Use of anti-promyostatin / anti-latent myostatin antibodies to treat spinal muscular atrophy

Abstract

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 subjects, either as monotherapy or as an adjunct to motor neuron-directed therapies such as SMN upregulator / modifier therapies.

Description

[Technical Field]

[0001] Sequence List This application includes a sequence listing submitted electronically in ASCII format, which is incorporated herein by reference in its entirety. The ASCII copy, created on October 22, 2021, is named 15094_0012-00304_SL.txt and has a size of 30,325 bytes.

[0002] Related applications This application covers the following U.S. Provisional Patent Applications: 63 / 105,850, filed on October 26, 2020, titled "USE OF ANTI-PRO / LATENT MYOSTATIN ANTIBODY FOR TREATING SPINAL MUSCULAR ATROPHY"; 63 / 106,172, filed on October 27, 2020; 63 / 200,955, filed on April 5, 2021; 63 / 201,157, filed on April 15, 2021; and 63 / 202,317, filed on June 6, 2021. This invention claims the benefits and priority thereto of the following specifications: No. 63 / 202,372 filed on 8 June 1; No. 63 / 202,900 filed on 29 June 2021; No. 63 / 260,725 filed on 30 August 2021; and No. 63 / 261,398 filed on 20 September 2021, the contents of which are expressly incorporated herein by reference as a whole.

[0003] This disclosure relates to therapeutic methods, uses, and compositions comprising anti-promyostatin / anti-latent myostatin antibodies for the treatment of spinal muscular atrophy (SMA) in human patients. [Background technology]

[0004] Myostatin, also known as GDF-8 or GDF8, is a growth differentiation factor 8, a regulator of muscle homeostasis. Mutations that cause myostatin loss, as well as 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 molecule and biologics, have been evaluated in human patients targeting the treatment of various muscle disorders, but to date, none have achieved clinical success (Hanna et al. (2019) Lancet Neurol. 18(9):834-844; Rooks et al. (2020) JAMA Netw Open. 3(10):e2020836). While many have shown efficacy (e.g., increased muscle mass) in preclinical models, to date, none have successfully bridged that gap to deliver clinical benefit in treating muscle disorders in human patients. Furthermore, most of these inhibitors lacked selectivity, antagonizing other relevant growth factors such as activin A, raising concerns about toxicity. Most of these programs have now been discontinued. Thus, in many cases, satisfactory preclinical results have not led to a successful transition to safe and effective drugs.

[0005] As the only therapeutic target for muscular diseases, specifically for SMA, myostatin inhibition has been met with some skepticism. For example, it has been suggested that myostatin expression is reduced in SMA patients, which implies that myostatin may not be an effective therapeutic target (Burch et al. (2017) J Neurol. 264(3): 541-553; Mariot et al. (2017) Nat Commun. 8(1): 1859). Latres et al. (April 2017) suggested that rather than myostatin, activin A is a more prominent regulator of muscle mass in primates, and pointed out that activin A may be a better therapeutic target. In fact, despite the availability of their own selective myostatin inhibitors, the group later chose to enter clinical trials with a combination of a selective myostatin inhibitor and an activin A inhibitor at IBM. This program was subsequently discontinued.

[0006] SMA is a rare autosomal recessive neuromuscular disease characterized by atrophy of voluntary muscles of the limbs and trunk caused by degeneration of motor neurons in the anterior horn of the spinal cord. SMA is directly caused by reduced levels of survival motor neuron (SMN) protein resulting from homozygous deletion, and more rarely by mutations within the survival motor neuron 1 (SMN1) gene on chromosome 5q13.2. Deficiency of SMN protein causes motor neuron dysfunction, ultimately leading to death.

[0007] In some countries, SPINRAZA® (nusinersen) is approved for the treatment of pediatric and adult patients with SMA, and ZOLGENSMA® (onasemnogene abeparvovec) is approved for the treatment of pediatric SMA patients under 2 years of age with biallelic mutations in the SMN1 gene. In the United States and Europe, EVRYSDI™ (risdiplam), a small-molecule SMN therapy, is also approved. Nusinersen is an SMN2-directed antisense oligonucleotide (ASO) designed to treat SMA caused by mutations that lead to SMN protein deficiency. Risdiplam acts in a similar manner and is a pyridazine derivative that modifies the splicing of SMN2 messenger RNA. Onasemnogene abeparvovec is a recombinant adeno-associated virus serotype 9-based gene therapy designed to deliver a copy of the gene encoding human SMN protein.

[0008] SMN therapy (or SMN-directed therapy), including nusinersen, risdiplam, onasemnogene abeparvovec, and other products under investigation, primarily acts on motor neurons to prevent further loss. Consistent with this concept, clinical data reported from extended SMN-directed therapy indicate that after improvement, as measured by the mean change from baseline in HFMSE scores, during the first 15 months of treatment with nusinersen, the effect appears to stabilize at a near-steady state. Further enhancement of motor function is limited over the following three years or more (Darras et al. (2019) Neurology 92(21):e2492-e2506). Similarly, long-term evaluations of risdiplam showed only stabilization or minor / undefined improvement 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 MDA Clinical and Scientific Conference 2021; March 15-18. Poster 80). Therefore, SMN-targeted therapy can help maintain motor function over time, but its ability to provide long-term enhancement of motor function is limited. Thus, while approved treatments show improvement in motor function in young SMA patients, especially in the early stages of treatment, they do not have a direct effect on the muscles that would address the pre-existing atrophy and motor dysfunction in symptomatic SMA patients.

[0009] The applicant of this disclosure previously identified at least three criteria for selecting indications in which myostatin inhibition is likely to be particularly advantageous: i) the target muscle exhibits anabolic activity (e.g., is still in the growth phase); ii) the motor unit (motor neuron and the target muscle it innervates) is at least partially functionally intact; and iii) the target muscle preferentially relies on fast-twitch (type II) fibers (see International Publication No. 2017 / 218592). Based on this understanding, the applicant has demonstrated the therapeutic effect of selective myostatin inhibition in a preclinical model of SMA in which motor unit function is enhanced by concomitant SMN augmentation therapy (e.g., SMN upregulator / corrector therapy) addressing criterion (ii) above, and has supported the concept that muscle enhancers such as myostatin inhibitors can be used to complement the effects of motor neuron enhancers, such as SMN upregulators / correctors. [Overview of the project] [Problems that the invention aims to solve]

[0010] Currently, there are no approved muscle-directed therapies (e.g., muscle-enhancing therapies) for the treatment of SMA. Consequently, there is a continuing need for effective muscle-directed therapies that can address muscle atrophy and motor dysfunction in SMA patients, but no such therapies have yet been pursued. [Means for solving the problem]

[0011] This disclosure includes, in particular, therapeutic methods, uses, and compositions for treating patients with SMA using muscle enhancers, such as apiteglomab, also known as SRK-015. In various embodiments, apiteglomab or compositions containing apiteglomab are used in the treatment of late-onset SMA in human subjects, either as monotherapy or as an adjunct to motor neuron-directed therapies, such as SMN upregulator / corrector therapy (i.e., SMN therapy). The data provided herein represent the first clinical demonstration of improved motor function in human patients by selective myostatin inhibition. Accordingly, this disclosure includes the identification and selection of SMA patients or patient populations that are likely to respond to or otherwise benefit from apiteglomab therapy as described herein. Data from type 2 and type 3 SMA patients who received this apiteglomab therapy over 12 months indicate, as a general trend, that the response is more robust in younger patient populations, regardless of the duration (or number of doses) of background therapy, such as SMN upregulator / corrector therapy. This is consistent with our earlier hypothesis that the anabolic capacity of target muscle may be a key factor in determining its responsiveness to myostatin inhibition (U.S. Patent No. 10,946,036, which is incorporated herein by reference in its entirety).

[0012] This specification provides apiteglomab therapy for treating subjects having SMA. According to this disclosure, delayed-onset SMA in human patients is treated using a composition comprising apiteglomab. Apiteglomab therapy involves intravenous administration of the composition to the patient at a therapeutic dose. The therapeutic dose refers to the amount of apiteglomab that produces a clinical benefit in the patient. The clinical benefit (e.g., efficacy) may be measured or determined by preferred clinical endpoints, such as those described herein. According to the data presented herein, in some embodiments, the therapeutic dose is apiteglomab greater than 2 mg / kg and less than or equal to 20 mg / kg when administered every four weeks (i.e., Q4W) or monthly. In some embodiments, therapeutic doses less than 20 mg / kg, such as 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12 mg / kg, and 15 mg / kg, may be considered. 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 a month. In some embodiments, the therapeutic dose is 20 mg / kg administered once every four weeks (i.e., Q4W) or once a month. In various embodiments, apiteglomab therapy may improve motor function in patients with late-onset SMA.

[0013] Pharmacokinetic (PK) analysis provides a relationship between the dosage (e.g., therapeutic dose) and bioavailability (serum exposure) of a therapeutic agent. In some embodiments, the therapeutic dose is defined as the serum concentration of apiteglomab measured in the trough at steady state (C trough This dose achieves or produces a serum exposure of approximately 25–250 μg / mL to apiteglomab. The dose that achieves this result may be administered via any preferred route, e.g., intravenously or subcutaneously.

[0014] In some embodiments, the therapeutic dose is determined by measuring the peak serum concentration of apiteglomab approximately 2 hours after administration (dose infusion) (C max), which is a dose that achieves or produces a serum exposure of approximately 1100 μg / mL or less, for example, approximately 25 to 1100 μg / mL. The dose that achieves this result may be administered by any preferred route, for example, intravenously or subcutaneously.

[0015] Pharmacodynamic (PD) analysis allows for the determination of target association as measured by serum concentration of latent myostatin (LM). In some embodiments, the therapeutic dose is preferably one that achieves or produces a serum concentration of at least about 100, or preferably at least about 250 ng / mL, of latent myostatin, measured at steady state, for example, 14 days or more after administration of apiteglomab. The dose that achieves this result may be administered by any preferred route, e.g., intravenously or subcutaneously. For example, the serum concentration of latent myostatin may be about 250 ng / mL or greater, 400 ng / mL or greater than 550 ng / mL or greater than 700 ng / mL or greater than 950 ng / mL or greater than 1100 ng / mL, etc.

[0016] Apiteglomab or another selective myostatin inhibitor may be used alone for the treatment of SMA (e.g., monotherapy) or in combination with another therapy, such as SMN-targeted therapy (e.g., add-on / adjuvant therapy or combination therapy). In some embodiments, subjects are treated with SMN upregulatory therapy. In some embodiments, SMN upregulatory therapy is nusinersen (SPINRAZA®), risdiplam (Evrysdi®), and / or onasemnogene abeparvovec (ZOLGENSMA®). In some embodiments, SMN control therapy is nusinersen. In some embodiments, SMN control therapy is risdiplam. In some embodiments, SMN control therapy is onasemnogene abeparvovec. In some embodiments, subjects initiated SMN upregulatory therapy at an age of 5 years or older.

[0017] In some embodiments, SMN-targeted therapy and apiteglomab therapy (e.g., muscle-targeted therapy) are used as a combination therapy. Thus, SMN modifiers and apiteglomab may be used in the treatment of a patient with late-onset SMA, where this therapy comprises the administration of an amount of SMN modifier and apiteglomab sufficient to treat the SMA, where apiteglomab therapy is administered intravenously to the patient every four weeks or monthly at a dose greater than 2 mg / kg and less than or equal to 20 mg / kg. In some embodiments, the SMN modifier is an SMN1-targeted gene therapy, where optionally, the SMN1-targeted therapy is a gene therapy. In some embodiments, the SMN modifier is an SMN2-targeted therapy, where optionally, the SMN2-targeted therapy is a splicing modifier. In some embodiments, the SMN modifier may be administered orally, intrathecally, or intravenously. In some embodiments, the patient has late-onset SMA. In some embodiments, the patient has type 2 SMA. In some embodiments, the patient has amblypophobic type 3 SMA. In some embodiments, the patient has walking-able type 3 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 starts this combination therapy at an age of less than 5 years. In some embodiments, the patient starts this combination therapy at an age of less than 2 years. In some embodiments, the patient starts this combination therapy at an age of less than 6 weeks after birth. In some embodiments, the patient starts this combination therapy at an age of 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), where optionally, the genetic screening is, for example, neonatal screening or intrauterine screening for one or more SMN1 mutations. In some embodiments, the patient is pre-symptomatic.

