poster 80. Onasemnogene abeparvovec is a recombinant adeno-associated virus vector type 9-based gene therapy designed to deliver a copy of the gene encoding the human SMN protein.

[0154] Clinical Benefits of SMN Therapy Based on the natural history (i.e., untreated) of non-ambulatory late-onset SMA patients aged 5 years and older, mean HFMSE scores are expected to worsen over a 12-month period, with less than 5% showing an increase of 3 points or more (Mercuri et al. (2016) Neuromuscul Disord. 26(2):126-131). Natural history data from longitudinal studies of ambulatory type 3 SMA patients provide additional insight. These patients commonly experience a decline in motor function, which can be severe in some cases, including loss of the ability to walk (Coratti et al. (2020) American Neurology Association, 88:1109-1117, e.g., Figure 1). In this study of 130 subjects with a mean age of 10.05 years and a mean HFMSE score of 52.81 at baseline, the mean change in HFMSE from baseline at 12 months was -0.79 points, and 11 patients had lost the ability to walk (mean age at loss of walking was 10.21 years (SD ± 6.43 years)). Subjects remained relatively stable until age 7 years, showing slight functional improvement, but rapid deterioration was observed over the following years.

[0155] Among non-ambulatory late-onset SMA patients aged 5 years and older, mean HFMSE scores are expected to worsen over a 12-month period based on the natural history of this patient population, with few patients (e.g., <5%) showing an increase of 3 or more points in HFMSE score (Mercuri et al. (2016) Neuromuscul Disord. 26(2):126-131). Among patients with type 2 and type 3 SMA who did not receive disease-modifying therapy, a deterioration in both upper limb muscle strength and MFM32 scores was observed over a 24-month natural history (Annoussamy et al. (2020) Annals of Clinical and Translational Neurology 8:359-373).

[0156] Against this background, nusinersen has been reported to provide limited clinical benefit in patients who initiated this therapy at age 5 years or older. More specifically, in the CHERISH study, patients who initiated nusinersen at age 5 years or older experienced a worsening of the mean HFMSE score of more than 0.5 points after 15 months of nusinersen treatment, with fewer than 15% experiencing an increase of 3 or more points in their HFMSE score during this period (Mercuri et al. (2018) N Engl J Med. 378:625-635, e.g., Figure 2A). These patients were observed even beyond 15 months in this prior study. In the CHERISH study, the majority of patients in this age group did not experience improvement in the HFMSE score, and an increase of 3 or more points was rare.

[0157] Nusinersen treatment has been shown to improve motor function during the first year of treatment, then plateau. In the initial CHERISH study and the subsequent SHINE study, subjects achieved a 3.9-point increase (mean ± SE) in HFSME score from baseline after the first 450 days of nusinersen treatment and a 4.6-point increase (mean ± SE) from baseline after 1650 days of treatment. Thus, after approximately one year of treatment, nusinersen provided a long-term improvement in HFSME of less than one point (Mercuri et al., presented at World Muscle Society Congress 2020, p. 257).

[0158] Figure 1 shows that disease burden persists after SMA treatment. The bottom gray bar represents the baseline HFMSE score observed after 15 months of treatment with nusinersen in the Phase 3 CHERISH trial. The solid black bar above it represents the mean improvement in HFMSE score in patients with type 2 and nonambulatory type 3 SMA. The diagonal bar indicates that these patients have room for improvement to reach the maximum possible score of 66. Thus, mobility limitations persist (Darras et al. (2019) Neurology 92(21):e2492-e2506). Furthermore, limitations in mobility and daily activities persist and are associated with a gradual deterioration of motor function (Yang et al. (2022) Adv Ther 39:1915; Wan et al. (2020) Orphanet J Rare Dis 15:70).

[0159] The SUNFISH study, reporting on the efficacy and safety of risdiplam in patients with type 2 and non-ambulatory type 3 SMA after 24 months of treatment, showed no improvement in 32 motor function performance outcomes (MFM32) between 12 and 24 months (Oskoui et al. (2023) J. Neurol. https: / / doi.org / 10.1007 / s00415-023-11560-1). The mean change in MFM32 from baseline was 1.7 points (0.8-2.5 points; 95% CI) at 12 months and 1.8 points (0.7-2.9 points; 95% CI) at 24 months. Nusinersen and risdiplam data consistently show that treatment with SMN therapy results in an initial period of improvement followed by disease stabilization, but improvement is limited or not sustained, unless initiated at an early age (Mercuri et al. (2018) N Engl J Med 378(7):625-635; Mercuri et al. (2020) 2 ndInt'l Sci Clin Cong SMA). Thus, long-term treatment with SMN-targeted therapies appears to initially improve and then stabilize the disease, which may prevent further loss of motor function, for example. Additional therapies to improve motor function in patients treated with SMN-targeted therapies continue to be needed (Mercuri et al. SUNFISH Part 2, presented at Amer Acad Neurol 2020).

[0160] Add-on / adjuvant therapy, combination therapy The present disclosure includes add-on therapy (also referred to as adjunctive therapy) and combination therapy, which include a first agent that is a motor neuron-directed therapy (e.g., SMN therapy) and a second agent that is a muscle-targeted therapy (e.g., a myostatin inhibitor, e.g., apitegromab) for the purpose of treating SMA in a patient. The use of these two agents in conjunction with each other enhances the therapeutic effect. Add-on or adjunctive therapy refers to a therapy administered to a patient while they are still undergoing background therapy. For example, a muscle-targeted therapy such as apitegromab may be administered to an SMA patient who is already receiving SMN therapy. In comparison, combination therapy refers to the administration of both therapies to a patient as part of a treatment regimen arranged or predetermined by a physician or team of physicians. The combination therapy and add-on therapy may be administered separately or in the same setting, e.g., during the same clinical visit.

[0161] In various embodiments, the present disclosure provides the use of an anti-promyostatin / anti-latent myostatin antibody (e.g., apitegromab) for the treatment of SMA in patients who are also receiving a motor neuron-directed therapy, e.g., a therapy that addresses motor neuron loss, such as an SMN-upregulating drug. The present disclosure encompasses methods of treating SMA in a subject being treated with an SMN-upregulating drug, the methods comprising administering an anti-promyostatin / anti-latent myostatin antibody. In various embodiments, the anti-promyostatin / anti-latent myostatin antibody is apitegromab.

[0162] In various embodiments, the disclosure provides the use of an anti-latent myostatin antibody (e.g., GYM329) for the treatment of SMA in patients who are also receiving a motor neuron-directed therapy, e.g., a therapy that addresses motor neuron loss, such as an SMN-upregulating drug. The disclosure encompasses methods of treating SMA in a subject being treated with an SMN-upregulating drug, comprising administering an anti-latent myostatin antibody. In various embodiments, the anti-promyostatin / anti-latent myostatin antibody is GYM329.

[0163] In some embodiments, apitegromab used in conjunction with SMN therapy provides an additive clinical benefit. In some embodiments, apitegromab used in conjunction with SMN therapy provides a synergistic clinical benefit. "Synergistic" means that when two agents are used in conjunction with each other, either as add-on or combination therapy, they together achieve an efficacy that is greater than the sum of the effects achieved by each agent alone.

[0164] Apitegromab can be administered to SMA patients who are either responders, poor responders, or non-responders to SMN-upregulator therapy. For poor or non-responders, simultaneous inhibition of myostatin signaling may improve neuromuscular signaling, in part due to enhanced muscle function, thereby making the motor neurons innervating non-responders more responsive to SMN-upregulators. Without wishing to be bound by any particular theory, it is contemplated that enhancement of the muscle component may affect the neuronal component through positive feedback, and vice versa due to the bidirectional nature of neuromuscular signaling.

[0165] Although poor and / or non-responders to SMN upregulators may nonetheless benefit from myostatin inhibition, exemplary patient populations include those who are responders to SMN upregulators. It is contemplated that motor function in these individuals may be further improved by myostatin inhibitor therapy, such as apitegromab, used in conjunction with a motor neuron-directed therapy, such as SMN upregulator therapy.

[0166] The phrase "in conjunction with," in the context of a treatment regimen for SMA that includes two or more therapeutic agents (e.g., apitegromab used in conjunction with an SMN-upregulator therapy), means that in a subject receiving those two or more therapies, the therapeutic effect of the first therapy overlaps in time and / or space with the therapeutic effect of the second and / or additional therapy. The two or more therapies need not be administered as a single formulation, nor need they be administered simultaneously or by the same route. The first, second, and / or additional compositions may be administered in combination (e.g., simultaneously), separately, or sequentially. Thus, the two or more therapies may be formulated as a single formulation for combined administration, or as separate formulations of the therapies for sequential, combined, or simultaneous administration. When a subject who has been treated with a first therapy to treat SMA (e.g., apitegromab) is administered a second additional therapy to treat SMA (e.g., an SMN upregulator therapy), the second additional therapy may be referred to as an "add-on" therapy or an "adjunctive" or "supportive" therapy.

[0167] In some embodiments, treatment regimens described herein that include two or more therapeutic agents (e.g., apitegromab used in conjunction with an SMN-targeted therapy, such as an upregulatory drug therapy) achieve improved clinical benefit in patients compared to monotherapy using each agent alone. Specifically, targeting affected muscles with a myostatin inhibitory therapy, such as apitegromab, in conjunction with a motor neuron-directed therapy, such as an SMN-upregulatory drug therapy, can produce beneficial clinical outcomes compared to the myostatin inhibitory therapy or the motor neuron-directed therapy alone. Such effects can be additive or synergistic compared to each monotherapy. In some embodiments, the effect of combining two or more therapies is additive, i.e., the effect of the therapies used together is equal to or approximately equal to the sum of the effects of the therapies when used independently. In some embodiments, the effect of combining two or more therapies is synergistic, i.e., superadditive, i.e., the effect of therapies used together is greater than the sum of the effects of the therapies when used independently.

[0168] In some embodiments, the one or more beneficial therapeutic effects of using apitegromab in combination with SMN-upregulator therapy (e.g., effect on at least one symptom or risk / rate of disease progression) are additive. In some embodiments, the one or more beneficial therapeutic effects of using apitegromab in combination with SMN-upregulator therapy (e.g., effect on at least one symptom or risk / rate of disease progression) are synergistic. In some embodiments, apitegromab used in combination with SMN-upregulator therapy provides a combined effect that is additive, synergistic, and / or provides one or more additional combined benefits. In some embodiments, apitegromab used in combination with SMN-upregulator therapy provides an additive or synergistic effect on at least one efficacy parameter of SMA (e.g., HFMSE score or RULM score). In some embodiments, apitegromab used in combination with SMN-upregulator therapy provides an additive or synergistic effect on HFMSE score in SMA patients and / or SMA patient populations. In some embodiments, apitegromab used in conjunction with SMN upregulator therapy provides a further increase in HFMSE score when compared to treatment with SMN upregulator therapy alone (see, e.g., Example 1; see also Darras et al. (2019) Neurology. 92(21) e2492-e2506). In some embodiments, the further improvement in HFMSE score is additive. In some embodiments, the further improvement in HFMSE score is synergistic. In some embodiments, the use of apitegromab in conjunction with SMN therapy provides an additive or synergistic effect on the RULM score of SMA patients and / or SMA patient populations. In some embodiments, the use of apitegromab in conjunction with SMN therapy provides a further increase in the RULM score when compared to treatment with SMN therapy alone. In some embodiments, the further improvement in the RULM score is additive. In some embodiments, the further improvement in the RULM score is synergistic.In some embodiments, the use of apitegromab in combination with SMN therapy provides an additive or synergistic effect on the RULM score in SMA patients over at least 24 months, and optionally, the combination therapy improves the RULM score over 24 months, or the combination therapy maintains the increase in RULM score over 24 months.

[0169] Patient Selection The present disclosure includes the identification or selection of human subjects suitable for treatment with a selective myostatin inhibitor, such as apitegromab. Suitable human subjects are patients who are likely to benefit from apitegromab therapy, either as monotherapy or in conjunction with (or in combination with) another therapy.

[0170] In some embodiments, the patient or patient population is an early-onset or infantile-onset SMA patient or patient population. In some embodiments, the patient or patient population is a late-onset SMA patient or patient population. In some embodiments, the patient or patient population is a Type 2 SMA patient or patient population. In some embodiments, the patient or patient population is a non-ambulatory Type 3 SMA patient or patient population. In some embodiments, the patient or patient population is an ambulatory Type 3 SMA patient or patient population. In some embodiments, the patient or patient population is an ambulatory late-onset SMA patient or patient population. In some embodiments, the patient or patient population is a non-ambulatory patient or patient population. In some embodiments, the patient or patient population is a pre-symptomatic or asymptomatic patient or patient population. In some embodiments, the patient or patient population is a symptomatic patient or patient population. In some embodiments, the patient or patient population has more than one copy of the SMN2 gene, e.g., 2-3 copies, 2-4 copies, 3-4 copies, etc. In some embodiments, the patient or patient population has late-onset SMA and has two or more copies of the SMN2 gene, for example, 2-3 copies, 2-4 copies, 3-4 copies, etc.

[0171] SMA patients likely to benefit from such therapy include those who meet one or more of the following criteria: have a documented diagnosis of SMA and late-onset (e.g., type 2 or 3) SMA; non-ambulatory subjects who are able to sit independently as defined by the WHO motor milestones; ambulatory subjects who can walk 10 meters independently without support in 30 seconds or less; subjects with an RHS score of 63 or less and / or an HFMSE score of 10 or more (e.g., HFMSE score ≥ 10 and ≤ 45 at screening); subjects who have not used tracheostomy positive pressure ventilation or chronic daytime non-invasive ventilatory support for more than 16 hours per day within 2 weeks prior to treatment; subjects who have no acute or coexisting medical conditions within 2 weeks prior to treatment that would interfere with the subject's well-being; subjects who have no severe scoliosis or contractures; and / or subjects who have not used systemic corticosteroids, valproic acid, or any therapy with potential muscle or neuromuscular effects within 60 days other than approved SMN-upregulator (also known as SMN-modifying) therapy. Potential therapies with muscle or neuromuscular effects include androgens, insulin-like growth factors, growth hormones, systemic beta-agonists, botulinum toxin, muscle relaxants, muscle-building supplements, or acetylcholinesterase inhibitors. In some embodiments, the patient has a documented diagnosis of 5q SMA and late-onset (e.g., type 2 or 3) SMA prior to receiving therapy for SMA and meets one or more of the additional criteria listed above. In some embodiments, for example, in type 2 SMA patients, there is a positive correlation between age-normalized changes in motor function and age-normalized fold changes in latent myostatin levels. In various embodiments, the methods disclosed herein include selecting one or more such patients or patient populations for treatment with a myostatin inhibitor, such as apitegromab, for example, according to the dosages or regimens disclosed herein.

[0172] SMA patients who may respond to apitegromab therapy, either as monotherapy or in conjunction with (or in combination with) another therapy, include those aged 2 years or younger with any form of SMA, as well as those who exhibit the SMA type 1 phenotype or have three or fewer copies of SMN2. In some embodiments, apitegromab may have enhanced therapeutic efficacy in younger patients, e.g., those under 21 years of age, due to higher background anabolic activity in these patients. In some embodiments, younger patients, e.g., patients under 21 years of age, or patients with anabolic activity, receive apitegromab therapy. In some embodiments, the patient is 2 years of age or younger, e.g., between birth and 24 months of age. In some embodiments, the patient is 6 weeks of age or younger, e.g., between birth and 6 weeks of age. In some embodiments, the patient is 2 to 21 years of age. In some embodiments, the patient is 13 to 21 years of age. In some embodiments, the patient is 12 years of age or younger. In some embodiments, the patient is between 2 and 12 years of age. In some embodiments, the patient is between 5 and 12 years of age. In some embodiments, apitegromab may be particularly effective in patients before the onset of puberty (e.g., before 12 years of age). In some embodiments, apitegromab treatment may be effective in preventing the dramatic deterioration in motor function associated with the onset of puberty in younger patients (e.g., patients younger than 12 years of age). In some embodiments, the patient is about 2 years of age. In some embodiments, the patient is younger than 2 years of age. In some embodiments, the patient exhibits the SMA type 1 phenotype. In some embodiments, the patient has three or fewer copies of SMN2. In various embodiments, the methods disclosed herein include selecting one or more such patients or patient populations for treatment with a myostatin inhibitor, such as apitegromab, e.g., according to the dosages or regimens disclosed herein.

[0173] Patients who may respond to apitegromab therapy, either as monotherapy or in combination with another therapy, include patients with type 2 SMA who have a baseline (i.e., prior to initiation of apitegromab therapy) serum latent myostatin (LM) concentration of at least 1 ng / mL (e.g., greater than 1.5 ng / mL, greater than 2 ng / mL, greater than 2.5 ng / mL, greater than 3 ng / mL, or higher). In some embodiments, apitegromab therapy, either as monotherapy or in combination with another therapy, may be more effective in patients with higher baseline serum LM concentrations compared to patients with lower baseline serum LM concentrations. In some embodiments, such therapy may be particularly effective in patients younger than 12 years of age. In some embodiments, such therapy may be particularly effective in patients aged 2-5 years. In some embodiments, such therapy may be particularly effective in type 2 SMA patients aged 12-21 years. In some embodiments, such therapy may be particularly effective in Type 3 SMA patients aged 12 to 21 years. In some embodiments, such therapy may be particularly effective in non-ambulatory patients aged 2 to 21 years. In some embodiments, such therapy may be particularly effective in non-ambulatory patients aged 2 to 12 years. In some embodiments, such therapy may be particularly effective in Type 2 and Type 3 non-ambulatory patients aged 2 to 21 years. In some embodiments, such therapy may be effective in patients under the age of 2 years. In some embodiments, Type 2 SMA patients under the age of 12 years and with baseline serum LM concentrations of at least 1 ng / mL (e.g., greater than 1.5 ng / mL, greater than 2 ng / mL, greater than 2.5 ng / mL, greater than 3 ng / mL, or higher) may respond to apitegromab therapy. In some embodiments, type 2 SMA patients younger than 2 years of age and with baseline serum LM concentrations of at least 1 ng / mL (e.g., greater than 1.5 ng / ml, greater than 2 ng / ml, greater than 2.5 ng / ml, greater than 3 ng / ml, or higher) may respond to apitegromab therapy.In some embodiments, apitegromab therapy includes administering more than 2 mg / kg of apitegromab, for example, 10 mg / kg or 20 mg / kg.

[0174] In some embodiments, methods of treating SMA include administering apitegromab therapy, either as monotherapy or in conjunction with another therapy, to patients with a baseline serum LM concentration of at least 1 ng / mL (e.g., greater than 1.5 ng / mL, greater than 2 ng / mL, greater than 2.5 ng / mL, greater than 3 ng / mL, or higher). In some embodiments, methods of treating SMA include administering apitegromab therapy, either as monotherapy or in conjunction with another therapy, to patients younger than 12 years of age who have a baseline serum LM concentration of at least 1 ng / mL (e.g., greater than 1.5 ng / mL, greater than 2 ng / mL, greater than 2.5 ng / mL, greater than 3 ng / mL, or higher). In some embodiments, methods of treating SMA include administering apitegromab therapy, either as monotherapy or in conjunction with (or in combination with) another therapy, to patients younger than 2 years of age who have a baseline serum LM concentration of at least 1 ng / mL (e.g., greater than 1.5 ng / mL, greater than 2 ng / mL, greater than 2.5 ng / mL, greater than 3 ng / mL, or higher). In some embodiments, the apitegromab therapy includes administering greater than 2 mg / kg of apitegromab, e.g., 10 mg / kg or 20 mg / kg.