[0018] In some embodiments, apiteglomab therapy is used as an add-on or adjunctive therapy to the treatment of SMA. Thus, a composition containing apiteglomab may be used in the treatment of a patient's late-onset SMA, wherein the treatment comprises intravenous administration of a therapeutic dose of a composition containing apiteglomab, 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 modification therapy. In some embodiments, the SMN modification therapy is SMN1-oriented therapy, wherein optionally, the SMN1-oriented therapy is gene therapy. In some embodiments, the SMN modification therapy is SMN2-oriented therapy, wherein optionally, the SMN2-oriented therapy is a splicing modifier. In some embodiments, any SMN modification therapy may be administered orally, intrathecally, or intravenously. In some embodiments, the patient has type 2 SMA. In some embodiments, the patient has non-walking type 3 SMA. In some embodiments, the patient has walking type 3 SMA. In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, the patient has 3 copies of the SMN2 gene. In some embodiments, the patient has 4 copies of the SMN2 gene. In some embodiments, the patient has 5 copies of the SMN2 gene. In some embodiments, the patient has 6 copies of the SMN2 gene. In some embodiments, the patient starts SMN corrective therapy at an age of less than 5 years. In some embodiments, the patient starts SMN corrective therapy at an age of 5 years or older. In some embodiments, the patient is diagnosed with SMA by genetic screening (e.g., identified as a carrier of the SMN1 mutation), where optionally, the genetic screening is neonatal screening. In some embodiments, the patient is pre-symptomatic. In some embodiments, the patient is treated with an SMN corrective before apiteglomab therapy. In some embodiments, the patient is treated with apiteglomab before receiving SMN corrective therapy.

[0019] SMA patients who may benefit from apiteglomab therapy include those who meet one or more of the following criteria: having a record of a 5q SMA and late-onset (and / or type 2 or 3) SMA prior to receiving therapy for SMA; being unable to walk and able to sit independently according to the WHO Motor Milestone definition; being able to walk independently and walk 10 meters in 30 seconds without assistance; and having a Revised Hammersmith Scale score of 63 or less and / or a Hammersmith Functional Motor Scale score of 10 or more. Subjects with an Expanded score; subjects not using positive pressure ventilation under tracheostomy or chronic daytime non-invasive ventilatory support for more than 16 hours daily within two weeks prior to treatment; subjects not having any acute or co-existing conditions that impair the subject's well-being within two weeks prior to treatment; subjects not having severe scoliosis or contracture; and / or subjects not having used any approved SMN-targeted therapies other than SMN upregulatory agents (also known as SMN modifiers) within the past 60 days. Therapies that may have effects on muscle or neuromuscular tissue include androgens, insulin-like growth factor, growth hormone, systemic β-agonists, botulinum toxin, muscle relaxants, muscle-building supplements, or acetylcholinesterase inhibitors. In some embodiments, the patient has a diagnostic record of 5q SMA and late-onset (and / or type 2 or type 3) 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, for example, the selection of one or more such patients or patient groups for treatment with apiteglomab according to the dosage or regimen disclosed herein.

[0020] SMA patients who may benefit from apiteglomab therapy include those who meet one or more of the following criteria: having one, two, three, or four copies of the smn2 gene and achieving one or more gross motor milestones based on the World Health Organization (WHO) Motor Development Assessment Scale: 1) sitting without support (e.g., keeping the head upright for at least 10 seconds; balancing without using arms or hands); 2) crawling on hands and knees (e.g., at least three consecutive movements without the abdomen touching the ground); 3) standing with assistance (e.g., standing upright on both feet for at least 10 seconds without leaning on anything); 4) walking with assistance (e.g., taking at least 5 steps while holding onto a stable object); 5) standing without support (e.g., without touching a person or object for at least 10 seconds); and 6) walking without support (e.g., taking at least 5 steps on their own).

[0021] SMA patients who may benefit from apiteglomab therapy include those who meet one or more of the following criteria: having 1, 2, 3, or 4 copies of the smn2 gene, and passing the Hammersmith Functional Motor Scale (Augmented). Achieve one or more gross motor milestones based on Expanded (HFMSE): 1) Head control (e.g., being able to raise or keep the head up while lying on one's back); 2) Rolling over; 3) Sitting on three legs (e.g., using hands to support oneself while sitting); 4) Sitting without support; 5) Standing with support; 6) Crawling on all fours; 7) Pulling up to stand (e.g., pulling oneself up to stand and walking along furniture); 8) Standing without support; 9) Taking a few steps on one's own but falling; 10) Walking independently (e.g., walking on one's own, walking without support); 11) Squatting down to pick up an object (e.g., a toy); 12) Walking / crawling up and down stairs; 13) Jumping; 14) Stepping up stairs by alternating legs; 15) Jumping on one leg; 16) Stepping down stairs by alternating legs.

[0022] In some embodiments, patients treated with apiteglomab as disclosed herein have previously received or will receive SMN-targeted therapy, such as SMN upregulatory (corrector) therapy, including nusinersen. In some embodiments, patients initiate SMN upregulatory (corrector) therapy at an age of less than 5 years. In some embodiments, patients initiate SMN upregulatory (corrector) therapy at an age of 5 years or older. In some embodiments, the SMN corrector therapy is SMN2 upregulatory therapy. In some embodiments, the SMN corrector therapy is SMN1 gene therapy.

[0023] In some embodiments, patients receive apiteglomab therapy for at least 6 months (e.g., 6 months, 12 months, or longer) at a therapeutic dose sufficient to achieve clinical benefits characterized by improved motor function, disease stabilization, or delayed disease progression.

[0024] In some embodiments, patients may receive apiteglomab therapy and achieve improved motor function. This improvement in motor function may correspond to an increase in the HFMSE score or RHS score. For example, a patient may achieve an increase of at least 1, 2, 3, 4, 5, or more points in the HFMSE score relative to baseline after 6 or 12 months of treatment with apiteglomab (i.e., apiteglomab therapy). In some embodiments, 12 months of apiteglomab therapy may produce an increase of 3 or more points in the HFMSE score relative to baseline (e.g., at least 3, at least 5, at least 10, or less than or equal to about 20 points) in patients who initiated background SMN therapy at a young age. In some embodiments, the improvement in the HFMSE score may be additive and synergistic with background therapy, e.g., background SMN upregulator / modifier therapy.

[0025] In some embodiments, patients receiving apiteglomab therapy may demonstrate disease stabilization. Disease stabilization may correspond to a net zero (e.g., at least no change or increase) or near-zero change in HFMSE or RHS scores relative to baseline. In some embodiments, this is a clinically meaningful outcome compared to the expected gradual deterioration of motor function in untreated patient populations (e.g., natural history) or patient populations treated with prior art methods (e.g., background therapy).

[0026] In some embodiments, patients receiving apiteglomab therapy may exhibit delayed disease progression. Delayed disease progression may include, for example, a slower rate of decline in HFMSE scores over time compared to a suitable control (e.g., untreated patients with a natural history in a particular patient population). In some embodiments, delay may include a postponement of the transition from a walkable SMA to a walk-impairing SMA.

[0027] In some embodiments, apiteglomab can increase the treatment response rate in a patient population compared to a control that does not receive apiteglomab.

[0028] In any embodiment, the therapeutically effective dose of apiteglomab does not cause serious adverse events in patients after 12 months of treatment.

[0029] This disclosure is based, at least in part, on the finding that anti-promyostatin / anti-latent myostatin antibodies having selective inhibitory activity of latent myostatin activation can improve muscle function in human patients with SMA, including SMA patients who may or may not be receiving background SMN upregulatory therapy (e.g., nusinersen), and in some cases, to an unexpected degree that is not typically expected or observed in certain patient populations, while avoiding adverse events (see, for example, Mercuri et al. (2018) New England Journal of Medicine. 378(7):625-635). Accordingly, this disclosure provides various embodiments of methods, uses, and compositions comprising anti-promyostatin / anti-latent myostatin antibodies for the treatment of SMA in human subjects. Furthermore, based on the data presented herein demonstrating the clinical benefits of selective myostatin inhibition for the treatment of neuromuscular diseases, this disclosure also encompasses the concept that other selective myostatin inhibitors may be used in a similar manner. These may include, for example, neutralizing antibodies that selectively inhibit myostatin but leave other relevant growth factors such as activin A intact, and ligand traps engineered to preferentially bind to myostatin.

[0030] In some embodiments, a therapeutically effective dose of apiteglomab greater than 2 and less than or equal to 20 mg / kg achieves in a subject one or more of the following: preservation of motor function compared to deterioration in a control; delay of disease progression; delay or prevention of ambulation in walkable type 3 SMA patients; delay or prevention of the need for respiratory support or intervention; reduced rate of deterioration of one or more motor function scores compared to a control; and / or maintenance of at least a net zero change in one or more motor function scores compared to baseline. In some embodiments, this dose is a dose of apiteglomab greater than 2 and less than or equal to 20 mg / kg administered intravenously every four weeks or monthly. In some embodiments, a mean deterioration from baseline may be observed in this patient population, but the majority of patients show disease stabilization (no change or increase in RHS). In some embodiments, a portion of the patient population (e.g., ≥10%, e.g., ≥15%, ≥20%) achieve an increase of 3 points or more in RHS after 12 months of treatment with apiteglomab as monotherapy.

[0031] In some embodiments, the Disclosure provides a method for treating SMA in human subjects, comprising administering to a subject a composition comprising apiteglomab and an SMN therapy (e.g., an SMN upregulator), wherein the subject is administered a dose of more than 2 and less than 20 (mg / kg) sufficient to produce a mean increase of at least 1 point in the Hammersmith Functional Motor Scale Expanded (HFMSE) score compared to the baseline score before treatment, for example, in a cohort of at least 14 subjects, every 4 weeks or monthly for at least 6 or 12 months. In some embodiments, the Disclosure provides a composition comprising apiteglomab for use in the treatment of SMA in human subjects receiving SMN upcontrolling agents, wherein the subjects are administered a dose of more 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 of at least 1 point in the HFMSE score compared to the baseline score before treatment, for example, in a cohort of at least 14 subjects, by intravenous infusion every 4 weeks or monthly for at least 6 months. In some embodiments, the Disclosure provides the use of apiteglomab in the manufacture of a therapeutic composition for SMA in human subjects receiving SMN upcontrolling agents, wherein the subjects are administered a dose of more 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 of at least 1 point in the HFMSE score compared to the baseline score before treatment, for example, in a cohort of at least 14 subjects, by intravenous infusion every 4 weeks or monthly for at least 6 months.

[0032] In some embodiments, SMA is late-onset SMA. In some embodiments, SMA is type 2 SMA. In some embodiments, SMA is type 3 SMA that causes ambulation. In some embodiments, the subjects are 5 to 21 years old. In some embodiments, the SMN upregulatory therapy is nusinersen, risdipram, and / or onasemnogene abeparvovec. In some embodiments, the SMN upregulatory therapy is nusinersen. In some embodiments, a sufficient dose is an intravenous dose greater than 2 and less than or equal to 20 mg / kg, optionally about 5, 10, 15, or 20 mg / kg. In some embodiments, the therapeutic dose of apiteglomab is sufficient to increase the HFMSE of a large portion of the patient population (e.g., greater than 50%, greater than 60%) by 1 point or more, and / or to increase the HFMSE of at least 20% (e.g., at least 25%) of the patient population by 3 points or more.

[0033] In some embodiments, the SMA is late-onset SMA, which is type 2 SMA, and the patients initiated background SMN corrective therapy at a young age (below 5 years of age). Apiteglomab therapy can achieve significant improvement in motor function in this patient population (e.g., an increase of 5 points or more in the HFMSE score). In some embodiments, patients achieve an increase of 3 points or more, an increase of 5 points or more, or an increase of 10 points or more in the HFMSE relative to baseline after 12 months of apiteglomab therapy, where baseline is measured before or at the time of the first dose of apiteglomab.

[0034] In some embodiments, the subjects are patients who, based on the WHO Motor Development Milestones classification, have not yet acquired the ability to sit independently at 4–9 months of age. In some embodiments, the subjects are patients who are able to sit independently at 4–9 months of age. In some embodiments, the subjects are patients who have not yet acquired the ability to stand with assistance at 5–11 months of age. In some embodiments, the subjects are patients who are able to stand with assistance at 5–11 months of age. In some embodiments, the subjects are patients who have not yet acquired the ability to crawl on their hands and knees at 5–13 months of age. In some embodiments, the subjects are patients who are able to crawl on their hands and knees at 5–13 months of age. In some embodiments, the subjects are patients who have not yet acquired the ability to walk with assistance at 6–14 months of age. In some embodiments, the subjects are patients who are able to walk with assistance at 6–14 months of age. In some embodiments, the subjects are patients who have not yet acquired the ability to stand without holding on at 7–14 months of age. In some embodiments, the subjects are patients aged 7–14 months who are able to stand independently. In some embodiments, the subjects are patients aged 8–18 months who have not yet acquired the ability to walk independently. In some embodiments, any of the above patients who are unable to walk may be characterized as having type 2 or type 3 SMA. In some embodiments, any of the above patients who are able to walk (with or without assistance) may be characterized as having type 3 SMA. In some embodiments, the subjects initiated SMN upregulatory / corrective therapy at an age of less than 5 years. In some embodiments, the subjects initiated SMN upregulatory / corrective therapy at an age of 5 years or older. In some embodiments, any of the above patients may 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., apiteglomab).In some embodiments, any of the aforementioned patients may achieve one, two, or three new milestones according to the WHO Motor Development Milestones, e.g., the ability to walk independently, the ability to stand independently, the ability to stand with assistance, the ability to crawl on hands and knees, and / or to walk with assistance, after 6 to 12 months of treatment with a myostatin inhibitor (e.g., apiteglomab).

[0035] In some embodiments, the target patient population to be treated with apiteglomab includes individuals who are 12 years of age or younger at the start of myostatin inhibitor (e.g., apiteglomab) therapy. In some embodiments, the target patient population includes individuals who are 2 years of age or older. In some embodiments, the target patient population includes individuals who are 2 to 12 years of age. In some embodiments, the target patient population includes individuals who are 2 to 5 years of age.

[0036] In some embodiments, apiteglomab is administered as monotherapy to SMA patients who are unable to receive the intrathecal injections required for SMN upregulation therapy (for example, due to spinal fusion) or who choose not to receive such treatment.

[0037] In some embodiments, this disclosure provides the use of apiteglomab in the manufacture of a therapeutic pharmaceutical composition (e.g., a drug) for late-onset SMA in human subjects. The drug is intended to be administered to subjects every four weeks or monthly at a dose of apiteglomab greater than 2 mg / kg and less than or equal to 20 mg / kg, wherein, optionally, the subjects have initiated motor neuron-directed therapy for SMA at an age of less than 5 years, and wherein the motor neuron-directed therapy increases SMN1 or SMN2 expression. The manufacturing method may include providing a cell line comprising one or more vectors having the nucleic acid sequences of the heavy and light chains of the apiteglomab immunoglobulin polypeptide, which has the ability to produce a recombinant antibody corresponding to apiteglomab, or its antigen-binding fragment. By using such a cell line, apiteglomab can be produced in cell cultures, such as mammalian cell cultures, e.g., CHO cells. In some embodiments, large-scale bioreactors (e.g., 250 L, 1000 L, 2000 L, 3000 L, 4000 L, etc.) may be used for the production of apiteglomab. Recombinant antibody molecules are then purified from the cell culture, and the purified antibody can be formulated into a pharmaceutical composition containing apiteglomab and one or more excipients. This method typically includes a sterile filtration step. In some embodiments, the pharmaceutical composition is a liquid formulation containing about 50 mg / mL of apiteglomab, suitable for intravenous administration.

[0038] In some embodiments, apiteglomab is contained in a multi-dose vial, such as a glass vial. In some embodiments, the container (such as a glass vial) containing apiteglomab is part of the kit. [Brief explanation of the drawing]

[0039] [Figure 1]This outlines the treatment duration design for an active treatment study evaluating the efficacy and safety of apiteglomab in patients with late-onset SMA. Over a 52-week treatment period, patients enrolled in Cohorts 1 and 2, as described in Example 1, Section 1.1, will receive a high dose (20 mg / kg) of apiteglomab, while patients enrolled in Cohort 3 will be randomly assigned (1:1) in a blinded manner to receive either a low dose (2 mg / kg) or a high dose (20 mg / kg) of apiteglomab. [Figure 2] The schematic design for an extension period of an active treatment study evaluating the efficacy and safety of apiteglomab in patients with late-onset SMA is shown in Example 1. Patients who complete the 52-week treatment period (Figure 1) can choose to enroll in a further 52-week extension period. [Figure 3A-B] This report presents the 6-month interim results from Cohort 3, as described in Section 1.1, Example 1, a randomized, double-blind portion of the apiteglomab active treatment study, which enrolled type 2 SMA patients under 5 years of age who had initiated treatment with an approved SMN upregulator (nusinersen). Patients were randomized in a 1:1 ratio to receive either a low dose (2 mg / kg apiteglomab every 4 weeks or monthly (Q4W)) or a high dose (20 mg / kg apiteglomab Q4W); both treatment groups were combined with the approved SMN upregulator (nusinersen) therapy. Figure 3A shows individual HFMSE responses. Figure 3B shows the mean (±SEM) change from baseline in HFMSE scores. [Figure 4] Example 1 presents the pharmacokinetic (PK) analysis of the 6-month interim results from cohorts 1, 2, and 3, as shown in Section 1.1. Starting from day 28, measurements are of pre-administration trough concentrations. [Figure 5] Example 1 shows the pharmacodynamic (PD) analysis of the 6-month interim results from cohorts 1, 2, and 3 as described in Section 1.1. [Figure 6A-B]This is an open-label, single-arm cohort study enrolling 15 patients with a mean age of 11.7 years (range 8–19 years) with type 2 or ham-less type 3 SMA who were already receiving treatment with an approved SMN upregulator. The 6-month interim results from Cohort 2, as described in Section 1.1, are shown in Example 1. Patients were treated with 20 mg / kg apiteglomab Q4W in addition to approved SMN upregulator therapy (nusinersen). Figure 6A shows individual HFMSE responses. Figure 6B shows the mean (±SEM) change from baseline in HFMSE scores. [Figure 7A-B] This is an open-label, single-arm cohort study enrolling 23 patients with amblyable type 3 SMA, and the 6-month interim results from Cohort 1, as described in Section 1.1, Example 1, are shown. Patients were treated with 20 mg / kg apiteglomab Q4W either as monotherapy or in combination with an approved SMN upregulator (nusinersen). Figure 7A shows individual RHS responses. Figure 7B shows the mean (±SEM) change from baseline in RHS scores. [Figure 8] This paper presents the results of the nusinersen SHINE trial in late-onset SMA, and is a reproduction of the presentation given at the 31st Annual Meeting of the American Academy of Managed Care Pharmacy, March 25-28, 2019, in San Diego, CA, USA. [Figure 9A-D]Example 1 shows the 12-month top-line results from Cohort 3 as described in Section 1.1. Figure 9A shows individual HFMSE responses. Figure 9B shows the mean (±SEM) change from baseline in HFMSE scores. Figure 9C shows the HFMSE responder analysis in patients in the Type 2 immobility >2-year cohort. Figure 9D shows a schematic of the overall treatment time series and the change in HFMSE scores compared to baseline in patients on the 20 mg / kg arm in the Type 2 immobility >2-year cohort. [Figure 10A-C] Example 1 shows the 12-month top-line results from Cohort 2 as described in Section 1.1. Figure 10A shows individual HFMSE responses. In the protocol-adherent analysis, one patient who showed a change of -7 points from baseline due to treatment with an acetylcholinesterase inhibitor was excluded. Figure 10B shows the mean (±SEM) change from baseline in HFMSE score. Figure 10C shows the HFMSE responder analysis in patients in the 2 / 3 type amblyable 5-21 year old cohort. [Figure 11A-C] Example 1 shows the 12-month top-line results from Cohort 1 as described in Section 1.1. Figure 11A shows individual RHS responses. Figure 11B shows the mean (±SEM) change from baseline in RHS scores. Figure 11C shows the RHS responder analysis of patients in the Type 3 walkable 5-21 year old cohort. [Figure 12A-B] The pharmacokinetic (PK) analyses of 12-month top-line results from cohorts 1, 2, and 3 are shown. In Figure 12A, starting from day 28, measurements are pre-administration trough concentrations. In Figure 12B, starting from day 28, measurements are pre-administration trough concentrations, except for days 140 and 336. On days 140 and 336, measurements are Cmax levels. [Figure 13] Example 1 shows the pharmacodynamic (PD) analysis of 12-month top-line results from cohorts 1, 2, and 3, as described in Section 1.1. [Figure 14]The graph shows the target associations plotted against the changes in HFMSE scores in Cohort 3, as described in Section 1.1, for patients receiving nusinersen in combination with 2 mg / kg (dark circles) or 20 mg / kg (light circles) of apiteglomab. [Figure 15A-C] Figure 15A shows a comparison of baseline latent myostatin concentrations between healthy volunteers (SAD and MAD) and cohorts 1, 2, and 3 as described in Example 1, Section 1.1. Figures 15B to 15C show the multipliers of change in latent myostatin concentrations in healthy volunteers (SAD) and cohorts 1, 2, and 3. [Figure 16] This section shows the correlation between baseline latent myostatin concentration and body weight when comparing healthy volunteers (SAD and MAD) with cohorts 1, 2, and 3 as described in Example 1, Section 1.1. [Figure 17] Example 1 shows a linear regression of the correlation between clearance and body weight in cohorts 1, 2, and 3, as shown in Section 1.1. [Figure 18] Example 1 shows a linear regression of the correlation between clearance and age in cohorts 1, 2, and 3, as shown in Section 1.1. [Figure 19] The results of the SMAD-reactive luciferase reporter assay are shown. Recombinant promyostatin was incubated with apiteglomab, mTLL2, and furin protease, and then incubated on CAGA cells transfected with a SMAD-reactive luciferase reporter vector. The ability of apiteglomab to inhibit proteolytic processing and the release of active growth factors was measured and plotted as a percentage inhibition rate. [Figure 20A-D]The serum concentration-time profiles of apiteglomab after multiple doses as shown in Example 1 are shown. Repeated weekly IV doses: Apiteglomab was measured in the serum of male and female animals after 4 weeks of 10, 30, and 100 mg / kg in cynomolgus monkeys followed by a 4-week recovery phase (Figure 20A), 4 weeks of 10, 30, and 100 mg / kg in adult rats followed by a 4-week recovery phase (Figure 20B), 26 weeks of 30, 100, and 300 mg / kg in adult rats followed by an 8-week recovery period (Figure 20C), and 7 weeks of 30, 100, and 300 mg / kg in juvenile rats followed by a 4-week recovery phase (Figure 20D). The data shown are mean ± standard deviation. Dose symbols: 10 (circle), 30 (square), 100 (triangle), and 300 (diamond) mg / kg. [Figure 21A-D] The serum latent myostatin concentration-time profiles of apiteglomab after multiple doses, as shown in Example 1, are presented. Serum latent myostatin was measured in animals administered weekly doses of apiteglomab: 10, 30, and 100 mg / kg to cynomolgus monkeys for 4 weeks followed by a 4-week recovery phase (Figure 21A), 10, 30, and 100 mg / kg to adult rats for 4 weeks followed by a 4-week recovery phase (Figure 21B), 30, 100, and 300 mg / kg to adult rats for 26 weeks followed by an 8-week recovery period (Figure 21C), and 30, 100, and 300 mg / kg to juvenile rats for 7 weeks followed by a 4-week recovery phase (Figure 21D). The data shown are mean ± standard deviation. Dosage symbols: 10 (filled circle), 30 (square), 100 (triangle), and 300 (diamond) mg / kg. [Figure 22A-B] Figure 22A shows the 12-month HFMSE change from baseline as a function of the duration of prior nusinersen treatment in Cohorts 2 and 3, as described in Example 1, Section 1.1. Figure 22B shows the 12-month HFMSE change from baseline as a function of the nusinersen maintenance dose received by patients unable to walk. [Figure 23A-D]The post-hoc analysis of 12-month HFMSE change as a function of age for cohorts 2 and 3, as shown in Example 1 and Section 1.1, is presented. Figure 23D shows the change from baseline in HFMSE in a pooled cohort of immobile patients treated with apiteglomab 20 mg / kg or 2 mg / kg. [Figure 24A-B] As shown in Example 1, a comparison of 12-month motor function scores is presented in patients with scoliosis or joint contractures compared to patients without scoliosis or joint contractures. Figure 24A shows pooled HFMSE scores from patients with non-walking type 2 and type 2 / 3 SMA. Figure 24B shows pooled RHS scores from patients with walkable type 3 SMA. [Figure 25] The dose-response data for patients in the type 2 ambulation >2 year cohort, as measured by motor function scores, is shown in Example 1. [Figure 26A-D] As shown in Example 1, this document analyzes the relationship between improvement in motor function, the multiplier of change in latent myostatin levels, and the pharmacokinetic concentration of apiteglomab, as measured by the change in HFMSE score relative to age in patients with type 2 SMA. Figure 26A shows the relationship between the change in HFMSE score and age. Figure 26B shows the relationship between the multiplier of change in latent myostatin levels (LM multiplier) and the pharmacokinetic concentration of apiteglomab. Figure 26C shows the relationship between age-normalized change in motor function and age-normalized multiplier of change in latent myostatin levels. Figure 26D shows the relationship between age-normalized change in motor function and age-normalized LM multiplier / PK concentration. [Figure 27A-B] Figure 27A shows the relationship between changes in HFME score and baseline latent myostatin. Figure 27B shows the age-normalized relationship as shown in Example 1. [Modes for carrying out the invention]

[0040] definition To facilitate a more readily understandable reading of this disclosure, certain terms are defined at the outset. These definitions should be read in the context of the remainder of this disclosure and in the manner that a person skilled in the art would understand. Unless otherwise defined, all scientific and technical terms used herein have the same meaning as generally understood by a person skilled in the art. Further definitions are provided throughout this detailed description.

[0041] Apiteglomab: Apiteglomab (also known as "SRK-015") is a fully human monoclonal antibody for clinical trials that inhibits myostatin activation by specifically binding with high affinity to myostatin proforms—namely, promyostatin and latent myostatin. See, for example, CAS registry number 2278276-46-1; International Name of Drug (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. Apiteglomab is a human immunoglobulin G4 (IgG4) / λ isotype. Apiteglomab is a selective myostatin inhibitor (myostatin selective activation inhibitor). See, for example, International Publication No. 2017 / 049011. The term "selective myostatin inhibitor" (or "myostatin selective inhibitor") refers to a drug that has the ability to block, inhibit, or otherwise antagonize the activation or activity of myostatin / GDF-8 without significantly affecting structurally related growth factors, such as activin A. Apiteglomab contains the heavy chain amino acid sequence of SEQ ID NO: 15 and the light chain amino acid sequence of SEQ ID NO: 16, as shown in Table 3B below.