[0175] In some embodiments, apitegromab is used to treat SMA, either as monotherapy or in conjunction with another therapy, in patients with a baseline serum LM concentration of at least 1 ng / mL (e.g., greater than 1.5 ng / mL, greater than 2 ng / mL, greater than 2.5 ng / mL, greater than 3 ng / mL, or higher). In some embodiments, apitegromab is used to treat SMA, either as monotherapy or in conjunction with another therapy, in patients under the age of 12 with a baseline serum LM concentration of at least 1 ng / mL (e.g., greater than 1.5 ng / mL, greater than 2 ng / mL, greater than 2.5 ng / mL, greater than 3 ng / mL, or higher). In some embodiments, apitegromab is used to treat SMA, either as monotherapy or in conjunction with (or in combination with) another therapy, in patients under the age of 2 years with a baseline serum LM concentration of at least 1 ng / mL (e.g., greater than 1.5 ng / mL, greater than 2 ng / mL, greater than 2.5 ng / mL, greater than 3 ng / mL, or higher). In some embodiments, apitegromab is suitable for administration at greater than 2 mg / kg of apitegromab, for example, 10 mg / kg or 20 mg / kg.

[0176] In various embodiments, the SMA patient (e.g., any of the exemplary SMA patients described above) is currently on (is receiving) or has previously been treated with an SMN-targeted therapy. In some embodiments, the SMN-targeted therapy includes nusinersen, risdiplam, and / or onasemnogene abeparvovec. In some embodiments, the patient is currently on (is receiving) or has previously been treated with nusinersen. In some embodiments, the patient has previously been treated with nusinersen. In some embodiments, the patient is currently on (is receiving) or has previously been treated with risdiplam. In some embodiments, the patient is currently on (is receiving) or has previously been treated with onasemnogene abeparvovec.

[0177] In various embodiments, the present disclosure provides methods of treating one or more patients or patient populations with a myostatin inhibitor, such as apitegromab, alone or in conjunction with (or in combination with) an SMN-targeted therapy, wherein the one or more patients or patient populations meet one or more of the following criteria: have any form of SMA at age 2 years or less, exhibit an SMA type 1 phenotype, and / or have three or fewer copies of SMN2. In some embodiments, the treatment includes apitegromab therapy as monotherapy, e.g., according to the dosages or regimens disclosed herein. In some embodiments, the treatment includes apitegromab therapy in conjunction with (or in combination with) an SMN-targeted therapy, such as nusinersen, risdiplam, or onasemnogene abeparvovec, e.g., according to the dosages or regimens disclosed herein. In some embodiments, the patient is currently receiving or has previously been treated with nusinersen. In some embodiments, the patient has previously been treated with nusinersen. In some embodiments, the patient is currently undergoing treatment with (is currently receiving) or has previously been treated with) risdiplam. In some embodiments, the patient has previously been treated with risdiplam. In some embodiments, the patient has previously been administered onasemnogene abeparvovec.

[0178] In some embodiments, the patient is symptomatic or pre-symptomatic.

[0179] Presymptomatic patients include those who have been genetically identified as carriers of one or more mutations in the SMN1 gene, either alone or in combination with the identification of one or more additional genetic modifications (e.g., SMN2 copy number determination). Genetic identification of SMA patients may be performed as part of newborn or in utero screening. At the time of identification (e.g., diagnosis), the patient (e.g., newborn) may not exhibit overt / overt symptoms (asymptomatic), but based on genetic characteristics and possibly other factors, the patient may be predicted to develop the disease.

[0180] In severe cases, newborn babies may already show signs of the disease (i.e., be symptomatic). Typically, such patients, based on the natural history of SMA, are likely to have Type 1 SMA and would generally not be expected to acquire the ability to sit independently without intervention.

[0181] In some embodiments, the patient is a neonatal patient (age 0-6 months). In some embodiments, the patient is a fetus. In some embodiments, the patient is a pediatric patient, age 6 months to 17 years. In some embodiments, the patient is under 5 years of age. Optionally, the patient is 5 years of age or younger, e.g., 2-5 years of age. In some embodiments, the patient is 2 years of age or younger, e.g., birth to 24 months of age. In some embodiments, the patient is 6 weeks of age or younger, e.g., birth to 6 weeks of age. In some embodiments, the patient is 2 years of age or older. In some embodiments, the patient is 2-10 years of age. In some embodiments, the patient is 2-12 years of age. In some embodiments, the patient is 13-21 years of age. In some embodiments, the patient is 5 years of age or older, e.g., 5-17 years of age. In some embodiments, the patient is 5-21 years of age. In some embodiments, the patient is an adult.

[0182] In some embodiments, the patient has not received or is not being treated with an SMN-modifying drug therapy, such as an SMN2 upregulator and / or SMN1 gene therapy. In some embodiments, the patient has received or is being treated with an SMN-modifying drug therapy, such as an SMN2 upregulator and / or SMN1 gene therapy. In some embodiments, the patient begins or has begun SMN-modifying drug therapy at the age of less than 5 years. In some embodiments, the patient begins or has begun SMN-modifying drug therapy at the age of 5 years or older.

[0183] In some embodiments, the patient exhibits disease progression, such as worsening motor function, as indicated by a decrease of 1 or more points in a motor function assessment test score (e.g., HFMSE, RHS, and / or RULM score) over a 12-month or 24-month period prior to treatment with a selective myostatin inhibitor, such as apitegromab.

[0184] In some embodiments, the patient treated herein is in a period of stable disease progression, e.g., the rate of deterioration of motor function (e.g., as measured by HFMSE and RHS scores) has not changed significantly for at least six months prior to initiation of treatment with a selective myostatin inhibitor (e.g., apitegromab). In some embodiments, the patient exhibits stable disease, e.g., the rate of deterioration of the patient's motor function (e.g., as measured by HFMSE and RHS scores) has not changed significantly for at least six months prior to initiation of treatment with a selective myostatin inhibitor (e.g., apitegromab). In some embodiments, the patient has non-ambulatory SMA. In some embodiments, the patient has Type 2 or Type 3 non-ambulatory SMA. In some embodiments, the patient has ambulatory SMA. In some embodiments, the patient has Type 3 ambulatory SMA. In some embodiments, the patient initiated SMN upregulator / modifier therapy at less than five years of age. In some embodiments, the patient initiated SMN upregulator / modifier therapy at age five or greater. In some embodiments, the patient is two years of age or younger, e.g., between birth and 24 months of age. In some embodiments, the patient is between 2 and 12 years of age. In some embodiments, the patient is 6 weeks of age or younger, e.g., between birth and 6 weeks of age. In some embodiments, the patient is between 2 and 12 years of age and initiated SMN upregulator / modifier therapy (e.g., nusinersen, risdiplam, or onasemnogene abeparvovec) at age less than 5 years of age. In some embodiments, the patient is between 2 and 12 years of age and initiated SMN upregulator / modifier therapy (e.g., nusinersen, risdiplam, or onasemnogene abeparvovec) at age 5 or later. In some embodiments, the patient is between 5 and 12 years of age and initiated SMN upregulator / modifier therapy (e.g., nusinersen, risdiplam, or onasemnogene abeparvovec) at age 5 or later.

[0185] In some embodiments, the patient is a 5q spinal muscular atrophy (SMA) patient with a biallelic mutation in the SMN1 gene and a clinical diagnosis of SMA type 1, or the patient is a 5q SMA patient with a biallelic mutation in the SMN1 gene and three or fewer copies of the SMN2 gene. Such patients may be treated with a selective myostatin inhibitor in conjunction with gene therapy (e.g., SMN1 gene therapy). In some embodiments, the patient weighs between 2.6 kg and 21.0 kg at the time of receiving gene therapy. In some embodiments, the patient's motor milestones may be monitored, such as being able to hold the head up, rolling from back to side, sitting unsupported for 30 seconds, sitting unsupported for at least 10 seconds, etc.

[0186] In some embodiments, the patient is a type 2 SMA patient who is able to sit but has never walked, wherein the patient is between 2 and 18 years of age. In some embodiments, SMN1 gene therapy is used to treat type 2 SMA in a patient between 2 and 18 years of age who is able to sit but has never achieved the ability to walk, and wherein the patient is treated with a myostatin inhibitor, wherein optionally the myostatin inhibitor is a myostatin-selective inhibitor such as apitegromab, GYM329, trevoglumab, or a variant of any one of the foregoing. In some embodiments, myostatin inhibitors are used to treat type 2 SMA in a patient between 2 and 18 years of age who is able to sit but has never achieved the ability to walk, and wherein the patient is treated with SMN1 gene therapy, wherein optionally the SMN1 gene therapy comprises onasemnogene abeparvovec. In preferred embodiments, the myostatin inhibitor is a myostatin-selective inhibitor, such as apitegromab, GYM329, trevoglumab, or a variant of any one of the foregoing. In some embodiments, SMN1 gene therapy and a myostatin inhibitor are used as combination therapy in the treatment of SMA in patients aged 2 to 18 years who are able to sit but have never acquired the ability to walk, and wherein the patient is treated with a myostatin inhibitor, optionally wherein the myostatin inhibitor is a myostatin-selective inhibitor, such as apitegromab, GYM329, trevoglumab, or a variant of any one of the foregoing, and further optionally wherein the SMN1 gene therapy comprises onasemnogene abeparvovec. In some embodiments, antibody variants may have significant nucleic acid and / or amino acid sequence homology (e.g., >90% sequence identity) when compared to known antibodies, and retain one or more physical and / or functional properties.

[0187] In some embodiments, the patient exhibits stable disease as determined by motor function, such as no significant change in motor function test scores (e.g., HFMSE and RHS scores) for at least six months prior to treatment with a selective myostatin inhibitor, such as apitegromab. In some embodiments, the patient has received or is being treated with an SMN-modifying drug therapy.

[0188] In some embodiments, the patient has undergone spinal fusion surgery, for example, primary posterior spinal fusion surgery.

[0189] According to the present disclosure, patient selection or classification may be based on highest achieved motor milestone relative to smn2 gene copy number. Accordingly, the present disclosure includes the therapeutic use of a myostatin-selective inhibitor (such as apitegromab, GYM329, or trevogrumab) in treating SMA in patients, where treatment involves administration of a composition comprising a myostatin-selective inhibitor. In a preferred embodiment, the myostatin-selective inhibitor is apitegromab, which may be administered intravenously at a therapeutic dose, where the therapeutic dose is greater than 2 mg / kg and less than or equal to 20 mg / kg (e.g., 10 mg / kg). In some embodiments, the patient has 1, 2, 3, or 4 copies of the smn2 gene and has gross motor milestones: 1) head up / support (i.e., neck stability, e.g., the ability to hold or hold the head up while lying supine); 2) roll over; 3) sit tripod (e.g., using hands to support body while sitting) or sit with support; 4) sit unsupported; 5) stand with support / assistance; 6) crawl / crawl; 7) stand with support ;8) Walk with assistance (e.g., cling to furniture); 9) Stand without support; 10) Take a few steps on one's own but fall; 11) Walk independently (e.g., walk independently, walk without support); 12) Crouch down to pick up an object (e.g., a toy); 13) Walk / crawl up and down stairs on all fours; 14) Run; 15) Jump; 16) Climb stairs with alternating feet; 17) Hop on one foot; 18) Descend stairs with alternating feet.

[0190] In some embodiments, the patient has one copy of the smn2 gene and the highest motor milestone achieved is sitting up or keeping the head up while lying face down. In some embodiments, the patient has one copy of the smn2 gene and the highest motor milestone achieved is rolling over. In some embodiments, the patient has one copy of the smn2 gene and the highest motor milestone achieved is sitting with support. In some embodiments, the patient has one copy of the smn2 gene and the highest motor milestone achieved is sitting without support. In some embodiments, the patient has one copy of the smn2 gene and the highest motor milestone achieved is standing with support. In some embodiments, the patient has one copy of the smn2 gene and the highest motor milestone achieved is crawling. In some embodiments, the patient has one copy of the smn2 gene and the highest motor milestone achieved is standing up. In some embodiments, the patient has one copy of the smn2 gene and the highest motor milestone achieved is walking with assistance. In some embodiments, the patient has one copy of the smn2 gene and the highest motor milestone achieved is standing without support. In some embodiments, the patient has one copy of the smn2 gene and the highest motor milestone achieved is walking independently (without support). In some embodiments, the patient has one copy of the smn2 gene and the highest motor milestone achieved is running. In some embodiments, the patient has one copy of the smn2 gene and the highest motor milestone achieved is jumping. In some embodiments, the patient has one copy of the smn2 gene and the highest motor milestone achieved is climbing stairs with alternating feet. In some embodiments, the patient has one copy of the smn2 gene and the highest motor milestone achieved is hopping on one foot. In some embodiments, the patient has one copy of the smn2 gene and the highest motor milestone achieved is descending stairs with alternating feet.

[0191] In some embodiments, the patient has two copies of the smn2 gene and the highest motor milestone achieved is sitting up or keeping the head up while lying face down. In some embodiments, the patient has two copies of the smn2 gene and the highest motor milestone achieved is rolling over. In some embodiments, the patient has two copies of the smn2 gene and the highest motor milestone achieved is sitting with support. In some embodiments, the patient has two copies of the smn2 gene and the highest motor milestone achieved is sitting without support. In some embodiments, the patient has two copies of the smn2 gene and the highest motor milestone achieved is standing with support. In some embodiments, the patient has two copies of the smn2 gene and the highest motor milestone achieved is crawling. In some embodiments, the patient has two copies of the smn2 gene and the highest motor milestone achieved is standing up. In some embodiments, the patient has two copies of the smn2 gene and the highest motor milestone achieved is walking with assistance. In some embodiments, the patient has two copies of the smn2 gene and the highest motor milestone achieved is standing without support. In some embodiments, the patient has two copies of the smn2 gene and the highest motor milestone achieved is walking independently (without support). In some embodiments, the patient has two copies of the smn2 gene and the highest motor milestone achieved is running. In some embodiments, the patient has two copies of the smn2 gene and the highest motor milestone achieved is jumping. In some embodiments, the patient has two copies of the SMN2 gene and the highest motor milestone achieved is climbing stairs with alternating feet. In some embodiments, the patient has two copies of the SMN2 gene and the highest motor milestone achieved is hopping on one foot. In some embodiments, the patient has two copies of the SMN2 gene and the highest motor milestone achieved is descending stairs with alternating feet.

[0192] In some embodiments, the patient has three copies of the SMN2 gene and the highest motor milestone achieved is sitting up or keeping the head up while lying face down. In some embodiments, the patient has three copies of the SMN2 gene and the highest motor milestone achieved is rolling over in bed. In some embodiments, the patient has three copies of the SMN2 gene and the highest motor milestone achieved is sitting with support. In some embodiments, the patient has three copies of the SMN2 gene and the highest motor milestone achieved is sitting without support. In some embodiments, the patient has three copies of the SMN2 gene and the highest motor milestone achieved is standing with support. In some embodiments, the patient has three copies of the SMN2 gene and the highest motor milestone achieved is crawling. In some embodiments, the patient has three copies of the SMN2 gene and the highest motor milestone achieved is standing up with support. In some embodiments, the patient has three copies of the SMN2 gene and the highest motor milestone achieved is walking with assistance. In some embodiments, the patient has three copies of the SMN2 gene and the highest motor milestone achieved is standing without support. In some embodiments, the patient has three copies of the SMN2 gene and the highest motor milestone achieved is walking unaided (without support). In some embodiments, the patient has three copies of the SMN2 gene and the highest motor milestone achieved is running. In some embodiments, the patient has three copies of the SMN2 gene and the highest motor milestone achieved is jumping. In some embodiments, the patient has three copies of the SMN2 gene and the highest motor milestone achieved is climbing stairs with alternating feet. In some embodiments, the patient has three copies of the smn2 gene and the highest motor milestone achieved is hopping on one foot. In some embodiments, the patient has three copies of the smn2 gene and the highest motor milestone achieved is descending stairs with alternating feet.

[0193] In some embodiments, the patient has four copies of the smn2 gene and the highest motor milestone achieved is sitting with support. In some embodiments, the patient has four copies of the smn2 gene and the highest motor milestone achieved is sitting without support. In some embodiments, the patient has four copies of the smn2 gene and the highest motor milestone achieved is standing with support. In some embodiments, the patient has four copies of the smn2 gene and the highest motor milestone achieved is crawling. In some embodiments, the patient has four copies of the smn2 gene and the highest motor milestone achieved is standing up. In some embodiments, the patient has two copies of the smn2 gene and the highest motor milestone achieved is walking with assistance. In some embodiments, the patient has four copies of the smn2 gene and the highest motor milestone achieved is standing without support. In some embodiments, the patient has four copies of the smn2 gene and the highest motor milestone achieved is walking independently (without support). In some embodiments, the patient has four copies of the smn2 gene and the highest athletic milestone achieved is running. In some embodiments, the patient has four copies of the smn2 gene and the highest athletic milestone achieved is jumping. In some embodiments, the patient has four copies of the smn2 gene and the highest athletic milestone achieved is climbing stairs with alternating feet. In some embodiments, the patient has four copies of the smn2 gene and the highest athletic milestone achieved is hopping on one foot. In some embodiments, the patient has four copies of the smn2 gene and the highest athletic milestone achieved is descending stairs with alternating feet.

[0194] In some embodiments, the patient has more than four copies of the smn2 gene and the highest motor milestone achieved is sitting with support. In some embodiments, the patient has more than four copies of the smn2 gene and the highest motor milestone achieved is sitting without support. In some embodiments, the patient has more than four copies of the smn2 gene and the highest motor milestone achieved is standing with support. In some embodiments, the patient has more than four copies of the smn2 gene and the highest motor milestone achieved is crawling. In some embodiments, the patient has more than four copies of the smn2 gene and the highest motor milestone achieved is standing with support. In some embodiments, the patient has more than four copies of the smn2 gene and the highest motor milestone achieved is walking with assistance. In some embodiments, the patient has more than four copies of the smn2 gene and the highest motor milestone achieved is standing without support. In some embodiments, the patient has more than four copies of the smn2 gene and the highest motor milestone achieved is walking unaided (without support). In some embodiments, the patient has more than four copies of the smn2 gene and the highest motor milestone achieved is running. In some embodiments, the patient has more than four copies of the smn2 gene and the highest motor milestone achieved is jumping. In some embodiments, the patient has more than four copies of the smn2 gene and the highest motor milestone achieved is climbing stairs with alternating feet. In some embodiments, the patient has more than four copies of the smn2 gene and the highest motor milestone achieved is hopping on one foot. In some embodiments, the patient has more than four copies of the smn2 gene and the highest motor milestone achieved is descending stairs with alternating feet.