[0042] Baseline: As used herein, the terms “baseline” or “baseline score” refer to the numerical values ​​of the patient’s SMA-related parameters at or before treatment with the SMA therapy described herein (e.g., before or at the time of the first dose of apiteglomab monotherapy or as an adjunct to background therapy including SMN upregulatory therapy), in the context of SMA-related parameters (e.g., scores based on motor function assessment scales, e.g., Revised Hammersmith Score (RHS) score or Hammersmith Functional Motor Scale Expanded (HFMSE) score).

[0043] In some embodiments, the baseline RHS score of patients who will be treated with apiteglomab, for example, apiteglomab monotherapy (e.g., patients with walkable SMA), is measured at or before the initiation of apiteglomab treatment. In some embodiments, the baseline RHS score of patients who will be treated with apiteglomab, for example, apiteglomab as an adjunct to SMN upcontrol therapy (e.g., patients with walkable SMA), is measured at or before the initiation of apiteglomab treatment. In some embodiments, the patient is receiving SMN upcontrol therapy at the time of baseline measurement. In some embodiments, the patient has been receiving SMN upcontrol therapy for at least 6 months prior to baseline measurement. For example, in some embodiments, patients who will be treated with apiteglomab (e.g., patients with walkable SMA) have a baseline RHS score of 26 or higher. In some embodiments, the patient has a baseline RHS score of 63 or lower. In some embodiments, the patient has a baseline RHS score in the range of 26 to 63.

[0044] In other embodiments, the baseline HFMSE score is measured for patients who will be treated with apiteglomab, for example, as an adjunct to background therapy for SMN upregulation (e.g., patients with late-onset SMA, e.g., patients with immobile SMA such as type 2 or type 3 immobile SMA). In some embodiments, the baseline score is measured at or before the initiation of apiteglomab treatment (i.e., apiteglomab therapy). In some embodiments, the patient is receiving SMN upregulation therapy at the time of baseline measurement. In some embodiments, the patient has been receiving SMN upregulation therapy for at least 6 months prior to baseline measurement. In some embodiments, the patient has been receiving SMN upregulation therapy for at least 2 years at the initiation of apiteglomab therapy, which is the time when baseline measurement is performed. In some embodiments, the baseline score used to determine the therapeutic effect of apiteglomab therapy is added to the therapeutic effect as a result of background therapy, if any. In some embodiments, patients responded to background therapy with an increase of, for example, 1 to 7 points in their measured motor function score compared to before treatment. In some embodiments, patients who will be treated with apiteglomab (e.g., patients with immobile SMAs such as type 2 and immobile type 3 SMA) have a baseline HFMSE score of 12 or higher. In some embodiments, patients have a baseline HFMSE score of 44 or lower. In some embodiments, patients have a baseline HFMSE score in the range of 12 to 44.

[0045] Cohort: As used herein, the term “cohort” or “cohort population” refers to a group or population of human subjects who share factors or influences such as age, SMA disease severity (e.g., type 2 and / or type 3 SMA), and concomitant therapy (e.g., SMN upcontrol therapy). In some embodiments, as used herein, “cohort” refers to a group of human subjects who share age, SMA disease severity, and / or concomitant therapy. For example, in some embodiments, the cohort includes walkable type 3 SMA patients aged 5–21 years, including those not receiving SMN upcontrol therapy and those already receiving SMN upcontrol therapy. In other embodiments, the cohort includes type 2 and walkable type 3 SMA patients aged 5–21 years who have already received SMN upcontrol therapy initiated after the patient turned 5 years old. In other embodiments, the cohort includes type 2 SMA patients aged 2 years or older who have already received SMN upcontrol therapy initiated before or before the patient turned 5 years old.

[0046] Control: The term “control” or “control sample” as used herein refers to any clinically or scientifically relevant comparative sample, population, or counterpart, including, for example, a sample from a healthy subject, a sample from a subject having a defect that can cause or make a subject susceptible to a certain disease or condition, a subject having the disease or condition of interest, a sample from a subject treated with placebo, a sample from a subject before treatment, a subject or sample treated with sham or buffer, or an untreated subject or sample. In some embodiments, a patient or patient population receiving or requiring treatment with apiteglomab 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 not receiving apiteglomab.

[0047] Inhibition of ~ or Inhibition of ~: When used herein, the terms "inhibition of ~" or "inhibition of ~" mean a reduction by a measurable amount and may include, but are not required to include, complete prevention or inhibition.

[0048] Effective Dose: The terms “effective” and “therapeutic effective” refer to the ability or amount to achieve one or more intended objectives, namely, to produce a desired biological or pharmaceutically acceptable response in a subject and / or a statistically significant clinical benefit (e.g., efficacy) in a patient population. For example, in certain embodiments of this disclosure, the intended objectives could be to inhibit myostatin activation in vivo and to achieve clinically meaningful outcomes associated with myostatin inhibition. An “effective dose” (or therapeutic effective dose, or therapeutic dose) can be a dosage or dose-setting regimen sufficient to produce a detectable change in disease parameters, e.g., a slowing, cessation, reversal, reduction, or improvement of disease parameters, symptoms, or downstream effects. The term encompasses, but is not required, the use of a dose that completely cures the disease. In this specification, the dose of an anti-promyostatin / anti-latent myostatin antibody (e.g., the dose of apiteglomab) may refer to the therapeutic effective dose as described herein.

[0049] The measurement of the relevant intended purpose may be objective (i.e., measurable by some assay or marker) or subjective (i.e., the subject provides an indicator or perception of the effect). In some embodiments, the therapeutically effective dose is the amount administered to a patient population that meets certain clinical criteria for SMA (as determined by, for example, the symptoms present, disease progression / stage, genetic profile, etc.) and produces a statistically significant therapeutic response in that population.

[0050] In some embodiments, an effective dose is the amount that, when administered according to a particular regimen, produces a positive clinical outcome while the adverse effects (e.g., toxicity) are reasonably acceptable to the patient, allowing them to continue the treatment regimen if any adverse effects exist, and the benefits of the therapy outweigh the risks of toxicity. Those skilled in the art will understand that, in some embodiments of this disclosure, a dosage may be considered to contain an effective dose if it contains an amount appropriate for administration in the context of a dosage regimen that correlates with a positive outcome.

[0051] Late-onset SMA: As used herein, unless otherwise explicitly defined, the term late-onset SMA refers to patients who do not present with SMA symptoms until after 6 months of age (e.g., no symptoms are detected at the 6-month checkup). Patients with late-onset SMA may also be patients who can be characterized as having type 2, type 3, or type 4 SMA based on conventional disease classifications known in the art. Patients with late-onset SMA typically have at least two copies of the SMN2 gene (e.g., two, three, four, or more, e.g., two to four copies). In some embodiments, patients with late-onset SMA are treated with or have received motor neuron-directed therapies, such as SMN-directed therapies, e.g., SMN upregulators (e.g., have received such therapy at an age of less than 5 years). In contrast to late-onset SMA, early-onset or infant-onset SMA refers to SMA in which symptoms appear before 6 months of age (including patients who can also be classified as type 1 SMA using conventional classifications known in the art). In comparison, patients with early-onset or infant-onset SMA typically have one or two copies of the SMN2 gene.

[0052] In some embodiments, late-onset SMA patients have 2 to 4 copies of the SMN2 gene. In some embodiments, late-onset SMA patients have 1 to 2 copies of the SMN2 gene. In some embodiments, late-onset SMA patients who have received early therapeutic intervention (i.e., patients who would have developed symptoms before 6 months of age without intervention) may also be referred to as “newly emerging” or “treatment-induced” late-onset SMA patients or patient population. In some embodiments, treatment-induced late-onset SMA patients may differ in genotype (e.g., 1 to 2 copies of the SMN2 gene), phenotype (e.g., walking), and / or disease course and response to myostatin treatment. In some embodiments, patients with late-onset SMA would not have been able to walk and / or sit without assistance without treatment, e.g., SMN-targeted therapy (e.g., they would have had type 1 and / or non-walking type 2 SMA), but are able to do so thanks to treatment. In some embodiments, late-onset SMA patients who would have had non-walking type 3 without treatment, such as SMN-targeted therapy, retain the ability to walk at 18 months of age thanks to the treatment. When considering the treatment of walkable type 3 SMA patients, in some embodiments, any walkable patient is treated. In some embodiments, type 3 patients are those who would retain the ability to walk at 18 months of age even without intervention. In some embodiments, type 3 patients are those who would have lost the ability to walk without intervention. In some embodiments, patients are identified through neonatal screening and treatment, such as SMN-targeted therapy, is initiated before the onset of disease. In some embodiments, the onset of SMA symptoms is not observed thanks to early initiation of treatment after neonatal screening. In some embodiments, treated patients have type 4 SMA (e.g., patients with four or more copies of the SMN2 gene and whose symptoms develop much later, e.g., at an age of 18 or older).

[0053] Natural history: The natural history of SMA refers to the progression of SMA over time in a person who does not receive treatment.

[0054] Progression: Disease progression (e.g., SMA) is the process of worsening symptoms or deterioration of the condition over a period of time. Without pharmacological intervention (e.g., therapy), progression reflects or corresponds to the natural history of the disease observed in a particular patient population. Disease progression can be determined by the rate at which the condition worsens and / or the degree to which the condition deteriorates. Accordingly, effectiveness may include the ability of a drug or therapy to delay or slow disease progression. For example, a patient may show a deterioration in motor function scores over time, but at a slower rate than might be expected based on the natural history. Effectiveness may include the ability of a drug or therapy to reduce the degree of deterioration. Effectiveness may include stabilization of the disease, i.e., at least net zero change over time in one or more functional parameters.

[0055] SMN Therapy / SMN-Targeted Therapy: In the context of this disclosure, the terms “SMN therapy” or “SMN-targeted therapy” (as used herein synonymously) 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. Such agents include SMN modifiers / upregulators. For example, SMN1-targeted therapy may include gene therapies intended to supplement or replace a deleted or mutated SMN1 gene. SMN2-targeted therapy may include splicing modifiers that target one or more exons of a certain type of SMN2 backup gene to increase the availability of at least partially functional SMN protein in the body. Non-limiting examples of SMN therapy include nusinersen, onasemnogene abeparvovec, and risdiplam.

[0056] Steady state: As used herein, the term “steady state” refers to a situation in which the total uptake of a molecule (e.g., apiteglomab) is in complete dynamic equilibrium with its elimination. In some embodiments, the steady-state serum concentration of apiteglomab is the maximum serum concentration (i.e., C) after administration of apiteglomab to, for example, a human subject or a human subject cohort. max ) or minimum (trough) serum concentration (i.e., C min or Ctrough ) is measured as. In some embodiments, the steady state of apiteglomab is determined using the maximum serum concentration of apiteglomab in pharmacokinetic (PK) analysis. In some embodiments, the steady state of apiteglomab is determined using the minimum serum concentration of apiteglomab in PK analysis. In some embodiments, the pharmacodynamic (PD) target is latent myostatin. In some embodiments, the PD profile of apiteglomab is evaluated by measuring the serum latent myostatin concentration. In some embodiments, the serum latent myostatin concentration is the steady-state concentration. In some embodiments, the serum latent myostatin concentration is, for example, the pre-administration or trough concentration (i.e., C) in a human subject or human subject cohort. min or C trough It is measured as follows:

[0057] Subject: In the context of therapeutic application, the term "subject" refers to an individual receiving or requiring treatment, diagnosis, or other clinical care or intervention. Suitable subjects include, but are not limited to, vertebrates, including mammals (e.g., humans and non-human mammals). When the subject is a human subject, the term "patient" may be used synonymously. In a clinical context, the terms "patient population" or "patient subpopulation" are used to refer to a group of individuals that fall within a set of criteria, such as clinical criteria, medical history, health status, sex, age group, genetic criteria, and / or lifestyle factors. In some embodiments, a patient or patient population is a patient or patient population with SMA. In some embodiments, a patient or patient population is an early-onset or infant-onset SMA patient or patient population. In some embodiments, a patient or patient population is a late-onset SMA patient or patient population. In some embodiments, a patient or patient population is a type 2 SMA patient or patient population. In some embodiments, a patient or patient population is a non-walking type 3 SMA patient or patient population. In some embodiments, the patient or patient group is a walkable type 3 SMA patient or patient group. In some embodiments, the patient or patient group is a walkable late-onset SMA patient or patient group. In some embodiments, the patient or patient group is a non-walking patient or patient group. In some embodiments, the patient or patient group is a pre-symptomatic or asymptomatic patient or patient group. In some embodiments, the patient or patient group is a symptomatic patient or patient group. In some embodiments, the patient or patient group has two or more copies of the SMN2 gene, for example, 2-3 copies, 2-4 copies, 3-4 copies, etc. In some embodiments, the patient or patient group 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.

[0058] Targeted association: As used herein, the term “targeted association” refers to the ability of a molecule (e.g., apiteglomab) to bind to its intended in vivo target (e.g., latent myostatin), for example, in skeletal muscle. In some embodiments, serum latent myostatin levels are relatively low at baseline (i.e., pre-treatment) and may increase after treatment with apiteglomab. In some embodiments, the increase in serum latent myostatin levels indicates targeted association with apiteglomab in skeletal muscle, for example. In some embodiments, low baseline serum levels compared to high post-treatment levels of latent myostatin indicate that the majority of the drug target is retained in skeletal muscle rather than circulating systemically. In some embodiments, saturation of targeted association indicates that the dosage is sufficient to achieve a certain therapeutic effect (e.g., efficacy), although efficacy may be achieved without saturation.

[0059] Therapeutic dose: The term “therapeutic dose” refers to the amount (e.g., the amount of apiteglomab) sufficient to achieve the efficacy as determined by the clinical endpoints that measure therapeutic effect (e.g., one or more of the clinical endpoint measures discussed herein) when administered to a patient in a specific manner (e.g., using a specific dose-setting regimen). For example, the therapeutic dose of apiteglomab may be greater than 2 mg / kg and less than or equal to 20 mg / kg when administered intravenously every four weeks. In certain embodiments, the therapeutic dose of apiteglomab is 10 mg / kg or 20 mg / kg when administered intravenously every four weeks.

[0060] Treatment: As used herein, “treating” a disease or disorder (e.g., SMA) or “treatment” means, for example, slowing, delaying, or preventing the onset of such disease or disorder, or reversing, mitigating, improving, inhibiting, slowing, stabilizing, or stopping the progression, worsening, or aggravation, progression, or severity of any condition associated with such disease or disorder, compared to a baseline without treatment (e.g., where treatment halts disease progression as observed without treatment). This term includes, but is not necessarily, complete treatment or prevention of the disease or disorder. In some embodiments, “treating” or “treatment” means the administration (simultaneously or sequentially) of one or more active agents, or one or more compositions comprising one or more active agents, to a subject having SMA, with the aim of eradicating, curing, mitigating, reducing, altering, restoring, improving, enhancing, or influencing the disorder, symptoms of the disease, or predisposition to SMA.

[0061] Treatment-Initiated Patient Populations: Conventional classifications or types of SMA patient populations (e.g., type 0, type 1, type 2, non-walking type 3, walkable type 3, type 4, etc.) are primarily based on the natural history of disease symptom development, which shows a strong correlation with SMN2 gene copy number. Based on conventional classifications, type 0 is the most severe form, occurring in utero with reduced or no mobility, and requiring mechanical ventilation at birth. In recent years, with the availability of approved SMN-targeted therapies (e.g., SMN2 upregulators, SMN1 gene therapy, etc.) and neonatal screening, further classifications may be needed to describe newly emerging patient populations, referred to herein as “newly emerging” or “treatment-initiated” patient populations. In these populations, if patients initiate SMN-targeted therapy at a young age, the expected SMA symptom development based on natural history and / or genetic analysis may change. In other words, regardless of disease genotype, early intervention may influence the course of disease progression expected from natural history. For example, an infant with confirmed SMN1 deletion and one copy of the SMN2 gene may be able to sit up independently at 12 months of age if they receive early SMN therapy, whereas otherwise they would have been expected to develop type 1 SMA. An SMA patient with two copies of the SMN2 gene might be expected to develop a severe (e.g., type 2) disease form if not treated with SMN-targeted therapy, but with SMN-targeted therapy, especially early intervention, the clinical findings of such patients may resemble those of a milder disease form. As a result of such therapy, a patient with ambly-impaired type 3 SMA (a patient who has lost the ability to walk) may regain the ability to walk, or a patient with type 2 SMA may be able to walk for the first time. Similarly, patients who were expected to develop non-walking type 3 SMA at age 18 months or older may retain the ability to walk into later age and exhibit even different phenotypes (e.g., walking) and / or responses to SMA treatment with early SMN-directed therapy (Mercuri et al. (2020) Nature Reviews Neurology, 16:706-715). In an effort to adapt to the changes brought about by advances in medical science in SMA therapy, this field continues to evolve, including adjustments to certain nomenclature / terminology, aiming to better describe a variety of diseases.Therefore, when used herein, the term “late-onset SMA” is intended to refer, unless otherwise specified, to patients or groups of patients whose symptoms (e.g., clinical manifestation) occur at age 6 months or older, regardless of genotype, and with or without SMN-targeted therapy. Patients whose symptoms occur before age 6 months are referred herein to as “early-onset” or “infant-onset” SMA, depending on the specific age at which symptoms are first detected.

[0062] Type 1 SMA: Typically, children with type 1 SMA experience rapid deterioration in the natural history of the disease. Early symptoms include hypotonia, small or weak muscles, dyspnea, dysphagia, a weak cough or cry, and inability to sit. Infants with type 1 SMA 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 1-2 copies of the SMN2 gene.

[0063] Type 2 SMA: Children with type 2 SMA are unable to walk without therapeutic intervention, often have three copies of the SMN2 gene, and become symptomatic between 6 and 18 months of age. Muscle weakness is very common, affecting the ability to stand or walk without assistance, and typically requiring a wheelchair. Generally, these children begin to lose abilities before the age of two. However, they can sit up, hold their heads, and roll over on their own.

[0064] Type 3 SMA: In patients with type 3 SMA, symptoms may begin in early infancy, usually after 18 months of age, based on clinical classification and / or physical milestones such as sitting or walking. These patients often have 3, 4 or more copies of the SMN2 gene; the more severe type of non-walking type 3 SMA is typically associated with 3 copies of the SMN2 gene (type 3a), while the less severe type of non-walking type 3 SMA is typically associated with 4 copies (type 3b). Typically, patients with type 3 SMA can walk and climb, eat with utensils, and dress themselves, at least initially, but are generally unable to run, jump, or climb without assistance. As they grow, these patients lose many motor functions, including the ability to walk and climb. Among type 3 patients, those who can walk are called walkable type 3 SMA, while those who have lost the ability to walk are called non-walking type 3 SMA. Patients with type 3 dementia often lose the ability to walk between the ages of 4 and 16, for example, on average around the age of 10.

[0065] Type 4 SMA: Type 4 SMA is a rare adult-onset form of SMA. Patients typically have four or more copies of the SMN2 gene and usually only experience mild muscle weakness. It can begin around age 18, but in many cases it can begin at an older age (e.g., in their 20s or 30s).

[0066] Unless otherwise indicated in the operating examples or otherwise, all numerical values ​​representing quantities of ingredients or reaction conditions used herein should be understood to be modified by the term “approximately.” When used in relation to percentages, the term “approximately” may mean ±1%.

[0067] The indefinite articles “a” and “an,” as used herein and in the claims, should be understood to mean “at least one” unless explicitly indicated otherwise.

[0068] When the phrase “and / or” is used herein and in the claims, it should be understood to mean “either or both” of the elements thus connected at equal intervals, that is, elements that are sometimes connected and sometimes disjunct. Unless explicitly indicated otherwise, other elements may exist, at their discretion, in addition to those specifically identified by the “and / or” clause, whether related to or unrelated to those specifically identified elements. Thus, as a non-restrictive example, when used in conjunction with non-restrictive phrases such as “comprising,” the expression “A and / or B” may, in some embodiments, refer to A without B (optionally including elements other than B); in other embodiments, refer to B without A (optionally including elements other than A); and in yet another embodiment, refer to both A and B (optionally including other elements), etc.

[0069] As used herein and in the claims, the phrase “at least one” referring to an enumeration of one or more elements means at least one element selected from any one or more of the elements in that enumeration, but not necessarily including at least one of all elements specifically listed in that enumeration, and not excluding any combination of elements in that enumeration. This definition also optionally allows for elements other than those specifically identified in the enumeration of elements to which the phrase “at least one” refers, whether related to or unrelated to those elements specifically listed. Thus, as a non-restrictive 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, in some embodiments, mean at least one A that optionally includes two or more elements and B is absent (and optionally includes elements other than B); in other embodiments, it may mean at least one B that optionally includes two or more elements and A is absent (and optionally includes elements other than A); and in yet another embodiment, it may mean at least one A that optionally includes two or more elements, and at least one B that optionally includes two or more elements (and optionally includes other elements), and so on.

[0070] The use of ordinal numbers such as "first," "second," and "third" in the claims does not in itself imply any temporal order of priority, precedence, or sequence or method of performing an action in relation to another claim element, but is merely used as a marker to distinguish a claim element of a particular designation from another element of the same designation (other than by using ordinal numbers).

[0071] The ranges provided herein are understood to be abbreviated representations of all values ​​within that range. For example, the range 1–10 is understood to include any number, combination of numbers, or partial range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, such as 2–8, 1–5, etc.

[0072] All references incorporated herein are incorporated by reference for any purpose. In the event of any conflict between the references and this specification, this specification shall prevail. For clarity, it should be understood that certain features of the compositions and methods of this disclosure described herein in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the compositions and methods of this disclosure described herein in the context of a single embodiment may also be provided separately or in any partial combination.

[0073] Spinal muscular atrophy (SMA) Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease that is often fatal and is the leading genetic cause of infant mortality (Awano et al. (2014) Neurotherapeutics 11:786-795). SMA is an autosomal recessive genetic disorder involving mutations or deletions of the survival motor neuron 1 (SMN1) gene. Specifically, SMA results from reduced levels of SMN protein, which is necessary to promote the survival of anterior horn cells in the spinal cord. The loss of motor neurons leads to severe muscle atrophy, often resulting in death due to respiratory failure (Monani (2005) Neuron 48:885-896). The muscle pathology of SMA is characterized by the presence of small-diameter atrophic fibers, which are thought to correspond to denervated or partially denervated muscle fibers. The presence of atrophic fibers is a classic indicator of motor neuron denervation caused by the loss or dysfunction of motor neurons. Unlike patients with Duchenne muscular dystrophy (DMD), SMA patients, even in the most severe cases of the disease, do not exhibit the characteristic features of necrosis and inflammatory changes (Le Verche V. et al. Spinal Muscular Atrophy; Disease Mechanisms and Therapy 2017; Ch.21:341-356).

[0074] SMA patients lack the functional SMN1 gene, but the paralogous gene, SMN2, produces low levels of functional SMN protein due to alternative splicing that truncates the transcript. Advances in molecular medicine techniques have led to improved diagnosis of SMA patients based on gene typing of both SMN1 and SMN2 copy numbers. SMA patients are also diagnosed based on clinical findings, with phenotyping classified based on the greatest motor milestone achieved and age at symptom onset. Disease-modifying drugs are changing some aspects of traditional diagnosis and classification. Classification may, in some embodiments, be based on one or more of the following: age at therapy initiation, age at symptom onset, and / or SMN2 copy number, for example, separately, or to improve the definition of the clinical SMA phenotype beyond traditional classifications defined solely by age of onset and severity (Jedrzejowska M. et al. Degener Neurol Neuromuscul Dis. 2020;10:39-47).

[0075] When used herein, unless otherwise explicitly defined, the term “late-onset SMA” is intended to encompass type 2, type 3 (walking and non-walking) and type 4 SMA as defined by the conventional SMA classification known in the art. In some embodiments, patients with late-onset SMA are treated with or have been treated with motor neuron-directed therapies such as SMN upregulators (e.g., have received such therapy at an age of less than 5 years). In some embodiments, patients with late-onset SMA have at least two copies of the SMN2 gene (e.g., at least three copies or at least four copies of SMN2). In some embodiments, patients with late-onset SMA develop diagnosable symptoms of SMA at an age of 6 months or older. Subjects with SMA may be treated before the onset of symptoms of the disease or after the onset of diagnosable symptoms.

[0076] As used herein, the terms “infant-onset SMA” or “early-onset SMA” encompass type 1 SMA as defined by conventional SMA classifications known in the art. In some embodiments, patients with infant-onset SMA are treated with, or have been treated with, motor neuron-directed therapies such as SMN upregulators. In some embodiments, patients with infant-onset SMA have one copy of SMN2. In some embodiments, patients with infant-onset SMA develop diagnosable symptoms of SMA at an age of less than 6 months of age. In some embodiments, patients with infant-onset SMA could have developed diagnosable symptoms at an age of less than 6 months of age but have not, for example, developed symptoms thanks to treatment with SMN upregulators. In some embodiments, such subjects are diagnosed with infant-onset SMA based, for example, on SMN2 copy number, and are distinguished from patients with late-onset SMA based on other factors besides age of disease onset, such as genotype (e.g., SMN2 copy number), phenotype (e.g., gait or other observed motor traits), and / or response to SMA therapy.

[0077] The following provides an overview of the SMA classification and disease characteristics.

[0078] [Table 1]

[0079] [Table 2]

[0080] Genotype-based SMA classification The clinical heterogeneity of SMA is partly due to the complex genetics of the disease. SMA arises from mutations in the SMN1 gene (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 transposition, 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, about 10% of the mRNA produced from SMN2 is correctly spliced ​​to produce a full-length SMN protein, but the amount is insufficient to completely compensate for the loss of SMN1.