[0195] In some embodiments, the patient has one copy of the smn2 gene and has achieved the WHO motor milestone of walking unaided. In some embodiments, the patient has one copy of the smn2 gene and has achieved the WHO motor milestone of standing unaided. In some embodiments, the patient has one copy of the smn2 gene and has achieved the WHO motor milestone of standing with assistance. In some embodiments, the patient has one copy of the smn2 gene and has achieved the WHO motor milestone of crawling on hands and knees. In some embodiments, the patient has one copy of the smn2 gene and has achieved the WHO motor milestone of walking with assistance.

[0196] In some embodiments, the patient has two copies of the smn2 gene and has achieved the WHO motor milestone of walking unaided. In some embodiments, the patient has two copies of the smn2 gene and has achieved the WHO motor milestone of standing unaided. In some embodiments, the patient has two copies of the smn2 gene and has achieved the WHO motor milestone of standing with assistance. In some embodiments, the patient has two copies of the smn2 gene and has achieved the WHO motor milestone of crawling on hands and knees. In some embodiments, the patient has two copies of the smn2 gene and has achieved the WHO motor milestone of walking with assistance.

[0197] In some embodiments, the patient has three copies of the smn2 gene and has achieved the WHO motor milestone of walking unaided. In some embodiments, the patient has three copies of the smn2 gene and has achieved the WHO motor milestone of standing unaided. In some embodiments, the patient has three copies of the smn2 gene and has achieved the WHO motor milestone of standing with assistance. In some embodiments, the patient has three copies of the smn2 gene and has achieved the WHO motor milestone of crawling on hands and knees. In some embodiments, the patient has three copies of the smn2 gene and has achieved the WHO motor milestone of walking with assistance.

[0198] In some embodiments, the patient has four copies of the smn2 gene and has achieved the WHO motor milestone of walking unaided. In some embodiments, the patient has four copies of the smn2 gene and has achieved the WHO motor milestone of standing unaided. In some embodiments, the patient has four copies of the smn2 gene and has achieved the WHO motor milestone of standing with assistance. In some embodiments, the patient has four copies of the smn2 gene and has achieved the WHO motor milestone of crawling on hands and knees. In some embodiments, the patient has four copies of the smn2 gene and has achieved the WHO motor milestone of walking with assistance.

[0199] In some embodiments, the patient has more than four copies of the smn2 gene and has achieved the WHO motor development milestone of walking unaided. In some embodiments, the patient has more than four copies of the smn2 gene and has achieved the WHO motor development milestone of standing unaided. In some embodiments, the patient has more than four copies of the smn2 gene and has achieved the WHO motor development milestone of standing with assistance. In some embodiments, the patient has more than four copies of the smn2 gene and has achieved the WHO motor development milestone of crawling on hands and knees. In some embodiments, the patient has more than four copies of the smn2 gene and has achieved the WHO motor development milestone of walking with assistance.

[0200] In some embodiments, the subject is able to sit up or support their head at under 3, 6, 9, or 12 months of age. In some embodiments, the subject is able to roll over at under 6, 9, or 12 months of age. In some embodiments, the subject is able to sit with support or in a tripod position at under 6, 9, or 12 months of age. In some embodiments, the subject is able to sit unsupported at under 6, 9, or 12 months of age. In some embodiments, the subject is able to stand with support at under 9 or 12 months of age. In some embodiments, the subject is able to stand unsupported at under 12 months of age. In some embodiments, the subject is able to crawl on all fours at under 6, 9, or 12 months of age. In some embodiments, the subject is able to stand up under 9 or 12 months of age.

[0201] In some embodiments, the subject is able to walk with assistance at age 12 or 15 months. In some embodiments, the subject is able to walk unassisted at age 12 or 15 months. In some embodiments, the subject is able to run at age 15, 18, or 24 months. In some embodiments, the subject is able to hop at age 15, 18, or 24 months. In some embodiments, the subject is able to crouch to pick up an object at age 15, 18, or 24 months. In some embodiments, the subject is able to walk or crawl up and down stairs at age 15, 18, or 24 months. In some embodiments, the subject is able to climb stairs by alternating feet at age 30 or 36 months (3 years). In some embodiments, the subject is able to descend stairs by alternating feet at age 36 months (3 years). In some embodiments, the subject is able to hop on one foot at age 4 or 5 years.

[0202] The present disclosure provides therapeutic uses of apitegromab in treating SMA in a patient, wherein the treatment comprises intravenous administration of a composition comprising a therapeutic dose of apitegromab, wherein the therapeutic dose is greater than 2 mg / kg and less than or equal to 20 mg / kg (such as 10 mg / kg or 20 mg / kg), and wherein optionally the patient may be selected from any one or more of the following classifications, or wherein the patient is characterized by:

[0203] The patient is 2 years of age or younger, e.g., newborn to 24 months of age, and optionally, the patient has non-ambulatory type 2 or type 3 SMA, and further optionally, the patient is receiving SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec).

[0204] The patient is 2 years of age or younger, e.g., newborn to 24 months of age, and optionally, the patient has ambulatory SMA, and further optionally, the patient is receiving SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec).

[0205] The patient is six weeks of age or younger, eg, a newborn to six weeks of age.

[0206] The patient is 2 years of age or older, and optionally, the patient has non-ambulatory type 2 or type 3 SMA, and further optionally, the patient is receiving SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec).

[0207] The patient is 2 years of age or older, and optionally, the patient has ambulatory SMA, and further optionally, the patient is receiving SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec).

[0208] The patient is between 2 and 21 years of age, optionally, the patient has non-ambulatory type 2 or type 3 SMA, and further optionally, the patient is receiving SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec).

[0209] The patient is between 2 and 21 years of age, optionally, the patient has ambulatory SMA, and further optionally, the patient is receiving SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec).

[0210] Patients are aged 2-12 years, 2-10 years, 2-5 years, or 5-12 years.

[0211] The patient is between 13 and 21 years of age, optionally, the patient has non-ambulatory type 2 or type 3 SMA, and further optionally, the patient is receiving SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec).

[0212] The patient is between 13 and 21 years of age, optionally, the patient has ambulatory SMA, and further optionally, the patient is receiving SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec).

[0213] The patient has late-onset SMA, and optionally, the patient is currently receiving SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec).

[0214] The patient has ambulatory SMA, where optionally the patient is receiving SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec).

[0215] The patient has non-ambulatory SMA, where optionally the patient is currently receiving SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec).

[0216] The patient has type 2 SMA.

[0217] The patient has Type 3 SMA, wherein optionally the patient has non-ambulatory Type 3 SMA.

[0218] The patient has Type 3 SMA, where optionally the patient has ambulatory Type 3 SMA.

[0219] The patient has at least two copies of the SMN2 gene, for example, 2, 3, 4, 5, or 6 copies of the SMN2 gene; or, optionally, wherein the patient has 2-4 copies of the SMN2 gene.

[0220] The patient has at least two copies of the SMN2 gene, for example, two, three, or four copies of the SMN2 gene; or, optionally, the patient has two to four copies of the SMN2 gene, optionally, the patient has SMA type 2 or non-ambulatory SMA type 3.

[0221] The patient has at least three copies of the SMN2 gene, for example, three, four, five, or six copies of the SMN2 gene; or, optionally, the patient has three to five copies of the SMN2 gene, optionally, the patient has ambulatory SMA, and further optionally, the ambulatory SMA is type 4 SMA.

[0222] The patient has SMA (e.g., any type of SMA) and is 2 years of age or younger, where optionally the patient has been treated with SMN therapy, and further optionally the SMN therapy includes an SMN2 upregulator (such as nusinersen, risdiplam, or onasemnogene abeparvovec) or SMN1 gene therapy.

[0223] The patient has type 1 SMA with three or fewer copies of the SMN2 gene, wherein optionally the patient has been treated with SMN therapy, wherein further optionally the SMN therapy comprises an SMN2 upregulator (such as nusinersen, risdiplam, or onasemnogene abeparvovec) or SMN1 gene therapy.

[0224] The patient is symptomatic for SMA.

[0225] The patient has pre-symptomatic SMA.

[0226] Patients are identified as carriers of one or more SMA mutations but are asymptomatic (presymptomatic).

[0227] The patient had not been treated with SMN-targeted therapy.

[0228] The patient is undergoing (is undergoing) or has been treated with an SMN-targeted therapy, where optionally the SMN-targeted therapy is a gene therapy, a splicing modifier, or a combination thereof, and further optionally, where the splicing modifier is a nucleic acid-based drug or a small molecular weight compound that modifies SMN2 splicing.

[0229] The patient is undergoing (is undergoing) or has been treated with an SMN-targeted therapy, where optionally the SMN-targeted therapy is a gene therapy, a splicing modifier, or a combination thereof, and further optionally the splicing modifier is a nucleic acid-based drug or a small molecular weight compound that modifies SMN2 splicing; and where the patient started the SMN-targeted therapy at age less than 5 years.

[0230] The patient is undergoing (is undergoing) or has been treated with an SMN-targeted therapy, where optionally the SMN-targeted therapy is a gene therapy, a splicing modifier, or a combination thereof, and further optionally the splicing modifier is a nucleic acid-based drug or a small molecular weight compound that modifies SMN2 splicing, and where the patient initiated the SMN-targeted therapy at age 5 or older.

[0231] Patients will be undergoing SMN-targeted therapy for at least 12 months at the time of initiation of apitegromab therapy (e.g., before receiving the first dose of apitegromab).

[0232] Patients will be undergoing SMN-targeted therapy for at least 15 months at the time of initiation of apitegromab therapy (e.g., before receiving the first dose of apitegromab).

[0233] Patients will be undergoing ongoing SMN-targeted therapy for at least 24 months at the time of initiation of apitegromab therapy (e.g., prior to receiving the first dose of apitegromab).

[0234] Patients were aged 5 years or younger at the time of initiation of apitegromab therapy.

[0235] Patients were 2 years of age or younger at the time of initiation of apitegromab therapy.

[0236] Patients were 6 weeks of age or younger at the time of initiation of apitegromab therapy.

[0237] Patients will be less than 5 years of age at the time of receiving their first dose of apitegromab.

[0238] The patient has a baseline HFMSE score of at least 10, e.g., at least 13, e.g., a score of 13 to 39, e.g., a score of 39 or less.

[0239] In some embodiments, the disclosure provides therapeutic uses of apitegromab in treating SMA in patients aged 2 to 12 years who have received at least 6 months of SMN-upregulator / modifier therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec) prior to initiation of apitegromab treatment, wherein the apitegromab treatment comprises intravenous administration of a composition comprising 10 mg / kg or 20 mg / kg of apitegromab, e.g., once every 4 weeks or once monthly. In some embodiments, the patient initiated SMN-upregulator / modifier therapy at age less than 5 years. In some embodiments, the patient initiated SMN-upregulator / modifier therapy at age 5 years or greater. In some embodiments, the present disclosure provides therapeutic uses of apitegromab in the treatment of SMA in patients 2 to 12 years of age who received risdiplam for at least 6 months prior to initiating apitegromab treatment, wherein the apitegromab treatment comprises intravenous administration of a composition comprising 10 mg / kg or 20 mg / kg of apitegromab once every 4 weeks or once monthly. In some embodiments, the present disclosure provides therapeutic uses of apitegromab in the treatment of SMA in patients 2 to 12 years of age who received nusinersen, risdiplam, and / or onasemnogene abeparvovec for at least 10 months prior to initiating apitegromab treatment, wherein the apitegromab treatment comprises intravenous administration of a composition comprising 10 mg / kg or 20 mg / kg of apitegromab once every 4 weeks or once monthly.

[0240] In some embodiments, the disclosure provides therapeutic uses of apitegromab in the treatment of SMA in patients aged 5 to 12 years who have been receiving SMN upregulator / modifier therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec) for at least 6 months prior to initiation of apitegromab treatment, wherein the apitegromab treatment comprises intravenous administration of a composition comprising 10 mg / kg or 20 mg / kg apitegromab, e.g., once every 4 weeks or once monthly. In some embodiments, the patient initiated SMN upregulator / modifier therapy at less than 5 years of age. In some embodiments, the patient initiated SMN upregulator / modifier therapy at more than 5 years of age. In some embodiments, the present disclosure provides the therapeutic use of apitegromab in the treatment of SMA in patients 5 to 12 years of age who have received risdiplam for at least 6 months prior to initiating apitegromab treatment, wherein the apitegromab treatment comprises intravenous administration of a composition comprising 10 mg / kg or 20 mg / kg of apitegromab once every 4 weeks or once monthly. In some embodiments, the present disclosure provides the therapeutic use of apitegromab in the treatment of SMA in patients 5 to 12 years of age who have received nusinersen, risdiplam, and / or onasemnogene abeparvovec for at least 10 months prior to initiating apitegromab treatment, wherein the apitegromab treatment comprises intravenous administration of a composition comprising 10 mg / kg or 20 mg / kg of apitegromab once every 4 weeks or once monthly (e.g., for at least 52 weeks).

[0241] In some embodiments, the present disclosure provides therapeutic uses of apitegromab in treating patients with late-onset SMA (e.g., Type 2 or Type 3) who have received an SMN-targeted therapy (e.g., an SMN-upregulator / modifier therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec) for at least six months prior to initiation of apitegromab treatment, wherein the apitegromab treatment comprises intravenous administration of a composition comprising 10 mg / kg or 20 mg / kg apitegromab once every four weeks or once monthly for at least 52 weeks. In some embodiments, the patient has received risdiplam for at least six months prior to initiation of apitegromab treatment. In some embodiments, the patient has received nusinersen, risdiplam, and / or onasemnogene abeparvovec for at least 10 months prior to initiation of apitegromab treatment. In some embodiments, the subject is 2 to 21 years of age. In some embodiments, the patient initiated SMN-targeted therapy at age less than 5 years. In some embodiments, the patient initiated SMN-targeted therapy at age greater than 5 years. In some embodiments, the subject has not previously received onasemnogene abeparvovec or apitegromab.

[0242] In some embodiments, the present disclosure provides therapeutic uses of apitegromab in treating SMA in patients aged 13-21 years who have received risdiplam for at least 6 months prior to initiating apitegromab treatment and have not previously received onasemnogene abeparvovec or apitegromab, wherein the apitegromab treatment comprises intravenous administration of a composition comprising 10 mg / kg or 20 mg / kg apitegromab once every 4 weeks or once monthly, for example, for at least 52 weeks. In some embodiments, the patient initiated risdiplam treatment at less than 5 years of age. In some embodiments, the patient initiated risdiplam treatment at more than 5 years of age.

[0243] In some embodiments, the present disclosure provides therapeutic uses of apitegromab in treating SMA in patients aged 13 to 21 years who have received nusinersen, risdiplam, and / or onasemnogene abeparvovec for at least 10 months prior to initiating apitegromab treatment and have not previously received onasemnogene abeparvovec or apitegromab, wherein the apitegromab treatment comprises intravenous administration of a composition comprising 10 mg / kg or 20 mg / kg apitegromab once every four weeks or once monthly, for example, for at least 52 weeks. In some embodiments, the patient initiated nusinersen, risdiplam, and / or onasemnogene abeparvovec treatment at less than 5 years of age. In some embodiments, the patient initiated nusinersen, risdiplam, and / or onasemnogene abeparvovec treatment at more than 5 years of age.

[0244] In some embodiments, the present disclosure provides therapeutic uses of apitegromab in the treatment of SMA in patients aged 5 years or younger, wherein the patient has not received an SMN-targeted therapy (e.g., an SMN-upregulator / modifier therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec) prior to initiation of apitegromab treatment, and wherein the treatment comprises combined (e.g., simultaneous, separate, or sequential) administration of a composition comprising apitegromab and a composition comprising an SMN-targeted therapy (e.g., an SMN-upregulator / modifier therapy, e.g., nusinersen, risdiplam, or onasemnogene abeparvovec). In some embodiments, the composition comprising apitegromab is administered intravenously. In some embodiments, the composition comprising apitegromab is administered once every four weeks or once a month.

[0245] In some embodiments, the disclosure provides therapeutic uses of apitegromab in the treatment of SMA in patients aged 2 years or less, e.g., birth to 24 months, wherein the patient has not received an SMN upregulator / modifier therapy prior to initiation of apitegromab treatment, and wherein the treatment comprises the combined (e.g., simultaneous, separate, or sequential) administration of a composition comprising apitegromab and a composition comprising an SMN-targeted therapy (e.g., an SMN upregulator / modifier therapy, e.g., nusinersen, risdiplam, or onasemnogene abeparvovec).

[0246] In some embodiments, the present disclosure provides therapeutic uses of apitegromab in the treatment of SMA in patients aged 6 weeks or younger, e.g., between birth and 6 weeks of age, wherein the patient has not received an SMN-targeted therapy (e.g., an SMN-upregulator / modifier therapy) prior to initiation of apitegromab treatment, and wherein the treatment comprises the combined (e.g., simultaneous, separate, or sequential) administration of a composition comprising apitegromab and a composition comprising an SMN-targeted therapy (e.g., an SMN-upregulator / modifier therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec). In some embodiments, the patient has pre-symptomatic SMA. In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, the composition comprising apitegromab is administered intravenously. In some embodiments, the composition comprising apitegromab is administered once every four weeks or once a month.

[0247] In some embodiments, the present disclosure provides therapeutic uses of a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevoglumab, in treating pre-symptomatic SMA in a human patient. In some embodiments, the patient has not previously received an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy) prior to initiation of myostatin-selective inhibitor treatment. In some embodiments, the patient has previously received or is currently receiving an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy). In some embodiments, the treatment involves the combined (e.g., simultaneous, separate, or sequential) administration of a composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevoglumab, and a composition comprising an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy). In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, a composition comprising a myostatin-selective inhibitor, such as apitegromab, GYM329, or trevoglumab, is administered intravenously. In some embodiments, a composition comprising a myostatin-selective inhibitor, such as apitegromab, GYM329, or trevoglumab, is administered once every four weeks or once a month. In some embodiments, the myostatin-selective inhibitor selectively binds to pro-latent myostatin. In some embodiments, the myostatin-selective inhibitor is apitegromab.

[0248] In some embodiments, the disclosure provides therapeutic uses of a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevoglumab, in treating SMA in patients who are 5 years of age or younger. In some embodiments, the patient has not previously received an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy) prior to initiation of myostatin-selective inhibitor therapy. In some embodiments, the patient has previously received or is currently receiving an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy). In some embodiments, the patient is administered an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy) at the age of 5 years or younger. In some embodiments, treatment of SMA involves combined (e.g., simultaneous, separate, or sequential) administration of a composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevoglumab, and a composition comprising an SMN upregulator / modifier therapy, e.g., SMN1 gene therapy. In some embodiments, a composition comprising a myostatin-selective inhibitor, such as apitegromab, GYM329, or trevoglumab, is administered intravenously. In some embodiments, the patient has pre-symptomatic SMA. In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, a composition comprising a myostatin-selective inhibitor, such as apitegromab, GYM329, or trevoglumab, is administered once every four weeks or once a month. In some embodiments, the myostatin-selective inhibitor selectively binds to pro-latent myostatin. In some embodiments, the myostatin-selective inhibitor is apitegromab.

[0249] In some embodiments, the disclosure provides therapeutic uses of a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevoglumab, in the treatment of SMA in patients aged 2 years or less, e.g., birth to 24 months. In some embodiments, the patient has not previously received an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy) prior to initiation of myostatin-selective inhibitor treatment. In some embodiments, the patient has previously received or is currently receiving an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy). In some embodiments, the patient is administered an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy) at age 2 years or less (e.g., birth to 24 months). In some embodiments, the treatment involves the combined (e.g., simultaneous, separate, or sequential) administration of a composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevoglumab, and a composition comprising an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy). In some embodiments, the patient has pre-symptomatic SMA. In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, the composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevoglumab, is administered intravenously. In some embodiments, the composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevoglumab, is administered once every four weeks or once a month. In some embodiments, the myostatin-selective inhibitor selectively binds to pro-latent myostatin. In some embodiments, the myostatin-selective inhibitor is apitegromab.

[0250] In some embodiments, the disclosure provides therapeutic uses of a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, in treating SMA in patients aged 6 weeks or younger, e.g., birth to 6 weeks, wherein the treatment comprises the combined (e.g., simultaneous, separate, or sequential) administration of a composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, and a composition comprising an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy). In some embodiments, the patient has not previously received an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy) prior to initiation of the myostatin-selective inhibitor treatment. In some embodiments, the patient has previously received or is currently receiving an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy). In some embodiments, the patient has pre-symptomatic SMA. In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, a composition comprising a myostatin-selective inhibitor, such as apitegromab, GYM329, or trevoglumab, is administered intravenously. In some embodiments, a composition comprising a myostatin-selective inhibitor, such as apitegromab, GYM329, or trevoglumab, is administered once every four weeks or once a month. In some embodiments, the myostatin-selective inhibitor selectively binds to pro-latent myostatin. In some embodiments, the myostatin-selective inhibitor is apitegromab.

[0251] In some embodiments, the disclosure provides a myostatin-selective inhibitor and an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy) for use in treating presymptomatic SMA in a patient, wherein the treatment comprises administering to the presymptomatic patient a myostatin-selective inhibitor and an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy) in amounts effective to treat SMA. In some embodiments, the patient has two copies of the SMN2 gene and / or wherein the patient is 6 weeks of age or younger at the time of administration of the SMN upregulator / modifier therapy (e.g., SMN1 gene therapy). In some embodiments, the myostatin-selective inhibitor is apitegromab, GYM329, or trevoglumab.

[0252] In some embodiments, the disclosure provides a myostatin-selective inhibitor and SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) for use in treating pre-symptomatic SMA in a patient, wherein the treatment comprises administration of a myostatin-selective inhibitor and SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) in an amount effective to treat SMA to a pre-symptomatic patient, wherein the patient has two copies of the SMN2 gene, wherein the patient is 6 weeks of age or younger at the time of administration of the SMN upregulator / corrector therapy (e.g., SMN1 gene therapy), and wherein the myostatin-selective inhibitor is apitegromab, GYM329, or trevoglumab.

[0253] In some embodiments, the present disclosure provides a myostatin-selective inhibitor for use in treating presymptomatic SMA in a patient, wherein the treatment comprises administering the myostatin-selective inhibitor to the presymptomatic patient in an amount effective to treat SMA. In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, the patient is administered an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy) at or below the age of 6 weeks. In some embodiments, the myostatin-selective inhibitor is apitegromab, GYM329, or trevoglumab.

[0254] In some embodiments, the disclosure provides a myostatin-selective inhibitor for use in treating pre-symptomatic SMA in a patient, wherein the treatment comprises administering to the pre-symptomatic patient a myostatin-selective inhibitor in an amount effective to treat SMA, wherein the patient has two copies of the SMN2 gene, wherein the patient was administered an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy) at or below 6 weeks of age, and wherein the myostatin-selective inhibitor is apitegromab, GYM329, or trevoglumab.

[0255] In some embodiments, the disclosure provides therapeutic uses of SMN upregulator / modifier therapy (e.g., SMN1 gene therapy) in the treatment of pre-symptomatic SMA in a human patient, wherein the treatment comprises combined (e.g., simultaneous, separate, or sequential) administration of a composition comprising an SMN upregulator / modifier therapy (e.g., SMN1 gene therapy) and a composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevoglumab. In some embodiments, the patient has not previously received a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevoglumab, prior to initiation of the SMN upregulator / modifier therapy. In some embodiments, the patient has previously received or is currently receiving a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevoglumab. In some embodiments, the patient is administered an SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) at age 5 or younger. In some embodiments, the patient is administered an SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) at age 2 or younger (e.g., birth to 24 months of age). In some embodiments, the patient is administered an SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) at age 6 weeks or younger (e.g., birth to 6 weeks of age). In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, the composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevoglumab, is administered intravenously. In some embodiments, the composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevoglumab, is administered every four weeks or monthly. In some embodiments, the myostatin selective inhibitor selectively binds to pro-latent myostatin, hi some embodiments, the myostatin selective inhibitor is apitegromab.

[0256] In some embodiments, myostatin-selective inhibitors are used in the treatment of SMA in patients 2 months of age or older who are being treated with an SMN therapy, such as nusinersen, risdiplam, or onasemnogene abeparvovec. In some embodiments, apitegromab is administered as an adjunct to an SMN-upregulator therapy, including nusinersen, risdiplam, or onasemnogene abeparvovec.

[0257] In some embodiments, the myostatin-selective inhibitor is used to treat pre-symptomatic SMA in patients with three or fewer copies of the SMN2 gene (e.g., two copies, three copies) or in patients diagnosed with type 1 SMA, where the patient is undergoing or has undergone gene therapy, such as onasemnogene abeparvovec. Optionally, the patient is six weeks of age or younger. Further optionally, the patient weighs between 2.6 kg and 21.0 kg.

[0258] In some embodiments, the disclosure provides an SMN1 upregulator / corrector therapy (e.g., SMN1 gene therapy) for use in treating pre-symptomatic SMA in a patient, wherein the treatment comprises administration of an SMN1 upregulator / corrector therapy (e.g., SMN1 gene therapy) to a pre-symptomatic patient in an amount effective to treat SMA, wherein the patient is administered the SMN1 upregulator / corrector therapy (e.g., SMN1 gene therapy) at or below 6 weeks of age, and wherein the patient is further treated with a myostatin-selective inhibitor, and wherein the myostatin-selective inhibitor is apitegromab, GYM329, or trevoglumab.

[0259] The data disclosed herein further support the concept that myostatin inhibitors may help improve SMA treatment in patients receiving SMN therapy. Specifically, these data suggest that subpopulations of patients experiencing or suffering from specific types of disease-related symptoms may particularly benefit from myostatin inhibitor therapy, pointing out that this should be considered in patient selection. Specific SMA patient subpopulations that are particularly likely to benefit from myostatin inhibitors include, but are not limited to, cohorts of patients experiencing the indicated disease-related symptoms: patients suffering from muscle weakness and / or stiffness; patients suffering from severe fatigue (e.g., as determined by art-recognized means such as PROMIS); patients suffering from difficulties or disorders of bulbar function (e.g., coughing, difficulty swallowing / feeding, difficulty chewing, or smiling); patients prone to respiratory infections; and / or patients suffering from difficulties or disorders of elimination (e.g., urinary urgency and frequency, and / or bowel movements). Thus, in some embodiments, a myostatin inhibitor is used in the treatment of SMA in a patient, wherein the treatment comprises administering a myostatin inhibitor to treat SMA, and wherein the patient has impaired bulbar function, and optionally the patient has difficulty coughing, swallowing or eating, and / or chewing or smiling. In some embodiments, a myostatin inhibitor is used in the treatment of SMA in a patient, wherein the treatment comprises administering a myostatin inhibitor to treat SMA, and wherein the patient is prone to respiratory infections. In some embodiments, a myostatin inhibitor is used in the treatment of SMA in a patient, wherein the treatment comprises administering a myostatin inhibitor to a patient suffering from severe fatigue, and optionally the severity of the fatigue is determined by PROMIS. In some embodiments, a myostatin inhibitor is used in the treatment of SMA in a patient, where the treatment involves administering a myostatin inhibitor to a patient having difficulty or impairment with elimination (e.g., urgency and frequency of urination, and / or bowel movements).

[0260] Thus, the present disclosure provides patient selection considerations aimed at helping identify SMA patients who are more likely to benefit from muscle-building therapies, such as myostatin inhibitors. According to the present disclosure, myostatin inhibitors are used in the treatment of SMA in patients undergoing SMN therapy, where the patient suffers from muscle weakness / stiffness, fatigue, bulbar dysfunction (optionally coughing, and / or difficulty swallowing or eating), and / or elimination disorders (optionally urinary urgency and frequency, and / or bowel movements). In some embodiments, myostatin inhibitors include agents that inhibit myostatin, GDF11, and activin A. In some embodiments, myostatin inhibitors include agents that inhibit myostatin and GDF11, but not activin A. In preferred embodiments, the myostatin inhibitor is an agent that selectively inhibits myostatin without binding to or inhibiting GDF11 or activin A (i.e., a myostatin-selective inhibitor). Myostatin-selective inhibitors include neutralizing antibodies or antigen-binding fragments thereof that selectively bind to myostatin but not GDF11 or activin A, and antibodies or antigen-binding fragments thereof that bind to promyostatin / latent myostatin, thereby inhibiting activation of mature myostatin. Examples of the latter include apitegromab (SRK-015), GYM329 (RO7204239), variants thereof, or antibodies that cross-block or cross-compete with apitegromab or GYM329 for antigen binding. In most preferred embodiments, the myostatin-selective inhibitor is apitegromab.

[0261] Further indications The data presented herein indicate that the disclosed treatment regimens for apitegromab, including, for example, dose selection, may provide clinical benefit to human patients other than those with SMA. Apitegromab may provide clinical benefit to human patients diagnosed with other indications that share certain attributes of SMA. Such attributes include one or more of the following criteria: diseases in a relatively young patient population; diseases in which muscles are structurally intact or functionally preserved; diseases affecting fast-twitch muscle fibers; and the availability of established endpoints that rely on fast-twitch muscle fibers.

[0262] Additional indications beyond SMA that may benefit from treatment with the antibodies disclosed herein (e.g., apitegromab) include, but are not limited to, dystrophies such as Becker muscular dystrophy, Becker muscular dystrophy under microdystrophin gene therapy, Duchenne muscular dystrophy, Duchenne muscular dystrophy under microdystrophin gene therapy, facioscapulohumeral muscular dystrophy (FSHD), and other muscular dystrophies, as well as Pompe disease, Pompe disease under enzyme replacement therapy (including, but not limited to, Lumizyme and Nexviazyme), late-onset Pompe disease, muscle recovery after cancer treatment, and glucocorticoid-induced myopathy (e.g., in some patients who cannot discontinue steroid therapy). Becker muscular dystrophy may be particularly suitable for treatment with the antibodies disclosed herein (e.g., apitegromab). Patients with Becker muscular dystrophy typically have higher circulating myostatin levels compared to patients with Duchenne muscular dystrophy (see, e.g., Burch et al. (2017) J Neurol. 264(3):541-553; Mariot et al. (2017) Nat Commun. 8:1859). In another embodiment, the indication being treated is amyotrophic lateral sclerosis (ALS). In another embodiment, the indication being treated is muscle recovery after cancer treatment, for example, muscle recovery after cancer treatment in pediatric patients (as some children may develop severe muscle wasting from chemotherapy). The antibodies disclosed herein (e.g., apitegromab) may be used as monotherapy or as add-on therapy to provide a muscle-targeted approach to enhance other stabilizing therapies (e.g., treatments such as gene therapy in Duchenne muscular dystrophy or enzyme replacement therapy in lysosomal storage disorders).

[0263] Dosage Selection and Administration In various embodiments of the methods, uses, and compositions disclosed herein, a human subject in need of treatment is administered an effective amount of an anti-promyostatin / anti-latent myostatin antibody (e.g., apitegromab) intravenously, for example, by continuous infusion over a period of time.

[0264] In some embodiments, apitegromab is administered to patients as a weight-based dose, i.e., a dose that depends on the patient's weight. In some embodiments, suitable dosages of apitegromab include greater than 2 and less than or equal to 20 mg / kg (mg / kg), optionally about 5, 10, 15, or 20 mg / kg. In some embodiments, the therapeutic dose of apitegromab is 10 mg / kg. In some embodiments, the therapeutic dose of apitegromab is 20 mg / kg. In some embodiments, doses greater than 20 mg / kg may be used while maintaining a similar safety profile, although the need for higher dosages may be reduced given the surprisingly favorable therapeutic and PK profiles of, for example, 20 mg / kg and 2 mg / kg, respectively.

[0265] PK analysis of apitegromab shows a correlation between drug clearance and age or body weight. These data indicate that younger patients (lower body weight) exhibit slower clearance of apitegromab compared with older patients (heavier body weight). This finding may indicate dose selection for a suitable intermediate dose, e.g., 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12 mg / kg, 15 mg / kg, etc. Apitegromab demonstrated linear pharmacodynamics in both healthy volunteers and subjects treated with apitegromab, with a mean terminal half-life of 23 to 40 days.

[0266] Target engagement analyses from the 6- and 12-month studies indicated that target saturation was achieved with apitegromab at 20 mg / kg, while partial target engagement was observed at 2 mg / kg. In some embodiments, due to this target saturation at 20 mg / kg, a lower dose, e.g., 10 mg / kg, is used. Target engagement analyses at 24 months were consistent with previous studies but further demonstrated that apitegromab target engagement correlated with improvement in motor function. Both the amount of latent myostatin and the fold change in latent myostatin, when normalized for the age at which subjects began treatment, provide pharmacodynamic markers of improvement in motor function.

[0267] In some embodiments, the suitable dosage of apitegromab is 20 mg / kg. In some embodiments, the suitable dosage of apitegromab is 10 mg / kg. In some embodiments, apitegromab is administered intravenously to patients every four weeks or monthly at 5 mg / kg, 7.5 mg / kg, 10 mg / kg, or 12 mg / kg.

[0268] In some embodiments, apitegromab is administered to a patient at a dose of 20 mg / kg. In some embodiments, due to its favorable safety profile when administered at a dose of 20 mg / kg, apitegromab may be administered to a patient at a dose higher than 20 mg / kg, for example, where the dose is 30 mg / kg or less, e.g., 25 mg / kg. In some embodiments, apitegromab is administered to a patient at a dose higher than 20 mg / kg (e.g., about 25 mg / kg, about 30 mg / kg). In some embodiments, apitegromab is administered to a patient intravenously at a dose of 10 to 20 mg / kg every four weeks or monthly.

[0269] In some embodiments, apitegromab is initially administered to the patient at 2 mg / kg, and this dose is later increased to a dose of at least 10 mg / kg (e.g., 10 mg / kg, 15 mg / kg, 20 mg / kg) if further motor improvement is required. In some embodiments, the dose is increased to at least 10 mg / kg after the patient has been treated with 2 mg / kg apitegromab for at least 4 months. In some embodiments, the dose is increased to at least 10 mg / kg after the patient has been treated with 2 mg / kg apitegromab for 6 months. In some embodiments, the dose is increased to at least 10 mg / kg after the patient has been treated with 2 mg / kg apitegromab for 12 months. In some embodiments, the dose is increased to at least 10 mg / kg after the patient has been treated with 2 mg / kg apitegromab for 24 months. In some embodiments, increasing the apitegromab dose from 2 mg / kg to at least 10 mg / kg (e.g., 10 mg / kg, 15 mg / kg, 20 mg / kg) results in a dose response, e.g., as determined by the subject's latent myostatin level. In some embodiments, motor improvement is measured by RULM. In some embodiments, motor improvement is measured by RHS. In some embodiments, motor improvement is measured by HFMSE.

[0270] In some embodiments, apitegromab is administered to a patient about once every four weeks, once a month, etc. Such antibodies may be administered by intravenous injection / infusion, e.g., by intravenous infusion, or by another suitable route of administration (e.g., subcutaneously (e.g., under the skin) or intrathecally (e.g., into the spinal cord). Similarly, an SMN upregulator, e.g., a splicing modifier, may be administered orally, e.g., by mouth, or by another suitable route of administration.

[0271] In some embodiments, the subject is administered with an SMN-upregulating drug before apitegromab is administered.In some embodiments, the subject is concurrently administered with an SMN-upregulating drug at the same time as apitegromab is administered.In some embodiments, the subject will be administered with an SMN-upregulating drug after apitegromab is administered.

[0272] In some embodiments, a subject receiving an SMN-upregulating agent is administered apitegromab at least 24 hours (e.g., at least 36 hours, at least 48 hours, or more) before a dose (e.g., a maintenance dose) of the SMN-upregulating agent (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec). In some embodiments, a subject receiving an SMN-upregulating agent is administered apitegromab at least 14 days (e.g., at least 21 days, or more) after a dose (e.g., a maintenance dose) of the SMN-upregulating agent (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec).

[0273] In some embodiments, the subject received the SMN-upregulating agent within 6 months of receiving apitegromab. In some embodiments, the subject received the SMN-upregulating agent within 3 months of receiving apitegromab. In some embodiments, the subject received the SMN-upregulating agent within 6 months, 5 months, 4 months, 3 months, 2 months, or 1 month of receiving apitegromab. In some embodiments, the subject received the SMN-upregulating agent within 4 weeks, 3 weeks, 2 weeks, or 1 week of receiving apitegromab. In some embodiments, the subject received the SMN-upregulating agent on the same day as receiving apitegromab.

[0274] In some embodiments, the subject is expected to receive an SMN-upregulating agent within 6 months of receiving apitegromab. In some embodiments, the subject is expected to receive an SMN-upregulating agent within 3 months of receiving apitegromab. In some embodiments, the subject is expected to receive an SMN-upregulating agent within 6 months, 5 months, 4 months, 3 months, 2 months, or 1 month of receiving apitegromab. In some embodiments, the subject is expected to receive an SMN-upregulating agent within 4 weeks, 3 weeks, 2 weeks, or 1 week of receiving apitegromab.

[0275] In some embodiments, the SMN upregulatory agent is an antisense nucleotide and is administered to the subject's central nervous system by intrathecal injection.In some embodiments, the antisense nucleotide is administered to the subject every few months, for example, every month, every two months, every three months, every four months, every five months, every six months, or every twelve months.In other embodiments, initial treatment involves more frequent administration, which can then be followed by less frequent maintenance doses.

[0276] In some embodiments, the SMN-upregulating agent is a small molecule and is orally administered to the subject. In some embodiments, the small molecule is administered to the subject daily. In other embodiments, the small molecule is administered to the subject weekly, biweekly, or monthly.