[0081] The copy number of SMN2 varies from individual to individual and is strongly correlated with the severity of SMA disease. Higher copy numbers (e.g., 3 or 4 copies) are generally associated with milder forms of SMA. While SMA patients with a single SMN2 copy are rare, this copy number is a very high predictor of the severe type 1 phenotype with a poor prognosis. The majority of patients with type 1 SMA have 1 or 2 copies of SMN2; most patients with type 2 have 3 copies of SMN2; and most patients with type 3 have 3 or 4 copies of SMN2. For example, according to Calucho et al. ((2018) Neuromuscular Disorders. 28:208-215 at Table 2), approximately 80% of type 1 SMA patients carry one or two SMN2 copies, approximately 94% of type 2 patients carry two or three copies, approximately 93% of type 3 patients carry three or four copies, and nearly 100% of type 4 patients carry four to six SMN2 copies.

[0082] Traditional SMA classification includes types 1, 2, 3, and sometimes 4, in order of increasing severity. Type 1 SMA is typically diagnosed between birth and 6 months of age, and without early intervention, patients never acquire sufficient muscle strength to sit independently. Without intervention, most type 1 patients do not survive past 2 years of age without respiratory support. Types 2 and 3 are less severe but still life-changing types of SMA, characterized by higher production of SMN protein. Type 2 patients are generally diagnosed between 6 and 18 months of age. These patients can sit without assistance but cannot walk without help. In type 3 SMA, patients are typically diagnosed after 18 months of age and can sit and walk independently, but may become wheelchair-bound later in life. Therefore, type 3 SMA includes both amblyable and non-ambulating subgroups. Many amblyable type 3 SMA patients become non-ambulating at some point as the disease progresses. Type 4 SMA is an adult-onset form with a mild phenotype and is extremely rare.

[0083] While stratification of SMA by type is a useful clinical paradigm, disease phenotypes exist as a continuum rather than a discrete classification. For example, it is possible for patients who carry an SMA gene mutation to be pre-symptomatic (not yet exhibiting an obvious disease phenotype).

[0084] In some cases, patients carrying mutations in the SMN gene (such as SMN1) may be phenotypic and can be identified based on genetic screening for treatment. In some embodiments, the reason for the delayed onset of the disease may be, at least in part, early intervention such as SMN upregulatory therapy (e.g., SMN2 upregulatory therapy and SMN1 gene therapy). Early intervention generally means that treatment is initiated before the age of five, for example, before the age of four, three, two, or one, or immediately after birth. In recent years, neonatal genetic screening has become widely available, which enables the identification of individuals born with genetic disorders such as SMA. For example, in the United States, many states include SMA in particular among the many known genetic disorders in their routine neonatal screening panels, and this screening is typically performed in the first few days after birth. Thus, infants who carry mutations in the SMN gene (SMN1) that are likely to develop the disease can be identified early, often while they are asymptomatic (pre-symptomatic). Early detection and diagnosis can lead to early therapeutic intervention, even before the child begins to develop symptoms. This can help prevent certain clinical manifestations and / or delay the onset or progression of SMA.

[0085] Genetic screening may be performed on neonates / infants as well as in utero (e.g., in the fetus). In some embodiments, subjects have been identified, or have been identified, as carriers of the SMN mutation by genetic screening, either in utero or as neonates / infants. In some embodiments, genetic screening is performed on neonates / infants (e.g., within 24 hours of birth). In other embodiments, genetic screening is performed in utero.

[0086] SMA classification based on onset Severe forms of SMA typically show initial symptoms, for example, before the age of six months.

[0087] This can be called the infant-onset type, in contrast to the late-onset type of SMA. When SMA symptoms are present at birth or by 6 months of age, the disease is also known as SMA type 1 (also called infant-onset or Werdnig-Hoffmann disease). Infants typically have generalized muscle weakness, a weak cry, and difficulty breathing.

[0088] Regardless of SMA classification based on genotype, such as SMN2 gene copy number, the term late-onset SMA is defined by the age of onset (when symptoms appear), unless otherwise specified. For example, late-onset SMA can be defined as a disease in which symptoms appear at age 6 months or older (most likely to be classified as SMA type 2 or 3).

[0089] Recently, with the availability of approved SMN upregulatory therapies such as nusinersen, early intervention has been shown to be particularly effective in delaying the onset of more severe phenotypes of SMA based on the genotype of specific patients, and / or reducing their severity. For example, some patients diagnosed with type 1 SMA (or at risk of developing it due to a low copy number of the SMN2 gene) may see their phenotype change to one more consistent with late-onset SMA through early intervention with SMN upregulatory therapy.

[0090] In some embodiments, a definition based on the onset of symptoms is useful for classifying certain patient populations that receive early intervention that alters the normal course or timeline of disease progression.

[0091] Improvement of muscle function through myostatin targeting - myostatin inhibition One therapeutic approach to improve a patient's motor function is to directly target the skeletal muscle of patients with muscle pathologies such as SMA to reduce muscle atrophy and, consequently, improve muscle strength. Myostatin inhibition offers a promising method for increasing muscle mass and function in patients with muscle pathologies, such as SMA patients. Myostatin is a member of the TGFβ superfamily and is a negative regulator of muscle growth. Genetically, myostatin is lost, leading to a significant increase in muscle mass, resulting in both myocyte hypertrophy and hyperplasia (McPherron et al. (1997) Nature 387:83-90). Similar to myostatin loss-of-function mutations, pharmacological inhibition of myostatin also increases muscle mass, mediated by muscle hypertrophy, not hyperplasia (Lee et al. (2001) Proc Natl Acad Sci USA 98:9306-9311). In addition, evidence from animal models suggests that blocking myostatin signaling prevents limb immobilization, cancer cachexia, and muscle atrophy associated with corticosteroid treatment (Latres et al. (2015) Skelet Muscle 5:34; Smith et al. (2015) Mol Cancer Ther 14:1661-1670; Wang et al. (2017) Am J Phys Med Rehabil 96(6):430-437; Zhou et al. (2010) Cell 142:531-543). Since the initial reports of knockout mice, myostatin mutations and associated muscle hypertrophy have been identified in cattle, dogs, and humans. Myostatin deficiency does not appear to cause any adverse effects.

[0092] Because myostatin loss has a significant effect on muscle mass, and no lesions are observed with myostatin mutations, this growth factor is an important therapeutic target for indications characterized by significant muscle wasting, including sarcopenia, cancer cachexia, muscular dystrophy, and inactive atrophy. Several companies are exploring various methods to inhibit myostatin and thus increase muscle mass and strength. The most common myostatin inhibition methods are (1) antibodies that bind to and inhibit mature growth factors (generally called "neutralizing" antibodies), (2) antibodies against the myostatin receptor ActRIIB, (3) soluble ligand traps such as ActRIIB-Fc, and (4) virus-mediated expression of myostatin inhibitors such as follistatin (Amato et al. (2014) Neurology 83:2239-2246; Becker et al. (2015) Lancet Diabetes Endocrinol 3:948-957; Campbell et al. (2017) Muscle Nerve 55(4):458-464; Mendell et al. (2015) Mol Ther 23:192-201; Wagner et al. (2008) Neurol 63:561-571). However, in addition to targeting myostatin, many of these therapies also inhibit related family members such as GDF-11 and activin. Because the amino acid sequences of mature myostatin and GDF-11 are 90% identical, it is difficult to produce antibodies that specifically bind to myostatin but not to GDF-11. Myostatin, GDF-11, and activin all signal through ActRIIB; therefore, antibodies that block ActRIIB or soluble ActRIIB ligand traps will thus inhibit the activity of all three growth factors (Lee et al. (2005) Proc Natl Acad Sci USA 102:18117-18122). Some of these therapies also bind, albeit with lower affinity, to more distantly related growth factors such as BMP9 and BMP10. This lack of specificity can lead to undesirable side effects.In summary, these observations highlight the importance of developing selective myostatin signaling inhibitors to minimize the risk of adverse effects that may result from inadvertently inhibiting one or more signaling pathways among the relevant growth factors.

[0093] Accordingly, this specification discloses antibodies having the ability to bind to promyostatin and / or latent myostatin, and thus having the ability to inhibit myostatin activity, and their use for the treatment of diseases and disorders associated with muscle atrophy, such as SMA. In some embodiments, given the prevalence of latent syndromes in circulation, this specification provides therapies that specifically target myostatin precursors, such as promyostatin and latent myostatin, which are more abundant and longer-lived than mature growth factors. Without intending to be bound by any particular theory, the antibodies described herein may, for example, by binding to type I (ALK4 / 5) and type II (ACTRIIA / B) receptors, prevent proteolytic activation of promyostatin and / or latent myostatin, which would otherwise lead to mature myostatin, considered to be the “active” type of myostatin capable of activating the myostatin pathway.

[0094] As used herein, the term “antibody” encompasses any naturally occurring, recombinant, modified, or engineered immunoglobulin or immunoglobulin-like structure, or its antigen-binding fragment or portion, or derivative thereof. Therefore, the term refers to an immunoglobulin molecule that specifically binds to a target antigen, and includes, for example, chimeric antibodies, humanized antibodies, fully human antibodies, and multispecific antibodies (including bispecific antibodies). An intact antibody generally contains at least two full-length heavy chains and two full-length light chains, although some examples, such as antibodies naturally occurring in camelids, may contain fewer chains. An antibody may originate from a single source or may be a “chimera,” meaning that different portions of an antibody may originate from two different antibodies. Antibodies, or their antigen-binding portions, may be produced by hybridomas, by recombinant DNA techniques, or by enzymatic or chemical cleavage of an intact antibody. The term antibody, as used herein, includes, respectively, monoclonal antibodies, multispecific antibodies such as bispecific antibodies, minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as “antibody mimes”), chimeric antibodies, humanized antibodies, human antibodies, and antibody fusions (sometimes referred to herein as “antibody conjugates”). In various embodiments of the therapeutic methods, uses, and compositions disclosed herein, the antibody is a promyostatin / latent myostatin antibody (e.g., apiteglomab). Promyostatin / latent myostatin: As used herein, the term “promyostatin / latent myostatin” refers to promyostatin, latent myostatin, or both. In some embodiments, the anti-promyostatin / anti-latent myostatin antibody specifically binds to promyostatin. In some embodiments, the anti-promyostatin / anti-latent myostatin antibody specifically binds to latent myostatin. In some embodiments, the anti-promyostatin / anti-latent myostatin antibody specifically binds to both latent myostatin and promyostatin. In some embodiments, the anti-promyostatin / anti-latent myostatin is apiteglomab, which specifically binds to both latent myostatin and promyostatin.

[0095] As used herein, the term “mature myostatin” refers to the mature, biologically active form of myostatin. In some embodiments, mature myostatin possesses myostatin receptor binding and / or activating ability. Activation and release of mature myostatin from its promyostatin form in vivo are achieved by several individual protease cleavage events. Firstly, “promyostatin” is cleaved by proprotein convertases to become “latent myostatin,” where a portion of the prodomain of mature myostatin prevents it from binding to its receptor. Activation and release of mature myostatin are achieved after cleavage of latent myostatin by further proteases from the BMP / toroid family, such as mTLL-2. As used herein, the term “mature myostatin” may refer to both full-length mature myostatin and fragments of full-length mature myostatin that retain biological activity. So-called neutralizing antibodies that bind to mature myostatin thereby interfere with the ability of mature myostatin to bind to its cell receptor and activate it.

[0096] As used herein, the term “myostatin proform” refers to the inactive (e.g., precursor or latent) form of myostatin growth factor associated with the N-terminal latent-associated peptide (LAP) domain. Myostatin proforms include dimers. This term encompasses both “promyostatin” and “latent myostatin.” This term excludes mature growth factor (GDF-8) that is not associated with the LAP domain.

[0097] The term "promyostatin" (also spelled "pro myostatin") refers to an inactive precursor of mature myostatin, which is a disulfide-bonded homodimer, wherein each molecule of the homodimer comprises an amino-terminal prodomain covalently bound to a carboxyl-terminal mature myostatin domain. In some embodiments, "promyostatin" is not cleaved by either proprotein convertases or proteases of the BMP / tolloid family. Promyostatin and latent myostatin (see below) are pro-forms of myostatin / GDF-8.

[0098] As used herein, the term "latent myostatin" refers to an inactive precursor of mature myostatin, which is a disulfide-bonded homodimer, wherein each molecule of the homodimer comprises an amino-terminal prodomain non-covalently bound to a carboxyl-terminal mature myostatin domain. In some embodiments, "latent myostatin" is generated from promyostatin that has been cleaved by a proprotein convertase but not cleaved by a protease of the BMP / tolloid family. In some embodiments, "latent myostatin" may be generated by combining the prodomain and the carboxyl-terminal mature myostatin domain in vitro and allowing them to fold correctly. See, for example, Sengle et al. (2011) J. Biol. Chem., 286(7):5087-5099. Promyostatin (see above) and latent myostatin are pro-forms of myostatin / GDF-8.