[0277] In some embodiments, the SMN upregulator is a gene therapy and is administered by intravenous injection. In some embodiments, the SMN upregulator is a gene therapy and is administered by intrathecal injection. In some embodiments, the initial treatment involves more frequent administration, followed by less frequent maintenance doses. In order to avoid inappropriate immune responses to gene therapy, less frequent maintenance doses may be preferred.

[0278] In some embodiments, apitegromab is administered to a subject intravenously, for example, by intravenous infusion. In some embodiments, apitegromab is administered to a subject once every four weeks or monthly. In some embodiments, initial treatment involves more frequent administration, followed by less frequent maintenance doses. In some embodiments, apitegromab may be given at an initial higher dose (e.g., a loading dose), followed by one or more subsequent lower doses (e.g., one or more maintenance doses). In some embodiments, one or more initial doses of apitegromab are administered at 20 mg / kg, followed by one or more lower doses (e.g., 15 mg / kg, 10 mg / kg, 5 mg / kg, 2 mg / kg, or 1 mg / kg), e.g., four weeks or one month after administration of the initial 20 mg / kg dose, e.g., where the one or more lower doses are administered every four weeks thereafter or once a month, or at longer intervals than those used for the loading dose.

[0279] In some embodiments, the SMA therapy comprises intravenous administration of greater than 2 mg / kg and up to 20 mg / kg of apitegromab every four weeks or monthly. In some embodiments, the SMA therapy comprises intravenous administration of about 20 mg / kg of apitegromab every four weeks or monthly. In some embodiments, the SMA therapy disclosed herein (e.g., SMA therapy comprising apitegromab) may achieve disease stabilization, such that a patient's motor function is maintained over time, or in other words, its deterioration is prevented, contrary to the natural history of the disease, which is expected to progress over time. In some embodiments, a net change of zero in motor function score relative to an appropriate baseline reflects disease stabilization.

[0280] In some embodiments, the SMA therapy comprises intravenous administration of more than 2 mg / kg and up to 20 mg / kg of apitegromab every four weeks or monthly. In some embodiments, the SMA therapy comprises intravenous administration of about 20 mg / kg of apitegromab every four weeks or monthly. In some embodiments, the SMA therapy comprises administering a therapeutically effective amount of apitegromab, the administration being sufficient to increase the subject's motor function by at least one milestone according to the WHO motor milestones. In some embodiments, the SMA therapy comprises administering a therapeutically effective amount of apitegromab, the administration being sufficient to increase the subject's motor function by one, two, or three milestones according to the WHO motor milestones. In some embodiments, the WHO motor milestones include one or more of the following: ability to walk independently, ability to stand independently, standing with assistance, crawling on hands and knees, and / or walking with assistance.

[0281] In some embodiments, SMA therapies disclosed herein (e.g., SMA therapies including apitegromab) may help maintain the disease state in a patient population receiving apitegromab compared to a control group not receiving the treatment. Maintaining the disease state refers to preventing further deterioration of the affected muscles in these patients, e.g., as determined by changes in motor function over time. In some embodiments, treatment may slow disease progression, as determined by, e.g., a slower rate of change in disease function compared to a suitable baseline (e.g., an untreated patient). Thus, even in the absence of improvement in motor function test scores, apitegromab may provide clinical benefit by countering disease progression. In this manner, such clinical benefit may manifest as a longer period during which a patient population treated with apitegromab is observed to maintain previous test scores or to show a slower rate of score decline over time compared to a control group. In some embodiments, a patient or patient population receiving or in need of apitegromab treatment may be compared to a control patient or patient population. In some embodiments, the control patient or patient population is a patient or patient population that has not received apitegromab.

[0282] In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) may slow disease progression, e.g., by delaying the decline in motor function as measured by a decrease in HFMSE, RHS, MFM, MyoGrip, or MyoPinch score, and / or by delaying the transition from ambulatory to non-ambulatory, delaying the need for respiratory support or intervention, etc.

[0283] Based on the unexpected degree of clinical benefit achieved by selective inhibition of myostatin in human patients, as demonstrated herein, it is contemplated that different myostatin-selective inhibitors (other than apitegromab) may be used in the treatment of SMA or other muscle disorders. Accordingly, the present disclosure includes myostatin-selective inhibitors for use in the treatment of muscle disorders such as SMA in a human subject, where optionally the subject is further treated with a motor neuron-directed therapy, and further optionally the motor neuron-directed therapy includes an SMN-upregulator therapy, such as an SMN2-upregulator therapy and an SMN1 gene therapy.

[0284] Biological effects of treatment The SMA therapies disclosed herein (e.g., SMA therapies comprising apitegromab) may be suitable for treating any form of SMA, particularly late-onset forms of SMA, in human subjects.

[0285] Patient populations that may benefit from the therapies described herein include those with non-ambulatory SMA and those with ambulatory SMA. In some embodiments, the SMA therapies disclosed herein are contemplated for non-ambulatory forms of SMA, such as Type 2 and non-ambulatory Type 3 SMA. In other embodiments, the SMA therapies disclosed herein are contemplated for ambulatory forms of SMA, such as ambulatory Type 3 SMA.

[0286] Genotype-based diagnosis can identify patients who carry an SMA gene mutation, including patients who may be presymptomatic (have not manifested an overt disease phenotype). In some embodiments, a subject suitable for treatment with an SMA therapy disclosed herein has a direct diagnosis of a mutation in SMN1 (e.g., a direct chromosomal diagnosis of 5q SMA). In some embodiments, a subject has a diagnosis of 5q SMA in addition to a diagnosis based on a motor phenotype. In some embodiments, a subject suitable for treatment with an SMA therapy disclosed herein does not have a mutation in SMN1 (e.g., a direct chromosomal diagnosis of 5q SMA). In some embodiments, a subject does not have a diagnosis of 5q SMA. In some embodiments, a subject has a non-5q SMA diagnosis.

[0287] In some embodiments, the subject with SMA is 2 years of age or older. In some embodiments, the subject with SMA is 2 to 12, 5 to 21, 13 to 21, or 2 to 21 years of age. In some embodiments, the subject with SMA is under 2 years of age. The clinical effect of an anti-promyostatin / anti-latent myostatin antibody (e.g., apitegromab) administered alone or in combination with an SMN-upregulating agent can be monitored and / or assessed by various means. Exemplary such beneficial biological effects are provided herein. A beneficial biological effect in a subject may be achieved by administering an anti-promyostatin / anti-latent myostatin antibody (e.g., apitegromab) as monotherapy or in combination with an SMN-upregulating agent. In some embodiments, apitegromab as monotherapy or in combination with an SMN-upregulating agent is administered in an amount effective to produce one or more of the biological effects described below.

[0288] The ability to determine functional assessment scales that can be reliably measured in SMA patients may be used to track a patient's disease progression over time as well as the effectiveness of therapy. While muscle function may be determined by physiological measurements, such as muscle strength and force generation, motor function assessment scales monitor disease progression in a manner that is more meaningful and relevant to a patient's function in daily life than measures that quantify muscle strength per se. In some embodiments, patients in need of or undergoing treatment for SMA are assessed using a functional assessment scale, such as any one or more of the motor function assessment tests or functional outcome measures described herein (e.g., one or more of the HFMSE, RHS, 6MWT, WHO Motor Milestones, RULM, 30-Second Standing Test, Motor Function Measure (MFM), CHOP-INTEND, Endurance Shuttle Nine Hole Peg Test (ESNHPT), and / or Endurance Shuttle Box and Block Test (ESBBT)).

[0289] In some embodiments, patients with SMA (e.g., late-onset SMA) are assessed using the RHS. In some embodiments, administration of the RHS includes a bed rise time and a 10-meter walk / run test. In some embodiments, the RHS is a 36-item clinical assessment of physical performance in patients with SMA Type 2 and ambulatory and non-ambulatory patients with SMA Type 3. The RHS includes 33 items rated on a 0-1-2 scale, with 0 representing the lowest level of ability / function and 2 representing the highest level of ability (Ramsey et al. (2017) PLoS One. 12(2):e0172346). The remaining three items are scored 0-1, with 0 representing inability and 1 representing ability. The highest possible score is 69.

[0290] In some embodiments, a patient (e.g., an ambulatory SMA patient) to be treated with apitegromab has a baseline RHS score of 26 or greater before treatment. In some embodiments, the patient has a baseline RHS score of 63 or less. In some embodiments, the patient has a baseline RHS score in the range of 26 to 63. In some embodiments, the patient has ambulatory SMA, e.g., ambulatory type 3 SMA. In some embodiments, treatment with apitegromab improves the patient's RHS score. In some embodiments, apitegromab continuously improves the patient's RHS score over 24 months of treatment. In some embodiments, apitegromab maintains the increase in RHS score over 24 months of treatment.

[0291] In some embodiments, patients with SMA (e.g., late-onset SMA) are evaluated using the 10-meter walk / run test. In some embodiments, the 10-meter walk / run test is an enhanced version of the RHS used in ambulatory Type 3 SMA patients. The 10-meter walk / run test measures the time it takes to walk / run 10 meters. In some embodiments, treatment with apitegromab improves a patient's 10-meter walk / run test score.

[0292] In some embodiments, patients with SMA (e.g., late-onset SMA) are evaluated using the Bed Rise Time Test. In some embodiments, the Bed Rise Time Test is an enhanced version of the RHS used in ambulatory patients with Type 3 SMA. The Bed Rise Time Test measures the time it takes to rise from the floor. In some embodiments, treatment with apitegromab improves a patient's Bed Rise Time Test score.

[0293] In some embodiments, patients with SMA (e.g., late-onset SMA) are evaluated using the 6-minute Walk Test (6MWT). The 6MWT is a measure of motor capacity and fatigue used in clinical studies of ambulatory patients with late-onset SMA (Young et al. (2016). Muscle Nerve. 54(5):836-842). Patients are instructed to walk as fast as possible along a 25-meter course for 6 minutes. Distance walked per minute and total distance walked in 6 minutes are measured. In some embodiments, treatment with apitegromab improves a patient's 6MWT score.

[0294] In some embodiments, patients with SMA (e.g., late-onset SMA) are evaluated using the 30-second stand test. The 30-second stand test is used by researchers and clinicians as a measure of functional strength in the lower extremities (Jones et al. (1999) Res Q Exerc Sport. 70:113-119). This test was adapted for ambulatory SMA populations based on studies of the modified 30-second stand, which is a reliable and feasible tool used in the general geriatric population with low levels of function (McAllister and Palombaro (2019). J Geriatr Phys Ther. 0(0):1-6), and has been associated with fall risk in institutionalized veterans (Applebaum et al. (2017). PLoS One. 12(5):e0176946; Le Berre et al. (2016) Percept Mot Skills. 123:138-152). This test measures the maximum number of times a patient can transition from a sit to a stand position in 30 seconds. In some embodiments, treatment with apitegromab improves a patient's score on the 30-second stand test.

[0295] In some embodiments, a patient to be treated with apitegromab (e.g., a patient with a non-ambulatory form of SMA, such as Type 2 or non-ambulatory Type 3 SMA) has a baseline HFMSE score of 12 or greater prior to treatment. In some embodiments, the patient has a baseline HFMSE score of 44 or less. In some embodiments, the patient has a baseline HFMSE score in the range of 12-44. In some embodiments, the patient has a non-ambulatory form of SMA. In some embodiments, the patient has Type 2 SMA. In some embodiments, the patient has non-ambulatory Type 3 SMA. In some embodiments, treatment with apitegromab improves the patient's HFMSE score.

[0296] In some embodiments, patients with SMA (e.g., late-onset SMA) are evaluated using the Revised Upper Limb Module (RULM). The RULM is a 20-item assessment of upper limb function in non-ambulatory SMA patients (young children and adults) (Mazzone et al. (2017) Muscle Nerve. 55(6):869-874). Nineteen scoring items test functions related to daily living, such as placing the hands on the knees, pressing a button, and picking up a token. Items are scored 0, 1, or 2, with 0 representing no ability, 1 representing ability with modification, and 2 representing ability without difficulty. The maximum achievable score is 37. In some embodiments, the RULM is used to assess non-ambulatory SMA patients. In some embodiments, the RULM is completed by patients 30 months of age or older, e.g., at baseline assessment. In some embodiments, treatment with apitegromab improves a patient's RULM score.

[0297] In some embodiments, patients with SMA (e.g., late-onset SMA) are evaluated using the World Health Organization (WHO) motor development milestones. The WHO Multicentre Growth Reference Study (MGRS) developed growth charts to assess the growth and development of infants and young children worldwide (de Onis et al. (2004) Food Nutr Bull. 25 Suppl:S1-89). The MGRS had as its primary goal the construction of charts and associated tools to assess the growth and development of children from birth to age 5 years. Another feature of the MGRS is its inclusion of the collection of ages of achievement of motor milestones, including gross motor development milestones such as sitting unsupported, crawling on hands and knees, standing with assistance, walking with assistance, standing unassisted, and walking unassisted (Wijnhoven et al. (2004) Food Nutr Bull. 25(1 Suppl):S37-45; WHO Multicentre Growth Reference Study Group (2006) Acta Paediatr Suppl;450:86-95). In some embodiments, the WHO MGRS performance criteria for gross motor development are utilized to assess motor development milestones in patients with, for example, SMA type 2 and non-ambulatory SMA type 3. In some embodiments, treatment with apitegromab improves a patient's WHO MGRS score.

[0298] In some embodiments, patients with SMA (e.g., late-onset SMA) are assessed using the Motor Function Measure (MFM). The MFM assesses motor function in three domains: (1) standing, walking, and locomotion; (2) axial and proximal motor function; and (3) distal motor function (Annoussamy et al. (2020) Annals of Clinical and Translational Neurology 8:359-373). The MFM was originally designed for children aged 7 years and older and includes 32 items across these three functional domains. The MFM-20 is a modified version of the MFM scale that removes some of the more difficult items, making it suitable for younger children. It includes 20 items and is suitable for children aged 2 years and older (Pierzchiewicz et al., Child Neurology Open (2021) 8:1-9). In some embodiments, patients with SMA (e.g., late-onset SMA) are assessed using the MFM-20. In some embodiments, treatment with apitegromab improves the patient's MFM20 score.

[0299] In some embodiments, patients with SMA (e.g., early-onset or Type 1 SMA) are evaluated using the CHOP-INTEND test (Glanzman et al. (2010) Neuromus. Disord. 20(3):155-161). The CHOP-INTEND measures five parameters of observationally evoked motor movements: (1) spontaneous movement of the left and right upper limbs; (2) spontaneous movement of the left and right lower limbs; (3) grip strength; (4) head midline support with visual cues; and (5) hip adduction. Each item is scored on a 0-4 scale, with 0 representing no response, 1 representing minimal response, 2 representing partial response, 4 representing almost complete response, and 4 representing complete response. The maximum score is 64. CHOP-INTEND was designed and validated for use in infants with SMA (Alfano et al. (2021) Pediatric Neurology 122:21-26).

[0300] A maximum CHOP-INTEND score of 64 is typically achieved by 3 to 6 months of age in healthy infants. These included patients receiving nusinersen (Duong et al. (2021) Neuromuscul Dis, 8(1), 63-77; Pechmann et al. (2018) J Neuromuscul Dis, 5(2), 135-143; Aragon-Gawinska et al. (2018) Neurology, 91:14), risdiplam (Baranello et al. (2021) N Engl J Med, 384(10), 915-923; Darras et al. (2021) N Engl J Med, 385(5), 427-435), and onasemnogen abeparvovec (Mendell et al. (2021) JAMA Neurol 78(7), 834-841; EMA / 200482 / 2020(2020) Zolgensma Most patients with EPAR reach a plateau with a CHOP-INTEND score below 50 within the first three years of life.

[0301] In some embodiments, patients evaluated with CHOP-INTEND are less than 2 years of age. In some embodiments, patients evaluated with CHOP-INTEND have early-onset or type 1 SMA. In some embodiments, patients evaluated with CHOP-INTEND have a baseline score of 40 or less.

[0302] In some embodiments, patients with SMA (e.g., late-onset SMA) are assessed using the Endurance Shuttle Nine Hole Peg Test (ESNHPT). The ESNHPT is an endurance test for patients with severe SMA. Patients are instructed to repeatedly perform the original nine-hole peg test at 75% of their maximum speed. The reciprocating movement is based on a set speed indicated by an auditory cue, and the test ends when the patient fails to respond to two consecutive beeps. The primary outcome parameter is "time to failure (Tlim)," i.e., the time the patient can maintain the effort at a preset intensity. The maximum test duration is 20 minutes (Stam et al. (2018) BMJ Open. 8(7):e019932). In some embodiments, the ESNHPT is used to evaluate non-ambulatory SMA patients. In some embodiments, the ESNHPT is completed by patients aged 8 years or older. In some embodiments, treatment with apitegromab improves the patient's ESNHPT score.

[0303] In some embodiments, patients with SMA (e.g., late-onset SMA) are assessed using the Endurance Shuttle Box and Block Test (ESBBT). The ESBBT is a muscle endurance measurement tool that measures how quickly the proximal muscles of a subject's arm fatigue. Patients may be instructed to perform the original box and block test repeatedly at 75% of their maximum speed. The reciprocating movement is based on a set speed indicated by an auditory cue, and the test ends when the patient fails to respond to two consecutive beeps. The primary outcome parameter is "time to failure (Tlim)," i.e., the time the patient can maintain work at a preset intensity. The maximum test duration is 20 minutes (Stam et al. (2018) BMJ Open. 8(7):e019932). The ESSBT is the first validated, sensitive fatigability test of proximal arm muscle function in SMA, and by adding an endurance dimension, its results complement those obtained with other measures of upper arm motor function, such as the RULM.

[0304] In some embodiments, the ESBBT is used to evaluate non-ambulatory SMA patients. In some embodiments, the ESBBT is completed by patients aged 8 years or older. In some embodiments, treatment with apitegromab improves the patient's ESBBT score.

[0305] In some embodiments, 12 months of treatment with apitegromab is sufficient to increase the subject's ESBBT score by at least 109.1 points (e.g., an increase in the subject's ESBBT score of about 110 to about 239 points). In some embodiments, 24 months of treatment with apitegromab is sufficient to increase the subject's ESBBT score by at least 147.9 points (e.g., an increase in the subject's ESBBT score of about 150 to about 300 points). In some embodiments, the subject has non-ambulatory Type 2 or Type 3 SMA, is 5 to 21 years of age, and has previously been treated with an SMN-upregulator / modifier therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec, where the subject was first treated with an SMN-upregulator / modifier therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec, after the age of 5 years.

[0306] Clinical benefits of SMA therapy may include: 1) improvement of motor function, 2) preservation of motor function (disease stabilization), 3) slowing of disease progression, or 4) improvement of quality of life.

[0307] Motor function may be assessed by any suitable means, such as the HFMSE and / or the RHS, with the latter often being used to assess motor function in ambulatory patients. In some embodiments, the HFMSE is more frequently used to assess motor function in non-ambulatory patients. An increase in the respective score compared to an appropriate baseline indicates improved motor function. In some embodiments, the increase is at least 1 point, at least 2 points, at least 3 points, at least 4 points, or at least 5 points. In some embodiments, the increase is 1 or more points, 2 or more points, 3 or more points, 4 or more points, or 5 or more points. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) enhances motor function such that the HFMSE score or RHS score (e.g., HFMSE score) measured 6 months, 12 months, or 24 months after initiation of treatment is at least 1, 3, 5, 7, or 10 points above baseline, where baseline is obtained at or before initiation of treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) produces an increase in HFMSE score of at least 5 points compared to the baseline score after at least 12 months (e.g., at least 24 months) of treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) produces an increase in HFMSE score of 6 to 20 points or more compared to the baseline score after at least 12 months (e.g., at least 24 months) of treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) produces an increase in HFMSE score of at least 7 points compared to the baseline score after at least 12 months (e.g., at least 24 months or at least 36 months) of treatment.

[0308] In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) enhances motor function such that the HFMSE score or RHS score (e.g., HFMSE score) measured 24 months after initiation of treatment is at least 1, 3, 5, 7, or 10 points above baseline, where baseline is obtained at or before initiation of treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) produces an increase in HFMSE score of at least 5 points compared to the baseline score after at least 24 months of treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) produces an increase in HFMSE score of 6 to 20 points or more compared to the baseline score after at least 24 months of treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) produces an increase in HFMSE score of at least 7 points compared to the baseline score after at least 24 months of treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) produces an increase in HFMSE score of at least 2 points (e.g., at least 3 points, at least 4 points, or at least 5 points, at least 6 points) compared to baseline after 12 months of apitegromab treatment, wherein the increase in HFMSE score is maintained 24 months after initiation of apitegromab treatment, and optionally wherein the increase in HFMSE score is maintained 36 months after initiation of apitegromab treatment. In some embodiments, the improvement in the subject's HFMSE score compared to baseline when measured 12 months after initiation of apitegromab treatment is maintained or even increases at 24 months. In some embodiments, the improvement in the subject's HFMSE score compared to baseline when measured 12 months after initiation of apitegromab treatment is maintained or even increases at 36 months.

[0309] In some embodiments, improvement in motor function scores (e.g., HFMSE or RHS scores) may be positively correlated with SMA severity and / or length of treatment with SMN-modifying drug therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec). In some embodiments, improvement in motor function scores (e.g., HFMSE or RHS scores) may be inversely correlated with age and / or advanced disease characteristics. In some embodiments, advanced disease characteristics include scoliosis and / or joint contractures. In some embodiments, joint contractures can occur due to shortening of muscles, tendons, and ligaments, causing deformity, and symptoms include pain and loss of joint movement. In some embodiments, methods of treating SMA include administering apitegromab therapy, either as monotherapy or in conjunction with (or in combination with) another therapy, to patients without scoliosis and / or joint contractures. In some embodiments, apitegromab is used to treat SMA, either as a monotherapy or in conjunction with (or in combination with) another therapy, in patients who do not have scoliosis and / or joint contractures.

[0310] In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) stabilizes disease progression such that the HFMSE score or RHS score measured 6 or 12 months after initiation of treatment does not fall below baseline or does not worsen by more than 0.1, 0.2, 0.3, 0.4, or 0.5 points, where baseline is obtained at or before initiation of treatment, and optionally, where the stabilization persists through at least 24 months of treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) stabilizes disease progression such that the RHS score after at least 12 months of treatment comprises a worsening of the RHS score by less than 1, 2, or 3 points compared to the baseline score, and optionally, where the stabilization persists through at least 24 months of treatment.

[0311] In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) stabilizes disease progression such that the HFMSE score or RHS score measured 24 months after initiation of treatment does not fall below baseline or does not worsen by more than 0.1, 0.2, 0.3, 0.4, or 0.5 points, where baseline is obtained at or before initiation of treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) stabilizes disease progression such that the RHS score after at least 24 months of treatment includes a worsening of the RHS score by less than 1, 2, or 3 points compared to the baseline score.

[0312] In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) produces an increase in the RULM score of at least 0.5 points (e.g., at least 0.75, 1, 1.25, 1.5, 2., 2.25, or 2.5 points) relative to baseline 12 months after initiation of apitegromab treatment. In some embodiments, the increase in the RULM score relative to baseline is maintained 24 months after initiation of apitegromab treatment. In some embodiments, the RULM score relative to baseline further increases 24 months after initiation of apitegromab treatment compared to the RULM score at 12 months after initiation of apitegromab treatment. In some embodiments, the improvement in the subject's RULM score relative to baseline when measured 12 months after initiation of apitegromab treatment is maintained or further increases at 24 months. In some embodiments, the improvement in the subject's RULM score relative to baseline when measured at 12 months after initiation of apitegromab treatment is maintained or even increased at 36 months.

[0313] In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) improves muscle function, such that the patient's HFMSE score increases by at least 2 points (e.g., at least 3, 4, 5, or 6 points) compared to baseline at 24 months of treatment. In some embodiments, the patient's RULM score increases by at least 0.5 points (e.g., at least 0.75, 1, 1.25, 1.5, 2., 2.25, or 2.5 points) compared to baseline at 24 months of treatment.

[0314] Quality of Life Although a few previous studies have reported on the effects of SMA treatments, such as nusinersen, on overall quality of life, to date, these have demonstrated mixed results, with no convincing evidence that they significantly improve quality of life. For example, Montes et al. measured the 6-minute walk test (6MWT) and fatigue in 14 ambulatory children aged 2 to 15 years with type II (1 case) or type III (13 cases) SMA after receiving their first dose of nusinersen. Fatigue was measured as the difference between the number of meters walked in the first minute and the number of meters walked in the sixth minute. The researchers observed that 6MWT fatigue was only slightly reduced or stable after nusinersen treatment and concluded that this small effect may represent an effect of nusinersen treatment, but qualified this finding by noting that further understanding of the mechanisms underlying fatigue may help understand this only small effect (Montes et al. (2019) Muscle Nerve 60(4):409-414).

[0315] Yao et al. evaluated quality of life in children aged 17 years or younger who were diagnosed with SMA and treated with nusinersen. Compared with children who did not receive nusinersen, children treated with nusinersen had higher mean scores in the Neuromuscular Diseases and Family Resources domain of the Pediatric Quality of Life Inventory 3.0 Neuromuscular Module (PedsQL NMM). However, the study authors cautioned that the results are not conclusive due to the small sample size of nusinersen-treated children (n=6) (Yao et al. (2021) Orphanet Journal of Rare Diseases 16:7).

[0316] Mix et al. evaluated overall quality of life, health-related quality of life, and depressive symptoms in adolescent and adult SMA patients treated with nusinersen and reported that patients' subjective sense of health improved over the first 6 months of treatment, but their subjective well-being did not (Mix et al. (2021) Front Neurol 12:626787).

[0317] Other studies have reported no change in quality of life in SMA patients as a result of therapies offered in reported clinical trials. A literature review of quality of life studies in SMA patients (Landfeldt et al. (2019) Eur. J. Paediatric Neurology 23:347) found four relevant publications from reported clinical trials: a phase 1 trial of nusinersen, a phase 2 trial of olesoxime, and a phase 2 trial of l-carnitine and valproic acid. None of these studies reported any significant change in quality of life.

[0318] Thimm et al. (2022) Frontiers in Neurology 12:8120 conducted a prospective study in adult patients with type 2 or type 3 SMA treated with nusinersen to assess health-related quality of life, measured by the abbreviated form of the Neuro-QoL for upper and lower limb function, before treatment initiation and after 2, 6, 10, and 14 months of nusinersen treatment. This study found no improvement at any of the time points measured.

[0319] One prior study reported on HRQoL in children aged 2 to 4 years diagnosed with SMA type II or III, finding a small, non-significant increase after 85 days of treatment with nusinersen (Chiriboga et al. (2016) Neurology 86:890-7). A comprehensive literature review (Yang et al. (2022) Adv Ther 39:1915) found that while SMN-targeted therapies improved survival outcomes in SMA patients, no treatments, except for Chiriboga, demonstrated significant improvements in HRQoL.

[0320] In some embodiments, in contrast, the present disclosure demonstrates that apitegromab is the first muscle-targeted SMA treatment to provide improved quality of life for SMA patients, and in some embodiments, such improvement is sustained through at least 24 months of treatment.

[0321] In some embodiments, quality of life is assessed by interviewing the subject using a semi-structured interview guide that includes questions regarding the subject's expectations for meaningful improvement in their condition and their perceptions of why they have or have not experienced meaningful improvement. Subjects may be interviewed regarding their experience with SMA and its treatment in certain aspects of their life, such as physical function, social impact, and psychological impact. Subjects may also be asked to rate their quality of life, for example, by rating it on a scale of 0 to 10, where 0 indicates minimal impact on quality of life and 10 indicates extremely severe impact on quality of life.

[0322] In some embodiments, patients with SMA (e.g., late-onset SMA) are assessed using one of the EUROQOL family of instruments, including the EQ-5d-3L, EQ-5D-5L, EQ-5D-Y, and EQ-HWB. These multi-utility instruments measure health-related quality of life. For example, the EQ-5D-5L is a descriptive system that includes dimensions of mobility, self-care, ability to perform daily activities, pain / discomfort, and anxiety / depression.

[0323] In some embodiments, treatment with apitegromab improves a subject's Clinical Global Impression of Change (CGI-C). The CGI-C scores a clinician's impression of a subject's change in overall health (Staunton et al. (2021) Health Qual Life Outcomes 19:184). In some embodiments, treatment with apitegromab improves a subject's Pediatric QoL Inventory (PedsQL). The PedsQL consists of a general core scale and disease-specific modules, such as a neuromuscular module, which can be used to assess health-related QoL in children aged 2 to 18 years with neuromuscular diseases, including SMA (Iannaccone et al. (2009) Neuromuscular Disord 19:805-812). In some embodiments, treatment with apitegromab improves a subject's Gross Motor Outcome (GRO) score. The GRO is a gross motor outcome measure designed to assess whole-body strength and function at all ability levels across the lifespan of patients with neuromuscular diseases and has been validated in SMA types 1-3 (Alfano et al. (2021) Pediatric Neurology 122:21-26).

[0324] In some embodiments, treatment with apitegromab is sufficient to improve one or more measures of quality of life in an SMA subject, e.g., at 24 months after initiation of apitegromab treatment and / or at 36 months after initiation of apitegromab treatment.

[0325] In some embodiments, patients with SMA (e.g., late-onset SMA) are assessed using the Patient Reported Outcomes Measurement Information System (PROMIS) before and / or after treatment, e.g., with apitegromab. PROMIS is a person-centered scale intended to be completed by the patient or surrogate parent without assistance (Ader (2007) Med Care. 5(5):S1-S2). The fatigue profile domain measures a range of symptoms, from mild subjective fatigue to an overwhelming, debilitating, prolonged feeling of exhaustion. This self-reported scale is appropriate for children aged 8-17 years, and a surrogate parent-reported scale is appropriate for children aged 5-17 years. Patients aged 18-21 years may complete the adult form of PROMIS. In some embodiments, PROMIS is completed by patients aged 2 years and older, 5 years and older, or 5-21 years. In some embodiments, treatment with apitegromab improves the patient's PROMIS score.

[0326] The Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) is a caregiver-administered questionnaire that assesses a patient's ability to perform daily functions (Haley et al. (2005) Arch Phys Med Rehabil. 86(5):932-939). The domain covering activities of daily living (ADL) includes 68 items covering areas such as dressing, cleaning, and housework. The domain covering mobility includes 75 items covering areas such as basic movements and transfers, standing and walking, stepping and leaning, etc. Responses are scored on a 4-point scale (unable to easily), making this test suitable for assessing function in newborns through 21 years of age. The properties of the PEDI-CAT have been studied in SMA populations, and the test has been validated; Rasch analysis revealed that the performance distributions in the motor and daily activities domains of the PEDI-CAT were best represented in type 2 and type 3 populations (Pasternak et al. (2016) Muscle Nerve. 54(6):1097-1107).

[0327] In some embodiments, patients with SMA (e.g., late-onset SMA) are evaluated using the PEDI-CAT. In some embodiments, a caregiver (who may or may not be a parent and / or legal guardian) completes the PEDICAT assessment. In some embodiments, the PEDICAT assessment is not administered to the patient or is not administered in the caregiver's absence. In some embodiments, the PEDICAT is completed by a caregiver in a location where the caregiver is not present to observe the patient performing any functional assessment tests. In some embodiments, treatment with apitegromab improves the patient's PEDI-CAT score.

[0328] In some embodiments, treatment with apitegromab improves the subject's quality of life as assessed by the PEDI-CAT scale, where optionally the subject's PEDI-CAT scores can include a PEDI-CAT performance score and a PEDI-CAT mobility score. In some embodiments, treatment with apitegromab improves the subject's quality of life by assessing the subject's fatigue level, where optionally the subject's fatigue can be assessed by a Patient Reported Outcomes Measurement Information System (PROMIS) score and / or an Endurance Shuttle Block and Box Test (ESBBT) score. In some embodiments, 12 months of treatment with apitegromab is sufficient to increase the subject's PEDI-CAT Performance score by at least 1.9 points (e.g., increase the subject's PEDI-CAT Performance score by about 2 to about 4 points), increase the subject's PEDI-CAT Motility score by at least 0.4 points (e.g., increase the subject's PEDI-CAT Motility score by about 0.5 to about 3 points), and / or decrease the subject's PROMIS score by at least 5.5 points (e.g., decrease the subject's PROMIS score by about 6 to about 10 points), optionally wherein the subject has non-ambulatory Type 2 SMA and is at least 2 years of age. In some embodiments, the subject's PEDI-CAT Performance score further increases at 24 months compared to 12 months after initiation of apitegromab treatment. In some embodiments, the subject has previously been treated with an SMN upregulator / modifier therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec, where the subject was first treated with an SMN upregulator / modifier therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec, before the age of 5 years.

[0329] In some embodiments, 12 months of treatment with apitegromab is sufficient to increase the subject's PEDI-CAT performance score by at least 0.9 points (e.g., increase the subject's PEDI-CAT score by about 1 to about 3 points) and / or decrease the subject's PROMIS score by at least 0.6 points (e.g., decrease the subject's PROMIS score by about 1 to about 6 points, or about 4 to about 35 points), optionally wherein the subject has non-ambulatory Type 2 SMA and is between 5 and 21 years of age. In some embodiments, the subject's PROMIS score is further decreased at 24 months compared to 12 months after initiation of apitegromab treatment. In some embodiments, the subject has previously been treated with an SMN upregulator / modifier therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec, where the subject was first treated with an SMN upregulator / modifier therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec, after the age of 5 years.

[0330] In some embodiments, 24 months of treatment with apitegromab is sufficient to increase the subject's PEDI-CAT Performance score by at least 1.8 points (e.g., increase the subject's PEDI-CAT Performance score by about 2 to about 4 points), increase the subject's PEDI-CAT Motility score by at least 0.4 points (e.g., increase the subject's PEDI-CAT Motility score by about 0.4 to about 5 points), and / or decrease the subject's PROMIS score by at least 5.0 points (e.g., decrease the subject's PROMIS score by about 5 to about 9 points), wherein, optionally, the subject has non-ambulatory Type 2 SMA and is at least 2 years of age. In some embodiments, the subject has previously been treated with an SMN upregulator / modifier therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec, where the subject was first treated with an SMN upregulator / modifier therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec, before the age of 5 years.

[0331] In some embodiments, 24 months of treatment with apitegromab is sufficient to increase the subject's PEDI-CAT Performance score by at least 0.7 points (e.g., increase the subject's PEDI-CAT Performance score by about 1 point to about 3 points) and / or decrease the subject's PROMIS score by at least 1.3 points (e.g., decrease the subject's PROMIS score by about 2 points to about 7 points or about 4 points to about 10 points), where optionally the subject has non-ambulatory Type 2 SMA and is between 5 and 21 years of age. In some embodiments, the subject has previously been treated with an SMN-upregulator / modifier therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec, where the subject was first treated with an SMN-upregulator / modifier therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec, after the age of 5 years.

[0332] In some embodiments, treatment with apitegromab is sufficient to increase the subject's PEDI-CAT Activities of Daily Living score at 12 months compared to baseline, and optionally, the subject's PEDI-CAT Activities of Daily Living score is further increased at 24 months compared to 12 months. In some embodiments, treatment with apitegromab is sufficient to increase the subject's PEDI-CAT Mobility score at 12 months compared to baseline, and optionally, the subject's PEDI-CAT Mobility score is further increased at 24 months compared to 12 months.

[0333] In some embodiments, treatment with apitegromab is sufficient to reduce the subject's PROMIS fatigue score at 12 months compared to baseline, and optionally, the subject's PROMIS fatigue score is further reduced at 24 months compared to 12 months. In some embodiments, the subject's improvement in PROMIS fatigue score is maintained at 36 months.

[0334] In some embodiments, treatment with apitegromab is sufficient to increase the subject's ESBBT score at 12 months compared to baseline, and optionally, the subject's ESBBT score is further increased at 24 months compared to 12 months.

[0335] The Columbia Suicide Severity Rating Scale (C-SSRS) measures suicidal ideation, ideation intensity, and suicidal behavior. It has been validated in various populations, including children as young as 5 years old (Salvi (2019) Emerg Med Pract 21(5):CD3-CD4). In some embodiments, treatment with apitegromab results in an improvement in a subject's C-SSRS score.

[0336] In some embodiments, treatment with apitegromab improves a subject's quality of life as measured by the severity of muscle function-related symptoms. In some embodiments, muscle function-related symptoms include muscle function severity, fatigue severity, bulbar function severity, and / or bowel function severity. In some embodiments, muscle function-related symptoms are measured by a symptom severity rating scale in which the subject rates the symptom on a scale of 0 to 10, with 0 indicating minimal severity and 10 indicating severe severity.

[0337] In some embodiments, treatment with apitegromab improves a subject's quality of life as measured by the severity of fatigue-related symptoms, which in some embodiments are measured by a symptom severity rating scale in which the subject rates the symptom on a scale of 0 to 10, with 0 indicating minimal severity and 10 indicating severe severity.

[0338] In some embodiments, treatment with apitegromab improves a subject's quality of life as measured by symptoms related to bulbar function. Bulbar function refers to functions controlled by the brainstem region; "bulbar" is an archaic term for the medulla oblongata. Bulbar function includes swallowing, chewing motor function and strength, coughing, breathing, snoring, and jaw range of motion. Bulbar dysfunction can affect these activities. Bulbar dysfunction remains a significant complication in most type 1 patients treated with nusinersen; only 4 of 24 patients maintained oral intake at 24 months, as measured by p-FOIS (Westrate et al. (2022) Dev Med Child Neurol 64:907-914). Similarly, type 2 and type 3 patients treated with nusinersen did not show improvement in bulbar function compared to that observed before treatment at either 6 or 14 months after nusinersen treatment, whereas nusinersen was observed to improve their HFMSE scores (Brakemeier et al. (2021) Brain Sci 11:1244). In some embodiments, treatment with apitegromab improves bulbar function in patients.