[0099] As used herein, the terms "specific binding" or "specifically binds" mean that an antibody or an antigen-binding portion thereof exhibits a specific affinity for a particular structure of an antigen (e.g., an antigenic determinant or epitope) (e.g., K measured by Biacore® D ) to the target. In some embodiments, an antibody has at least about 10 -8 M, 10 -9 M, 10 -10M, 10 -11 M, 10 -12 M, or K below that. D If such an antibody or its antigen-binding moiety has the properties of promyostatin / latent myostatin, it specifically binds to the target, such as promyostatin / latent myostatin. In the context of this disclosure, "antibody that specifically binds to an antigen with high affinity" generally means 1.0 × 10⁻⁶ -8 K below M D This refers to the following. In some embodiments, an antibody or its antigen-binding moiety may also be said to bind "selectively" (i.e., "preferentially") to a target antigen if it binds to that target antigen (e.g., promyostatin / latent myostatin) with a relative affinity 10 times, 100 times, 1000 times, or more than the affinity it has for a non-target antigen (e.g., mature myostatin (GDF-8), GDF-11, and / or other members of the TGFβ growth factor superfamily).

[0100] In some embodiments, the anti-promyostatin / anti-latent myostatin antibodies for use in the therapeutic methods, uses, and compositions disclosed herein inhibit the activation step of myostatin from its precursor. In some embodiments, the anti-promyostatin / anti-latent myostatin antibodies for use in the therapeutic methods, uses, and compositions disclosed herein inhibit the activation of latent myostatin. In some embodiments, the anti-promyostatin / anti-latent myostatin antibodies comprise the heavy and light chain CDR sequences, heavy and light chain variable region sequences, and / or complete heavy and light chain sequences shown in Tables 1 to 4 below.

[0101] [Table 3]

[0102] [Table 4]

[0103] [Table 5]

[0104] [Table 6]

[0105] Apiteglomab (also known as "SRK-015") is a fully human monoclonal antibody for clinical trials that binds with high affinity and specificity to myostatin proforms—namely, promyostatin and latent myostatin. Apiteglomab is a human immunoglobulin G4 (IgG4) / λ isotype, comprising the sequence shown above (including the heavy chain amino acid sequence of SEQ ID NO: 15 and the light chain amino acid sequence of SEQ ID NO: 16). International application PCT / US2016 / 052014 (International Publication No. 2017 / 049011) and U.S. Patent Application No. 15 / 760,393 (U.S. Patent Publication No. 2018-0344844; U.S. Patent No. 10,751,413) disclose the sequence of apiteglomab, which are incorporated herein by reference, respectively. In some embodiments, the anti-promyostatin / anti-latent myostatin antibody for use in the therapeutic methods, uses, and compositions disclosed herein is apiteglomab.

[0106] In some embodiments, the anti-promyostatin / anti-latent myostatin antibody or antigen-binding fragment described herein comprises three heavy chain complementarity-determining regions (HCDRs) including the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3) as defined by the Kabat numbering scheme; and three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0107] In some embodiments, the anti-promyostatin / anti-latent myostatin antibody or antigen-binding fragment described herein comprises three heavy chain complementarity-determining regions (HCDRs) including the amino acid sequences of SEQ ID NO: 7 (HCDR1), SEQ ID NO: 8 (HCDR2), and SEQ ID NO: 9 (HCDR3) as defined by the IMGT numbering scheme; and three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 10 (LCDR1), SEQ ID NO: 11 (LCDR2), and SEQ ID NO: 12 (LCDR3).

[0108] In various embodiments, the anti-promyostatin / anti-latent myostatin antibody or antigen-binding fragment includes a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 13 and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 14.

[0109] In various embodiments, the anti-promyostatin / anti-latent myostatin antibody or antigen-binding fragment comprises the heavy chain amino acid sequence of SEQ ID NO: 15 and / or the light chain amino acid sequence of SEQ ID NO: 16.

[0110] Apiteglomab binds to the “arm” region within the prodomain of the promyostatin / latent myostatin complex, inhibiting the release of mature growth factor (i.e., GDF-8) from the latent / inactive complex. Because apiteglomab binding is specific to promyostatin / latent myostatin, and therefore does not bind to mature GDF-8 or GDF-11 (or any other member of the TGFβ growth factor superfamily), it is possible to selectively target myostatin signaling without affecting other biological pathways.

[0111] Inhibition of myostatin activation by apiteglomab can lead to the accumulation of promyostatin and latent myostatin. Since promyostatin is mainly found in skeletal muscle and latent myostatin is mainly found in serum, in some embodiments, serum latent myostatin levels can serve as a marker for targeted association of apiteglomab, e.g., targeted association of apiteglomab with skeletal muscle. Similarly, in some embodiments, serum latent myostatin levels can serve in a similar manner as a marker for targeted association of other promyostatin / latent (atent) myostatin antibodies, such as GYM329. In some embodiments, serum latent myostatin levels may be relatively low at baseline (i.e., pre-treatment) and may increase after treatment with apiteglomab. In some embodiments, an increase in serum latent myostatin levels indicates targeted association with apiteglomab, e.g., targeted association of apiteglomab with skeletal muscle. In some embodiments, low baseline serum levels compared to high post-treatment levels of latent myostatin indicate that the majority of the drug target is retained within the skeletal muscle rather than circulating throughout the body. In some embodiments, saturation of target association indicates that the dosage is sufficient to achieve a certain therapeutic effect (e.g., efficacy), although efficacy may be achieved without saturation.

[0112] In certain embodiments, this disclosure includes the use of alternative anti-myostatin antibodies or antigen-binding fragments, such as anti-promyostatin / anti-latent myostatin antibodies or antigen-binding fragments, such as selective anti-promyostatin / anti-latent myostatin antibodies, such as any one of the antibodies or antigen-binding fragments disclosed in PCT / JP2015 / 006323 (which is incorporated herein by reference in whole). The 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, this disclosure includes an anti-promyostatin / anti-latent myostatin antibody or antigen-binding fragment that is a humanized variant of MST1032-G1m as disclosed in PCT / JP2015 / 006323. In certain embodiments, the Disclosure comprises an anti-promyostatin / anti-latent myostatin antibody or antigen-binding fragment 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 CDR comprises 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 CDR comprises 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; 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 includes a heavy chain variable domain containing one of the amino acid sequences of SEQ ID NOs. 47-50. In certain embodiments, the antibody or antigen-binding fragment includes a light chain variable domain containing one of the amino acid sequences of SEQ ID NOs. 51-54. In some embodiments, the antibody or antigen-binding fragment includes a set of six CDRs (e.g., from the same MST1032 variant antibody) or a pair of VH / VLs (e.g., from the same MST1032 variant antibody) from those listed in the table below.

[0113] [Table 7]

[0114] [Table 8]

[0115] [Table 9]

[0116] [Table 10]

[0117] [Table 11]

[0118] [Table 12]

[0119] In certain embodiments, the disclosure includes the use of an antibody comprising either GYM329 or a sequence from Tables 3C-3H 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 having SMA. In certain embodiments, an antibody comprising either GYM329 or a sequence from Tables 3C-3H above is used in conjunction with SMN upregulatory therapy for the treatment of SMA (e.g., risdiplam, nusinersen, and / or onasemnogene abeparvovec). In certain embodiments, an antibody comprising either GYM329 or a sequence from Tables 3C-3H above is used for the treatment of SMA subjects who are able to walk 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 non-walking SMA. In certain embodiments, the subject is between 2 and 10 years of age. In certain embodiments, the subject has a history of treatment with an SMN upregulator. In certain embodiments, the subject has a history of treatment with risdipram, nusinersen and / or onasemnogen abeparvovec. In certain embodiments, the subject has no history of treatment with an SMN upregulator. In certain embodiments, GYM329 is used for the treatment of SMA in subjects who are able to walk or have the ability to walk independently, preferably subjects aged 2 to 10 years, wherein this use comprises administering GYM329 to the subject in combination with risdipram, wherein the subject has a history of receiving at least one dose of risdipram, nusinersen or onasemnogen abeparvovec. In some embodiments, the subject is able to walk or run 10 meters in 30 seconds and / or has a confirmed genetic diagnosis of 5q autosomal recessive SMA and symptomatic disorder. In some embodiments, the use of an antibody containing GYM329 or any of the sequences from Tables 3C to 3H above, either alone or in combination with an SMN upregulator, may lead to improvement compared to no treatment. Improvement can be measured by RHS and / or Motor Function Measure-32 (MFM32) scores.Improvement may be an improvement in muscle mass as measured by MRI and / or dual-energy X-ray absorptiometry (DXA) scans. Improvement may be an improvement in muscle strength as measured by a dynamometer. Improvement may be as determined by the SMA Independence Scale (SMAIS). Improvement may be observed in two or more of the aforementioned measurement criteria.

[0120] In some embodiments, a composition comprising an anti-myostatin antibody, such as an anti-promyostatin / anti-latent myostatin antibody like GYM329 or apiteglomab, is used to treat SMA in patients aged 2 months or older, and optionally, this treatment further comprises risdiplam (EVRYSDI®). In some embodiments, GYM329 or apiteglomab and risdiplam are administered to the patient as a combination therapy. In some embodiments, GYM329 or apiteglomab is administered as an add-on or adjuvant therapy to patients with a history of treatment with risdiplam (i.e., patients with a history of administration of risdiplam). In some embodiments, risdiplam is administered as an add-on or adjuvant therapy to patients with a history of treatment with GYM329 or apiteglomab (i.e., patients with a history of administration of risdiplam). In some embodiments, the patient is 2 to 7 months old, and optionally, the patient has or is suspected of having type 1 SMA. In some embodiments, the patient is 2 to 25 years old and, optionally, has type 2 or type 3 SMA. In some embodiments, the patient is of any age (e.g., infant, child, or adult) and has type 1, type 2, or type 3 SMA.

[0121] SMN therapy Numerous studies have been conducted on therapeutic methods to restore SMN protein levels, including SMN1 gene replacement therapy, small molecules that regulate SMN2 splicing, and methods that use antisense oligonucleotides (ASOs) to block the SMN2 intron splicing silencer and thereby increase exon 7 inclusion.

[0122] The benefits of SMN1 gene replacement therapy using adeno-associated virus vectors (AAVs) have been demonstrated in a mouse SMA model, and AVXS-101, an AAV9-SMN1 vector from AveXis, is being evaluated in a Phase I clinical trial (see NCT02122952) (Passini et al. (2010) J Clin Invest 120:1253-1264).

[0123] Other approaches focus on regulating SMN2 splicing so that a larger proportion of transcripts retain exon 7, leading to increased production of full-length SMN protein. 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). These small molecules from both companies have been evaluated in Phase 2 clinical trials (see trials NCT02913482, NCT03032172, NCT02908685, and NCT022688552). Oral administration of RG7800, SMN-C2, and SMN-C3 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 to the medium. These molecules also efficiently crossed the blood-brain barrier (BBB). In severe SMA mouse models, both compounds normalized motor behavior and increased body weight and survival compared to the medium. However, this clinical program was discontinued due to safety concerns.

[0124] Further 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 (each of which is incorporated herein by reference in whole). 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 obvious to those skilled in the art are within the scope of this disclosure.

[0125] A third approach involves using antisense oligonucleotides (ASOs) to block, for example, the SMN2 intron splicing silencer, thereby increasing exon 7 inclusions. In this case, too, the disease is rescued in the mouse SMA model (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 has developed nusinersen, an ASO splicing modifier, which has shown clinical efficacy and has been approved by the FDA and 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 decisional memorandum (2016)). However, nusinersen requires intrathecal delivery under general anesthesia with each administration. In addition, while the antisense modifier nusinersen has shown promise, its clinical efficacy appears to be moderate: among infant-onset SMA (type I), 60% of patients have been reported to be non-responders, and 43% of nusinersen-treated patients did not achieve an increase of 3 points or more on the Hammersmith Functional Motor Scale (Expanded: HFMSE) compared to placebo, while the average increase in the treated group was less than 6 points. Therefore, nusinersen treatment may only result in partial improvement.

[0126] While all of these molecules have shown significant efficacy preclinically, and nusinersen has shown significant efficacy clinically, none have resulted in a complete cure for the disease. In mouse models, both small molecules and ASO splicing modifiers significantly reduced disease severity, yet treated animals were still inferior to healthy animals in terms of lifespan, body weight, muscle mass, and muscle function (Hua et al. (2011) Nature 478:123-126; Feng et al. (2016) Hum Mol Genet 25:964-975). In a double-blind clinical trial of infant-onset SMA, nusinersen demonstrated a clinically meaningful benefit at the interim analysis (41% of treated patients showed improvement in motor milestones using the Hammersmith Infant Neurological Examination compared to 0% in the placebo group). The motor function milestones achieved are impressive for type I patients, with 5 out of 81 treated patients being able to sit independently (a milestone rarely achieved in these patients). Nevertheless, these patients did not achieve the full range of developmental milestones, and in a normal individual, the milestones achieved would be considered disappointing. In a second placebo-controlled trial in type II SMA, nusinersen again showed clinically meaningful improvement, with Hammersmith Functional Motor Scale-Expanded (HFMSE) scores increasing by 5.9 points compared to the placebo group. The highest HFMSE score was 66, and it should be noted that most type II patients score below 20 (Glanzman et al. (2011) J Child Neurol 26:1499-1507; Kaufmann et al. (2011) Arch Neurol 68:779-786). Nevertheless, in this trial, 43% of patients failed to achieve at least a 3-point improvement in motor function.These results suggest that SMN2 splicing modifiers may have a significant effect on the quality of life of patients with SMA, but further improvements to reduce the burden of the disease are needed to achieve additional functional gains.