[0339] In some embodiments, bulbar function-related symptoms are measured by a scale of symptom severity in which the subject scores from 0 to 10, with 0 indicating minimal severity and 10 indicating severe severity.

[0340] In some embodiments, patients with SMA are assessed for bulbar function using the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (AMLFRSR), a questionnaire-based scale that measures physical function in performing activities of daily living and has been shown to correlate with quality of life (Cedarbaum et al. (1999) J. Neurolog. Sci 169:13-21).

[0341] In some embodiments, patients with SMA are assessed for bulbar function using the Sydney Swallow Questionnaire (SSQ), an instrument that assesses the severity of oropharyngeal dysphagia (Dwivedi et al. (2010) Oral Oncol. E10-e14).

[0342] In some embodiments, patients with SMA are assessed using the MD Anderson Dysphagia Inventory (MDADI), a questionnaire that assesses the relationship between swallowing and quality of life (Chen et al. (2001) Arch Otolaryngol Head Neck Surg 127(7):870-876).

[0343] In some embodiments, patients with SMA are assessed using the SWAL-QoL, a 93-item quality of life outcome tool that measures swallowing disorders (McHorney et al. (2002) Dysphagia 17:97-114).

[0344] In some embodiments, patients with SMA are determined by conducting a qualitative semi-structured interview with the patient or their caregiver.

[0345] In some embodiments, patients with SMA (e.g., early-onset SMA, including but not limited to SMA Type 1) are assessed using the Pediatric Functional Oral Intake Scale (p-FOIS), a clinician-rated, 6-point outcome measure ordinal scale tool for use in pediatric eating disorder populations to determine change in functional feeding ability.

[0346] In some embodiments, treatment with apitegromab improves a subject's quality of life as measured by symptoms related to elimination, which in some embodiments are measured by a scale of symptom severity rated by the subject on a scale of 0 to 10, with 0 indicating minimal severity and 10 indicating severe severity.

[0347] In some embodiments, treatment with apitegromab improves a subject's quality of life as measured by the severity of symptoms related to impact on daily living. In some embodiments, impact on daily living may be measured by physical function, balance, daily activities, mobility, sleep, transfers, and / or falls. In some embodiments, symptom severity is measured by a symptom severity rating scale in which the subject rates the symptom on a scale of 0 to 10, with 0 indicating minimal severity and 10 indicating severe severity.

[0348] In some embodiments, SMA subjects selected for treatment with a myostatin inhibitor, e.g., a selective myostatin inhibitor, e.g., apitegromab, complain of at least one of muscle weakness or stiffness, fatigue, pain, elimination dysfunction, or bulbar dysfunction. In some embodiments, symptoms of bulbar dysfunction include respiratory infections; use of assistive devices; inability to clear lung secretions by coughing; difficulty breathing; difficulty eating / swallowing; difficulty speaking; and snoring. In some embodiments, symptoms of muscle weakness or stiffness include problems with balance, stiff muscles and tendons, decreased muscle tone, and difficulty chewing or smiling. In some embodiments, symptoms of elimination dysfunction include urinary and bowel disorders. In some embodiments, treatment with a myostatin inhibitor, e.g., a selective myostatin inhibitor, e.g., apitegromab, unexpectedly results in an improvement in the quality of life of such patients, e.g., after 24 months of apitegromab treatment, wherein the improvement includes an improvement in at least one of the symptoms of muscle weakness or stiffness, fatigue, pain, elimination dysfunction, or bulbar dysfunction as reported by the subject or the subject's caregiver.

[0349] Methods, Uses, and Compositions for Treating SMA In various embodiments, apitegromab therapy is administered to achieve a mean serum concentration (C) of about 25 to 250 micrograms per milliliter. trough In some embodiments, apitegromab therapy is administered in an amount (alone or in combination with at least one additional therapy) that achieves a mean serum concentration (C) of about 25 to 700 micrograms per milliliter. max The therapeutic agent is administered (alone or in combination with at least one additional therapy) in an amount that achieves the therapeutic effect.

[0350] In some embodiments, the present disclosure provides a method of treating SMA in a human subject, comprising administering to the subject a composition comprising apitegromab by intravenous infusion every four weeks or monthly for at least six or twelve months in an amount sufficient to prevent or delay a decline in RHS score compared to the pre-treatment baseline score. In some embodiments, the present disclosure provides a composition comprising apitegromab for use in treating SMA in a human subject, wherein the subject is administered apitegromab by intravenous infusion every four weeks or monthly for at least six, twelve, or twenty-four months in an amount sufficient to prevent or delay a decline in RHS score compared to the pre-treatment baseline score. In some embodiments, the present disclosure provides a use of a composition comprising apitegromab for treating SMA in a human subject, wherein the subject is administered apitegromab by intravenous infusion every four weeks or monthly for at least six, twelve, or twenty-four months in an amount sufficient to prevent or delay a decline in RHS score compared to the pre-treatment baseline score. In some embodiments, the disclosure provides the use of apitegromab in the manufacture of a composition for treating SMA in a human subject, wherein the subject is administered apitegromab by intravenous infusion every four weeks or monthly for at least six, twelve, or twenty-four months in an amount sufficient to prevent or delay a decline in RHS score compared to a pre-treatment baseline score.

[0351] In some embodiments, the SMA is late-onset SMA. In some embodiments, the SMA is ambulatory type 3 SMA. In some embodiments, the subject is 2 to 12, 5 to 21, 13 to 21, or 2 to 21 years old. In some embodiments, the sufficient amount is a dose of more than 2 mg / kg up to 20 mg / kg, optionally about 5, 10, 15, or 20 mg / kg. In some embodiments, the sufficient amount is a dose of 10 mg / kg or 20 mg / kg of apitegromab every four weeks or monthly.

[0352] In some embodiments, apitegromab is administered in an amount that stabilizes or reduces the RHS score by less than 0.4 points, for example, after at least 12 months of treatment. In some embodiments, apitegromab is administered in an amount that causes an average increase in RHS score of at least 0.2 points compared to the baseline score before treatment, optionally an average increase in RHS score of 0.3 points, 0.5 points, at least 0.7 points, at least 1 point, at least 2 points, or at least 3 points compared to baseline, for example, an average increase in a cohort of at least 11 subjects. In some embodiments, apitegromab is administered in an amount that causes an average increase in RHS score of at least 1 point compared to baseline, for example, an average increase in a cohort of at least 11 subjects. In some embodiments, apitegromab is administered in an amount that causes an average increase in RHS score of at least 3 points compared to baseline, for example, an average increase in a cohort of at least 11 subjects. In some embodiments, apitegromab is administered in an amount that stabilizes the RHS score, e.g., when assessed relative to baseline after at least 12 months of treatment. In some embodiments, apitegromab is administered in an amount that prevents a decline in the RHS score of about 0.5, 0.4, 0.3, 0.2, or 0.1, e.g., when assessed relative to baseline after at least 12 months of treatment.

[0353] In some embodiments, the subject is treated with an SMN-upregulator therapy. In some embodiments, the SMN-upregulator therapy is nusinersen or risdiplam. In some embodiments, the subject is treated with gene therapy. In some embodiments, the gene therapy is onasemnogene abeparvovec. In some embodiments, the SMN-upregulator therapy is nusinersen. In some embodiments, the subject initiated the SMN-upregulator therapy at age 5 or later. In some embodiments, apitegromab is administered in an amount that stabilizes the RHS score, e.g., when assessed relative to baseline after at least 12 months of treatment. In some embodiments, apitegromab is administered in an amount that prevents a decline in the RHS score of about 0.5, 0.4, 0.3, 0.2, or 0.1, e.g., when assessed relative to baseline after at least 12 months of treatment. In some embodiments, apitegromab is administered in an amount that results in a mean increase in RHS score of at least 0.3 points compared to baseline, e.g., in a cohort of at least 11 subjects. In some embodiments, apitegromab is administered in an amount that results in a mean increase in RHS score of at least 0.7 points compared to baseline after 8 weeks, e.g., in a cohort of at least 11 subjects. In some embodiments, this amount is a dose of 20 mg / kg apitegromab every 4 weeks or every month.

[0354] In some embodiments, the subject is not treated with an SMN-upregulatory drug. In some embodiments, apitegromab is administered in an amount that stabilizes the RHS score, for example, when assessed relative to baseline after at least 12 months of treatment. In some embodiments, apitegromab is administered in an amount that inhibits a decline in the RHS score of about 0.5, 0.4, 0.3, 0.2, or 0.1, for example, when assessed relative to baseline after at least 12 months of treatment. In some embodiments, apitegromab is administered in an amount that causes a mean increase in the RHS score of at least 0.7 points relative to baseline, for example, a mean increase in a cohort of at least 11 subjects. In some embodiments, apitegromab is administered in an amount that causes a mean increase in the RHS score of at least 0.7 points relative to baseline after 8 weeks, for example, a mean increase in a cohort of at least 11 subjects. In some embodiments, this amount is a dose of 20 mg / kg apitegromab every 4 weeks or monthly.

[0355] In some embodiments, apitegromab is administered at a serum concentration (C) of at least about 100 micrograms per milliliter, e.g., about 100 to 500 micrograms per milliliter (e.g., about 100, 200, 300, 400, or 500 micrograms per milliliter), e.g., as determined on average over a course of treatment of at least 12 months. trough In some embodiments, the serum concentration (C trough ) is about 100 to 450 micrograms per milliliter. In some embodiments, this amount is a 20 mg / kg apitegromab dose every four weeks or every month.

[0356] In some embodiments, apitegromab has a serum concentration (C) of at least about 300 micrograms per milliliter, e.g., as determined on average over a course of treatment of at least 12 months. max In some embodiments, the serum concentration (C max) is at least about 300 to 1100 micrograms per milliliter, e.g., 300 to 800. In some embodiments, the serum concentration (C max ) is at least 600 micrograms of apitegromab per milliliter (e.g., at least 600, 700, 800, 900, 1000 micrograms per milliliter, or more). In some embodiments, the serum concentration is about 600-1000 micrograms per milliliter. In some embodiments, the serum concentration is a steady-state serum concentration. In some embodiments, apitegromab is administered in an amount that achieves a steady-state serum concentration after about 112 days. In some embodiments, this amount is a 20 mg / kg apitegromab dose every four weeks or every month.

[0357] In some embodiments, apitegromab is administered in an amount sufficient to achieve target engagement as measured by a serum latent myostatin concentration of at least about 100 nanograms per milliliter when determined at steady state over a course of at least 12 months of treatment. In some embodiments, apitegromab is administered in an amount sufficient to achieve target engagement as measured by a serum latent myostatin concentration of at least about 250 nanograms per milliliter when determined at steady state over a course of at least 12 months of treatment. In some embodiments, apitegromab is administered in an amount sufficient to achieve target engagement as measured by a serum latent myostatin concentration of at least about 400 nanograms per milliliter. In some embodiments, apitegromab is administered in an amount sufficient to achieve target engagement as measured by a serum latent myostatin concentration of at least 500 nanograms per milliliter (e.g., at least 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, or 1100 nanograms per milliliter). In some embodiments, the serum latent myostatin concentration is about 550 to 2400 nanograms per milliliter. In some embodiments, the serum latent myostatin concentration is a steady-state concentration measured at trough. In some embodiments, this amount is a 20 mg / kg apitegromab dose every four weeks or every month.

[0358] In some embodiments, apitegromab is administered in an amount that achieves one or more of the following in a subject: preserving motor function compared to deterioration in a control, delaying disease progression, delaying or preventing ambulatory loss in ambulatory patients with type 3 SMA, delaying or preventing the need for respiratory support or intervention, reducing the rate of deterioration of one or more motor function scores compared to a control, and / or maintaining at least a zero net change in one or more motor function scores compared to baseline. In some embodiments, this amount is a dose of 20 mg / kg apitegromab every four weeks or monthly. In certain embodiments, the control refers to the natural history of untreated subjects with SMA.

[0359] In some embodiments, the disclosure provides a method of treating SMA in a human subject, the method comprising administering to the subject a composition comprising apitegromab and a composition comprising an SMN-upregulating agent, wherein the subject is administered apitegromab by intravenous infusion every 4 weeks or monthly for at least 6, 12, or 24 months in an amount sufficient to produce a mean increase in HFMSE score of at least 0.5 or 1 point (e.g., at least 2, 3, 4, 5, or 6 points) relative to the pre-treatment baseline score, e.g., a mean increase in a cohort of at least 13 or 14 subjects. In some embodiments, the disclosure provides a composition comprising apitegromab for use in treating SMA in a human subject receiving an SMN-upregulating drug, wherein the subject is administered apitegromab by intravenous infusion every 4 weeks or monthly for at least 6, 12, or 24 months in an amount sufficient to produce a mean increase in HFMSE score of at least 0.5 or 1 point (e.g., at least 2, 3, 4, 5, or 6 points) relative to the pre-treatment baseline score, e.g., a mean increase in a cohort of at least 13 or 14 subjects. In some embodiments, the disclosure provides for the use of a composition comprising apitegromab to treat SMA in a human subject receiving an SMN-upregulating drug, wherein the subject is administered apitegromab by intravenous infusion every 4 weeks or monthly for at least 6, 12, or 24 months in an amount sufficient to produce a mean increase in HFMSE score of at least 0.5 or 1 point (e.g., at least 2, 3, 4, 5, or 6 points) relative to the pre-treatment baseline score, e.g., a mean increase in a cohort of at least 13 or 14 subjects.In some embodiments, the disclosure provides for the use of apitegromab in the manufacture of a composition for treating SMA in a human subject receiving an SMN-upregulating drug, wherein the subject is administered apitegromab by intravenous infusion every 4 weeks or monthly for at least 6, 12, or 24 months in an amount sufficient to produce a mean increase in HFMSE score of at least 0.5 or 1 point (e.g., at least 2, 3, 4, 5, or 6 points) relative to the pre-treatment baseline score, e.g., a mean increase in a cohort of at least 13 or 14 subjects.

[0360] In some embodiments, the SMA is late-onset SMA. In some embodiments, the SMA is Type 2 SMA. In some embodiments, the SMA is non-ambulatory Type 3 SMA. In some embodiments, the subject is 2-12, 5-21, 13-21, or 2-21 years old. In some embodiments, the SMN-upregulatory drug therapy is nusinersen or risdiplam. In some embodiments, the gene therapy is onasemnogene abeparvovec. In some embodiments, the SMN-upregulatory drug therapy is nusinersen. In some embodiments, the sufficient amount is a dose of greater than 2 mg / kg up to and including 20 mg / kg, optionally about 5, 10, 15, or 20 mg / kg. In some embodiments, the sufficient amount is a dose of 10 mg / kg or 20 mg / kg apitegromab every four weeks or every month.

[0361] In some embodiments, apitegromab is administered in an amount that results in an increase in HFMSE score of at least 0.5 or 1 point compared to baseline, e.g., an average increase in a cohort of at least 13 or 14 subjects, after 16 weeks. In some embodiments, apitegromab is administered in an amount that results in an increase in HFMSE score of at least 2 points, at least 3 points, at least 4 points, or at least 5 points compared to baseline, e.g., an average increase in a cohort of at least 13 or 14 subjects. In some embodiments, apitegromab is administered in an amount that results in an increase in HFMSE score of at least 3 points compared to baseline, e.g., an average increase in a cohort of at least 13 or 14 subjects. In some embodiments, apitegromab is administered in an amount that results in an increase in HFMSE score of at least 5 points compared to baseline, e.g., an average increase in a cohort of at least 13 or 14 subjects. In some embodiments, this amount is a dose of 20 mg / kg apitegromab every 4 weeks or every month.

[0362] In some embodiments, apitegromab is administered to a patient with a serum concentration (C) of apitegromab of at least about 300 micrograms per milliliter, e.g., at least about 400, 500, 600, 700, 800, 900, 1000, or 1100. max In some embodiments, apitegromab is administered in an amount that achieves a serum concentration of at least 600 micrograms per milliliter of apitegromab (e.g., at least 600, 700, 800, 900, 1000 micrograms per milliliter, or more). In some embodiments, the serum concentration is about 600-1000 micrograms per milliliter. In some embodiments, the serum concentration is a steady-state serum concentration. In some embodiments, apitegromab is administered in an amount that achieves a steady-state serum concentration after about 112 days. In some embodiments, this amount is a 20 mg / kg apitegromab dose every four weeks or every month.

[0363] In some embodiments, apitegromab has a serum concentration (C) of at least about 100 micrograms per milliliter, e.g., at least about 200, 300, or 400 micrograms per milliliter. trough In some embodiments, this amount is a 20 mg / kg apitegromab dose every four weeks or every month.

[0364] In some embodiments, apitegromab is administered in an amount sufficient to achieve target engagement of at least about 250 nanograms per milliliter, e.g., at least about 400 or 500 nanograms per milliliter (e.g., at least 500, 550, 600, or 650 nanograms per milliliter), as measured by serum latent myostatin levels. In some embodiments, the serum latent myostatin level is between about 550 and 1650 nanograms per milliliter. In some embodiments, the serum latent myostatin level is a steady-state level measured at trough. In some embodiments, this amount is a 20 mg / kg apitegromab dose every four weeks or every month.

[0365] In some embodiments, apitegromab is administered in an amount that achieves one or more of the following in a subject: preserving motor function compared to deterioration in controls, delaying disease progression, delaying or preventing ambulatory loss in ambulatory Type 3 SMA patients, delaying or preventing the need for respiratory support or intervention, reducing the rate of deterioration of one or more motor function scores compared to controls, and / or maintaining at least a zero net change in one or more motor function scores compared to baseline. In some embodiments, this amount is a dose of 20 mg / kg apitegromab every four weeks or every month.

[0366] In some embodiments, the disclosure provides a method of treating SMA in a human subject, the method comprising administering to the subject a composition comprising apitegromab and a composition comprising an SMN-upregulator, wherein the subject is administered apitegromab by intravenous infusion every 4 weeks or monthly for at least 6, 12, or 24 months in an amount sufficient to produce a mean increase in HFMSE score of at least 2 points compared to the pre-treatment baseline score, e.g., a mean increase in a cohort of at least 8 or 9 subjects, and wherein the subject initiated SMN-upregulator therapy at less than 5 years of age.

[0367] In some embodiments, the disclosure provides a composition comprising apitegromab for use in treating SMA in a human subject receiving an SMN-upregulator, wherein the subject is administered apitegromab by intravenous infusion every 4 weeks or monthly for at least 6, 12, or 24 months in an amount sufficient to produce a mean increase in HFMSE score of at least 2 points compared to the pre-treatment baseline score, e.g., a mean increase in a cohort of at least 8 or 9 subjects, and wherein the subject initiated SMN-upregulator therapy at less than 5 years of age.

[0368] In some embodiments, the disclosure provides for the use of a composition comprising apitegromab to treat SMA in a human subject receiving an SMN-upregulator, wherein the subject is administered apitegromab by intravenous infusion every 4 weeks or monthly for at least 6, 12, or 24 months in an amount sufficient to produce a mean increase in HFMSE score of at least 2 points compared to the pre-treatment baseline score, e.g., a mean increase in a cohort of at least 9 subjects, and wherein the subject initiated SMN-upregulator therapy at less than 5 years of age.

[0369] In some embodiments, the disclosure provides for the use of apitegromab in the manufacture of a composition for treating SMA in a human subject receiving an SMN-upregulator, wherein the subject is administered apitegromab by intravenous infusion every 4 weeks or monthly for at least 6, 12, or 24 months in an amount sufficient to produce a mean increase in HFMSE score of at least 2 points compared to the pre-treatment baseline score, e.g., a mean increase in a cohort of at least 8 or 9 subjects, and wherein the subject initiated SMN-upregulator therapy at less than 5 years of age.

[0370] In some embodiments, the SMA is late-onset SMA. In some embodiments, the SMA is type 2 SMA. In some embodiments, the subject is 2 years of age or older. In some embodiments, the SMN-upregulatory drug therapy is nusinersen or risdiplam. In some embodiments, the gene therapy is onasemnogene abeparvovec. In some embodiments, the SMN-upregulatory drug therapy is nusinersen. In some embodiments, the sufficient amount is a dose of more than 2 mg / kg up to 20 mg / kg, optionally about 5, 10, 15, or 20 mg / kg. In some embodiments, the sufficient amount is a dose of 10 mg / kg or 20 mg / kg apitegromab every 4 weeks or every month.

[0371] In some embodiments, apitegromab is administered in an amount that results in a mean increase in HFMSE score of at least 2 points compared to baseline, e.g., a mean increase in a cohort of at least 8 or 9 subjects, after 12 or 24 months. In some embodiments, apitegromab is administered in an amount that results in a mean increase in HFMSE score of at least 3 points, at least 4 points, at least 5 points, at least 6 points, or at least 7 points compared to baseline, e.g., a mean increase in a cohort of at least 8 or 9 subjects, e.g., after at least 12 months of treatment, e.g., after at least 24 months of treatment. In some embodiments, apitegromab is administered in an amount that results in a mean increase in HFMSE score of at least 3 points compared to baseline, e.g., a mean increase in a cohort of at least 8 or 9 subjects. In some embodiments, apitegromab is administered in an amount that results in a mean increase in HFMSE score of at least 5 points compared to baseline, e.g., a mean increase in a cohort of at least 8 subjects. In some embodiments, apitegromab is administered in an amount that results in a mean increase in HFMSE score of at least 6 points compared to baseline, e.g., a mean increase in a cohort of at least 8 or 9 subjects. In some embodiments, apitegromab is administered in an amount that results in a mean increase in HFMSE score of at least 7 points compared to baseline, e.g., a mean increase in a cohort of at least 8 or 9 subjects. In some embodiments, this amount is a dose of 20 mg / kg apitegromab every 4 weeks or every month.

[0372] In some embodiments, apitegromab is administered to a patient with a serum concentration (C) of apitegromab of at least about 25 to 1100 micrograms per milliliter. maxIn some embodiments, apitegromab is administered at 2 mg / kg to achieve a serum concentration of about 25 to 55 micrograms per milliliter. In some embodiments, apitegromab is administered at greater than 2 mg / kg but not greater than 20 mg / kg to achieve a serum concentration of about 250 to 1100 micrograms per milliliter. In some embodiments, the serum concentration is 600 micrograms per milliliter of apitegromab (e.g., at least 600, 700, 800, 900, 1000 micrograms per milliliter or more). In some embodiments, the serum concentration is about 600 to 1000 micrograms per milliliter. In some embodiments, the serum concentration is a steady-state serum concentration. In some embodiments, apitegromab is administered in an amount to achieve a steady-state serum concentration after about 112 days or about 5 half-lives. In some embodiments, the amount of more than 2 mg / kg up to 20 mg / kg is a dose of 20 mg / kg apitegromab every four weeks or every month. In some embodiments, increasing the dose of apitegromab increases serum concentrations (C max ) there is a dose response, for example, a 10-fold increase in dose from 2 mg / kg to 20 mg / kg results in a C max A ten-fold increase occurs.

[0373] In some embodiments, apitegromab is administered to a patient with a serum concentration (C) of at least about 25 micrograms per milliliter of apitegromab, e.g., at least about 50, 100, 200, 300, or 400 micrograms per milliliter of apitegromab. trough ) in some embodiments. In some embodiments, apitegromab is administered at 2 mg / kg to achieve a serum concentration of about 25 to 55 micrograms per milliliter. In some embodiments, apitegromab is administered at more than 2 mg / kg but not more than 20 mg / kg to achieve a serum concentration of about 100 to 400 micrograms per milliliter. In some embodiments, the amount of more than 2 mg / kg but not more than 20 mg / kg is a dose of 20 mg / kg of apitegromab every four weeks or every month. In some embodiments, increasing the dose of apitegromab increases the serum concentration (C trough) there is a dose response, for example, a 10-fold increase in dose from 2 mg / kg to 20 mg / kg results in a C trough A ten-fold increase occurs.

[0374] In some embodiments, apitegromab is administered in an amount sufficient to achieve target engagement as measured by serum latent myostatin levels of at least about 250 nanograms per milliliter, e.g., at least about 400 nanograms per milliliter or 500 nanograms per milliliter (e.g., at least 500, 550, 600, or 650 nanograms per milliliter). In some embodiments, the serum latent myostatin level is about 550-1100 or 600-1000 nanograms per milliliter. In some embodiments, the serum latent myostatin level is a steady-state level measured at trough. In some embodiments, this amount is a 20 mg / kg apitegromab dose every four weeks or every month.

[0375] In some embodiments, apitegromab is administered in an amount that achieves one or more of the following in a subject: preserving motor function compared to deterioration in controls, delaying disease progression, delaying or preventing ambulatory loss in ambulatory Type 3 SMA patients, delaying or preventing the need for respiratory support or intervention, reducing the rate of deterioration of one or more motor function scores compared to controls, and / or maintaining at least a zero net change in one or more motor function scores compared to baseline. In some embodiments, this amount is a dose of 20 mg / kg apitegromab every four weeks or every month.

[0376] In some embodiments, the disclosure provides a method of treating SMA, comprising administering to a patient population a composition comprising apitegromab, wherein the patient population is administered apitegromab by intravenous infusion every 4 weeks or monthly for at least 6, 12, or 24 months in an amount sufficient to increase the clinical response rate (proportion of responders) in the patient population, and wherein the clinical response rate is measured by the 6-minute walk test and / or the 30-second stand test. In some embodiments, the disclosure provides a composition comprising apitegromab for use in the treatment of SMA, wherein the patient population is administered apitegromab by intravenous infusion every 4 weeks or monthly for at least 6, 12, or 24 months in an amount sufficient to increase the clinical response rate (proportion of responders) in the patient population, and wherein the clinical response rate is measured by the 6-minute walk test and / or the 30-second stand test. In some embodiments, the disclosure provides the use of a composition comprising apitegromab for treating SMA, wherein a patient population is administered apitegromab by intravenous infusion every 4 weeks or monthly for at least 6, 12, or 24 months in an amount sufficient to increase the clinical response rate (proportion of responders) in the patient population, and wherein the clinical response rate is measured by the 6-minute walk test and / or the 30-second stand test. In some embodiments, the disclosure provides the use of apitegromab in the manufacture of a composition for treating SMA, wherein a patient population is administered apitegromab by intravenous infusion every 4 weeks or monthly for at least 6, 12, or 24 months in an amount sufficient to increase the clinical response rate (proportion of responders) in the patient population, and wherein the clinical response rate is measured by the 6-minute walk test and / or the 30-second stand test.

[0377] In some embodiments, the patient population is a late-onset SMA population. In some embodiments, the patient population is an ambulatory type 3 SMA population. In some embodiments, the patient population includes human subjects between the ages of 5 and 21. In some embodiments, the patient population is treated with an SMN-upregulatory drug therapy. In some embodiments, the SMN-upregulatory drug therapy is nusinersen or risdiplam. In some embodiments, the gene therapy is onasemnogene abeparvovec. In some embodiments, the SMN-upregulatory drug therapy is nusinersen. In some embodiments, the patient population initiated SMN-upregulatory drug therapy at age greater than 5 years. In some embodiments, the sufficient amount is a dose of greater than 2 mg / kg and up to 20 mg / kg, optionally about 5, 10, 15, or 20 mg / kg. In some embodiments, the sufficient amount is a dose of 10 mg / kg or 20 mg / kg apitegromab every 4 weeks or every month.

[0378] In some embodiments, apitegromab is administered in an amount that achieves a serum concentration of at least 600 micrograms per milliliter of apitegromab (e.g., at least 600, 700, 800, 900, 1000 micrograms per milliliter, or more). In some embodiments, the serum concentration is about 600-1000 micrograms per milliliter. In some embodiments, the serum concentration is a steady-state serum concentration. In some embodiments, apitegromab is administered in an amount that achi...

Claims

1. A composition comprising an antibody or an antigen-binding fragment thereof for use in the treatment of spinal muscular atrophy (SMA) in humans, wherein the treatment comprises intravenous administration of the composition at intervals of once every four weeks for at least 24 months or 2 years. The composition comprises the antibody or its antigen-binding fragment in an amount of 20 mg / kg. The antibody or its antigen-binding fragment comprises six complementarity-determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3: a) CDRH1 contains the amino acid sequence of SEQ ID NO: 1, CDRH2 contains the amino acid sequence of SEQ ID NO: 2, CDRH3 contains the amino acid sequence of SEQ ID NO: 3, CDRL1 contains the amino acid sequence of SEQ ID NO: 4, CDRL2 contains the amino acid sequence of SEQ ID NO: 5, and CDRL3 comprises the amino acid sequence of Sequence ID No. 6, where the CDR sequence is numbered according to the Kabat numbering scheme; or b) CDRH1 contains the amino acid sequence of SEQ ID NO: 7, CDRH2 contains the amino acid sequence of SEQ ID NO: 8, CDRH3 contains the amino acid sequence of SEQ ID NO: 9, CDRL1 contains the amino acid sequence of SEQ ID NO: 10, CDRL2 contains the amino acid sequence of SEQ ID NO: 11, and CDRL3 contains the amino acid sequence of Sequence ID No. 12, where the CDR sequence is numbered according to the IMGT numbering scheme. Composition for use.

2. The composition for use according to claim 1, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 13 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

14.

3. The composition for use according to claim 1, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 15 and a light chain having the amino acid sequence of SEQ ID NO:

16.

4. The composition for use according to claim 1, wherein the composition is administered as monotherapy or as an add-on therapy to survival motor neuron (SMN) therapy.

5. The aforementioned SMN therapy, (i) SMN2 splicing modifiers; (ii) SMN1 gene replacement or gene therapy; (iii) SMN1 or SMN2 transcription enhancers; (iv) SMN protein translation enhancers; or (v) SMN protein stabilizers A composition for use according to claim 4, comprising:

6. The composition for use according to claim 4, wherein the SMN therapy comprises nusinersen or risdiplam.

7. The composition for use according to claim 1, wherein the treatment is sufficient to increase the motor function of the human subject compared to baseline when measured 24 months after the start of administration of the composition.

8. The composition for use according to claim 1, wherein the treatment is sufficient to delay the loss of motor function in the human subject compared to baseline, as measured 24 months after the start of administration of the composition.

9. The composition for use according to claim 7, wherein the aforementioned increase in motor function is measured by the Hammersmith Functional Motor Scale-Expanded (HFMSE) score, the Revised Hammersmith Scale (RHS) score, the Revised Upper Limb Module (RULM) score, and / or one or more of the WHO Motor Development Milestones.

10. The composition for use according to claim 9, wherein the increase in motor function is measured by an HFMSE score, and the HFMSE score of the subject increases by at least 1, 2, 3, or 4 points compared to baseline at 24 months after the start of administration of the composition.

11. The composition for use according to claim 9, wherein the increase in motor function is measured by an HFMSE score, and the HFMSE score of the subject increases by at least 1, 2, 3, or 4 points at 24 months after the start of administration of the composition compared to 12 months after the start of administration of the composition.

12. The composition for use according to claim 9, wherein the increase in motor function is measured by the HFMSE score and / or RULM score at 24 months after the start of administration of the composition.

13. The composition for use according to claim 8, wherein the delay in loss of motor function is measured by the Hammersmith Functional Motor Scale-Expanded (HFMSE) score, the Revised Hammersmith Scale (RHS) score, the Revised Upper Limb Module (RULM) score, and / or one or more of the WHO Motor Development Milestones.

14. The composition for use according to claim 7, wherein the increase in motor function compared to baseline correlates with the level of target engagement compared to baseline, as measured 24 months after the start of administration of the composition.

15. The composition for use according to claim 1, wherein the subject is at least two years old.

16. The composition for use according to claim 1, wherein the subject is between 2 and 21 years of age.

17. The composition for use according to claim 1, wherein the subject is 2 to 12 years of age.

18. The composition for use according to claim 1, wherein the subject is 5 to 21 years of age.

19. The composition for use according to claim 1, wherein the subject has a walkable SMA.

20. The composition for use according to claim 1, wherein the subject has a non-walking SMA.

21. The composition for use according to claim 1, wherein the treatment is sufficient to improve the quality of life of the human subject as measured 24 months after the start of administration of the composition.

22. The composition for use according to claim 21, wherein the quality of life is measured by the Endurance Shuttle Box and Block Test (ES-BBT).

23. The composition for use according to claim 22, wherein the ES-BBT score of the subject increases compared to baseline 12 months after administration of the composition.

24. The composition for use according to claim 23, wherein the ES-BBT score of the subject increases further 24 months after administration of the composition compared to the score at 12 months.

25. A composition comprising a myostatin inhibitor for use in the treatment of spinal muscular atrophy (SMA) in a subject receiving survival motor neuron (SMN) therapy, wherein the subject suffers from fatigue, bulbar dysfunction, and / or excretory dysfunction as measured by subject or caregiver-reported outcomes.

26. The composition for use according to claim 25, wherein the myostatin inhibitor inhibits myostatin, GDF11, and activin A.

27. ​​The composition for use according to claim 25, wherein the myostatin inhibitor inhibits myostatin and GDF11 but does not inhibit activin A.

28. The composition for use according to claim 25, wherein the myostatin inhibitor is a myostatin selective inhibitor that does not bind to or inhibit GDF11 or activin A.

29. The composition for use according to claim 28, wherein the myostatin selective inhibitor is a neutralizing antibody or an antigen-binding fragment thereof that selectively binds to myostatin but does not bind to GDF11 or activin A.

30. The composition for use according to claim 28, wherein the myostatin selective inhibitor is an antibody or antigen-binding fragment thereof that binds to promyostatin / latent myostatin.

31. The composition for use according to claim 28, wherein the myostatin selective inhibitor inhibits the activation of mature myostatin.

32. The antibody or its antigen-binding fragment comprises six complementarity-determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3: a) CDRH1 contains the amino acid sequence of SEQ ID NO: 1, CDRH2 contains the amino acid sequence of SEQ ID NO: 2, CDRH3 contains the amino acid sequence of SEQ ID NO: 3, CDRL1 contains the amino acid sequence of SEQ ID NO: 4, CDRL2 contains the amino acid sequence of SEQ ID NO: 5, and CDRL3 comprises the amino acid sequence of Sequence ID No. 6, where the CDR sequence is numbered according to the Kabat numbering scheme; or b) CDRH1 contains the amino acid sequence of SEQ ID NO: 7, CDRH2 contains the amino acid sequence of SEQ ID NO: 8, CDRH3 contains the amino acid sequence of SEQ ID NO: 9, CDRL1 contains the amino acid sequence of SEQ ID NO: 10, CDRL2 contains the amino acid sequence of SEQ ID NO: 11, and CDRL3 contains the amino acid sequence of Sequence ID No. 12, where the CDR sequence is numbered according to the IMGT numbering scheme. A composition for use according to claim 30.

33. The composition for use according to claim 30, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 13 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

14.

34. The composition for use according to claim 30, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 15 and a light chain having the amino acid sequence of SEQ ID NO:

16.

35. The composition for use according to claim 28, wherein the myostatin selective inhibitor is apiteglomab (SRK-015), GYM329 (RO7204239), a variant of apiteglomab or GYM329, or an antibody that cross-blocks or cross-competes with apiteglomab or GYM329 in terms of antigen binding.

36. a) The subject has a type 2 SMA or a type 3 SMA; b) The subject has two, three, four, or five copies of the smn2 gene; c) The subject has a walkable SMA or a non-walkable SMA; and / or, d) The subject is 2 years of age or older at the start of administration of the composition, The composition for use according to claim 25.

37. The composition for use according to claim 36, wherein the subject is 2 to 13 years of age.

38. The composition for use according to claim 36, wherein the subject is between 2 and 21 years of age.

39. The composition for use according to claim 25, wherein the SMN therapy is an smn2 splicing modifier or an smn1 gene therapy.

40. A composition comprising an antibody or an antigen-binding fragment thereof for use in the treatment of a subject having type 2 or non-walking type 3 SMA, wherein the composition comprises the antibody or the antigen-binding fragment thereof in an amount sufficient to achieve an increase of at least 2 points from baseline in the subject's Revised Upper Limb Module (RULM) score as measured 24 months after the start of administration of the composition. The antibody or its antigen-binding fragment comprises six complementarity-determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3: a) CDRH1 contains the amino acid sequence of SEQ ID NO: 1, CDRH2 contains the amino acid sequence of SEQ ID NO: 2, CDRH3 contains the amino acid sequence of SEQ ID NO: 3, CDRL1 contains the amino acid sequence of SEQ ID NO: 4, CDRL2 contains the amino acid sequence of SEQ ID NO: 5, and CDRL3 comprises the amino acid sequence of Sequence ID No. 6, where the CDR sequence is numbered according to the Kabat numbering scheme; or b) CDRH1 contains the amino acid sequence of SEQ ID NO: 7, CDRH2 contains the amino acid sequence of SEQ ID NO: 8, CDRH3 contains the amino acid sequence of SEQ ID NO: 9, CDRL1 contains the amino acid sequence of SEQ ID NO: 10, CDRL2 contains the amino acid sequence of SEQ ID NO: 11, and CDRL3 contains the amino acid sequence of Sequence ID No. 12, where the CDR sequence is numbered according to the IMGT numbering scheme. Composition for use.

41. The composition for use according to claim 40, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 13 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

14.

42. The composition for use according to claim 40, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 15 and a light chain having the amino acid sequence of SEQ ID NO:

16.

43. A method for determining the therapeutic efficacy of myostatin inhibitor therapy in patients with spinal muscular atrophy (SMA), i) Determining the baseline level of serum creatinine from a serum sample taken from the subject before initiating the myostatin inhibitor treatment; ii) Determining the level of serum creatinine from a serum sample taken from the subject after the initiation of myostatin inhibitor treatment; and iii) Comparing the serum creatinine level from step (ii) with the baseline serum creatinine level from step (i). Including; A method wherein the increase in the serum creatinine level from step (ii) compared to the serum creatinine level from step (i) serves as an indicator of the effectiveness of the myostatin inhibitor treatment.

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