[0127] As used herein, the term “motor neuron-directed therapy” refers to a drug intended to improve (e.g., enhance or restore) neuronal 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 the incomplete but partial loss of neurons innervating muscles. In some embodiments, motor neuron-directed therapy is a gene therapy, small molecule, or antisense oligonucleotide. In some embodiments, motor neuron-directed therapy is a “SMN upregulator.” Exemplary motor neuron-directed therapies (e.g., SMN upregulators) suitable for use in combination with apiteglomab as disclosed herein include, but are not limited to, nusinersen; risdiplam; and onasemnogene abeparvovec. In some embodiments, motor neuron-directed therapy is a drug having the ability to completely restore motor neuron function in cells (e.g., cells within the body of the subject). In some embodiments, motor neuron-directed therapy is a drug having the ability to partially restore motor neuron function in cells (e.g., cells within the body of the subject). In some embodiments, motor neuron-directed therapy is a drug having the ability to restore 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 cells (e.g., cells within the body of the subject). Those skilled in the art will understand that motor neuron function typically includes membrane excitability, axonal transport, vesicular transport, neurotransmitter release, mitochondrial function, and / or mitochondrial availability, and that such functions can be measured using assays known to those skilled in the art.

[0128] As used herein, the terms “SMN upregulator” or “SMN upregulator therapy” (which may also be synonymously referred to as SMN therapy, SMN-directed therapy, SMN modifier, SMN augmentation therapy, or SMN auger) refer to 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. SMN upregulators may be central modifiers or systemic modifiers. Central upregulators may be administered directly to the central nervous system (CNS) via an intrathecal route. In contrast, systemic upregulators may be administered via any route, for example, orally, and affect not only the CNS but also other tissues throughout the body. SMN upregulators include, for example, splicing modifiers / modifiers that alter the splicing of the SMN2 transcript. Systemically delivered SMN splicing modifiers may also affect SMN splicing in other (i.e., non-neuronal) tissues where SMN is expressed.

[0129] In some embodiments, the "functional SMN protein" has the ability to promote motor neuron function and / or survival. In some embodiments, the "functional SMN protein" has the ability to completely restore motor neuron function in cells (e.g., cells in the body of the subject). In some embodiments, the functional SMN protein has the ability to partially restore motor neuron function in cells (e.g., cells in the body of the subject). In some embodiments, the functional SMN protein has the ability to restore 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 motor neuron function in cells (e.g., cells in the body of the subject). In some embodiments, the full-length SMN protein is the result of protein translation (e.g., in cells) of correctly spliced ​​SMN mRNA. In some embodiments, the functional SMN protein is encoded from SMN2 mRNA having exon 7.

[0130] Examples of suitable SMN upregulators include splicing modifiers, SMN gene replacements or gene therapies, SMN transcription enhancers, SMN protein translation enhancers, and SMN protein stabilizers. In some embodiments, such SMN upregulators may be small molecule drugs, biologics, or nucleic acids. In some embodiments, the SMN upregulator is a small molecule splicing modifier of SMN2. In some embodiments, the SMN upregulator is an antisense RNA splicing modifier of SMN2. In some embodiments, gene therapy involves the introduction of one or more transgenes into the patient. In some embodiments, gene delivery is achieved by the use of suitable vectors, such as viral vectors and lipid-based carriers. For viral vector-mediated gene delivery, gene therapy may involve using a specific serotype for initial treatment followed by a different serotype for subsequent treatment to minimize adverse immune responses in the target. In some embodiments, gene therapy involves targeted genome editing, such as CRISPR / Cas9 technology or its variations. Non-limiting examples of SMN upregulators suitable for use in combination with apiteglomab as relating to this 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 works similarly, being a pyridazine derivative that modifies SMN2 messenger RNA splicing.For example, see 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.

[0131] In some embodiments, the SMN upregulator is a gene therapy, a small molecule, or an antisense oligonucleotide. 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 the expression of the SMN2 gene. In some embodiments, the SMN upregulator is an antisense molecule that increases the expression of SMN2 mRNA having exon 7. In some embodiments, the SMN upregulator is an antisense molecule that increases the expression of a functional SMN protein, for example, an SMN protein encoded by SMN2 mRNA having exon 7. For example, an antisense oligonucleotide aimed at inhibiting the intron splicing silencer site (ISS) in intron 7 of the SMN2 gene can regulate premRNA processing, leading to an increased probability of exon 7 inclusion in the mature SMN2 mRNA transcript, thus resulting in increased production of a functional SMN protein.

[0132] The terms “splicing modifier,” “splicing regulator,” and “splicing modifier” are, as used herein, synonymous and refer to agents that correct splicing abnormalities in RNA transcripts and / or modulate the expression of SMN proteins, such as those encoded by the SMN2 gene. In some embodiments, SMN2 splicing modifiers increase the inclusion of exon 7 in SMN2 premRNA. In some embodiments, increased inclusion of exon 7 in SMN2 premRNA leads to increased expression of functional SMN proteins (e.g., from the SMN2 gene) in cells or subjects, such as SMN proteins that have the ability to promote neuronal function and / or survival.

[0133] In some embodiments, SMN upregulators are gene therapies. As used herein, the term “gene therapy” refers to any procedure that uses nucleic acids to cure, eradicate, or otherwise improve a disease condition of interest. In gene therapy, nucleic acids are delivered to specific cells. Delivery methods include viral and nonviral 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 means for delivering gene therapy involve the use of viral vectors. Viral vectors are genetically modified viruses that are capable of carrying a therapeutic gene payload and are reprogrammed to allow infection and subsequent transmission of the payload to specific tissues without the side effects typically associated with wild-type virus infection. Several viruses can be used as viral vectors, including retroviruses, adenoviruses, herpes simplex viruses, lentiviruses, poxviruses, and Epstein-Barr viruses. Although safer than wild-type viruses, viral vectors can trigger an immune response, and in some cases, the use of nonviral delivery methods is necessary. In some embodiments, the viral vector is an AAV virus vector. Nonviral delivery methods include, but are not limited to, physical methods such as injection of naked DNA, electroporation, gene gun bombardment, and ultrasound, as well as biochemical methods. Another delivery technique, magnetofection, combines physical and biochemical elements.

[0134] In some embodiments, the “effective dose” of an SMN upregulator is the amount of drug having the ability to completely restore motor neuron function in cells (e.g., cells in the body of the subject). In some embodiments, the SMN upregulator is a drug having the ability to partially restore motor neuron function in cells (e.g., cells in the body of the subject). In some embodiments, the “effective dose” of an SMN upregulator is the amount of drug having the ability to restore 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 cells (e.g., cells in the body of the subject). In some embodiments, motor neuron function includes membrane excitability, axonal transport, vesicular transport, neurotransmitter release, mitochondrial function, and / or mitochondrial utilization.

[0135] In some embodiments, the SMN upregulator is a drug, e.g., a small molecule or oligonucleotide (e.g., an antisense oligonucleotide), that increases the expression of functional SMN proteins, for example, by promoting the inclusion of exon 7 in SMN2 mRNA transcripts. In some embodiments, the cells are cells in the body of a subject, e.g., a subject to be administered the SMN upregulator. In some embodiments, the SMN upregulator increases the relative amount of SMN2 mRNA containing exon 7 compared to SMN2 mRNA without exon 7, in cells, e.g., cells of the subject. In some embodiments, an "effective amount" of the SMN upregulator increases the amount of correctly spliced ​​SMN2 mRNA in a cell (e.g., a cell in the body of the subject) 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 intracellular SMN2 mRNA has exon 7. In some embodiments, an "effective dose" of the SMN upregulator increases the level of SMN2 mRNA with exon 7 in the 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 dose" of the SMN upregulator increases the level of functional SMN protein in the 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.

[0136] Clinical benefits of SMN correction drugs Among patients with delayed-onset SMA who are unable to walk, based on the natural history of this patient population, a worsening of the mean HFMSE score over a 12-month period is expected, and only a small percentage (e.g., less than 5%) of patients show an increase of 3 points or more in their HFMSE score (Mercuri et al. (2016) Neuromuscul Disord. 26(2):126-131). Against this backdrop, nusinersen has been reported to provide only limited clinical benefit in patients who initiate this therapy at an age of 5 or older. More specifically, in the CHERISH study, patients who initiated nusinersen at an age of 5 or older experienced a mean HFMSE worsening of more than 0.5 points after 15 months of nusinersen treatment, and less than 15% of patients showed an increase of 3 points or more 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 still observed beyond 15 months in this previous study. Long-term treatment with nusinersen appears to provide disease stabilization, for example, prevention of further motor function loss. The majority of patients in this age group do not show improvement in HFMSE, and it is rare to achieve an increase of 3 points or more.

[0137] In patients with delayed-onset SMA who were unable to walk and initiated nusinersen early (before age 5), previously published data suggest that nusinersen-treated patients primarily stabilize or show moderate gradual improvement after the first 15 months of therapy. Most nusinersen-treated patients in the CHERISH study were under 5 years old at the start of therapy. In the CHERISH study, patients treated with nusinersen showed an average improvement of approximately 4 points in HFMSE during the first 15 months of treatment. When patients were carried over to the long-term SHINE study after this initial 15-month nusinersen treatment in CHERISH, these patients showed an average improvement of primarily stabilization or moderate gradual improvement in motor function during the long-term nusinersen treatment phase. Patients showed an increase of approximately 4.6 points after approximately 4.5 years of treatment (see Figure 8, reproduced from Williams et al). Minimal clinically important differences of the Expanded Hammersmith Functional Motor Scale in later-onset spinal muscular atrophy: results from the phase 3 CHERISH trial. (Presented at the 31st Annual Meeting of the American Academy of Managed Care Pharmacy; March 25-28, 2019; San Diego, CA, USA).

[0138] Natural history data from a longitudinal study of walkable type 3 SMA patients provide further background insights into this patient population. These data indicate that motor function deterioration is common in walkable type 3 SMA patients, and in some cases, it is severe (e.g., loss of walking ability) (Coratti et al. (2020) American Neurology Association, 88:1109-1117, e.g., Figure 1). In a study of 130 walkable type 3 SMA patients (some patients were lost to follow-up over time), the mean age at baseline was 10.05 years and the mean HFMSE score was 52.81. At 12-month assessment, the mean change from baseline in HFMSE was -0.79, and 11 patients had lost walking ability (the mean age of loss of walking ability was 10.21 years (SD ± 6.43 years)). Patients up to 7 years of age showed relative stability with moderate functional improvement, followed by a sharp deterioration in the following years.

[0139] Similarly, a long-term evaluation of risdiplam, another SMN modifier, demonstrated therapeutic benefits, but only stabilization or minor / unspecified improvement 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 MDA Clinical and Scientific Conference 2021; March 15-18. Poster 80).

[0140] Additional / adjunctive therapy, combination therapy This disclosure includes add-on therapy (also referred to as adjuvant therapy) and combination therapy, comprising a first agent which is motor neuron-directed therapy (e.g., SMN therapy) and a second agent which is muscle-directed therapy (e.g., a myostatin inhibitor, e.g., apiteglomab), for the purpose of treating a patient's SMA. When these two agents are used together, the therapeutic effect is enhanced. Add-on or adjuvant therapy means that the therapy is administered to a patient who is continuing background therapy. For example, a muscle-directed therapy such as apiteglomab may be administered to an SMA patient who is already receiving SMN therapy. In contrast, 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. Combination therapy and add-on therapy may be administered separately or in the same setting, for example, during the same clinical visit.

[0141] In various embodiments, the Disclosure provides the use of an anti-promyostatin / anti-latent myostatin antibody (e.g., apiteglomab) for the treatment of SMA in patients receiving motor neuron-directed therapy, such as SMN upregulators, to address motor neuron deficiency. The Disclosure encompasses a method for treating SMA in a target patient treated with an SMN upregulator, comprising the administration of an anti-promyostatin / anti-latent myostatin antibody. In various embodiments, the anti-promyostatin / anti-latent myostatin antibody is apiteglomab.

[0142] In some embodiments, apiteglomab used in combination with SMN therapy provides additive clinical benefits. In some embodiments, apiteglomab used in combination with SMN therapy provides synergistic clinical benefits. "Synergistic" means that when two drugs are used together as either add-on therapy or combination therapy, they together achieve a greater efficacy than the sum of the effects achieved by each monotherapy.

[0143] Apiteglomab may be administered to SMA patients who have responded, poorly responded, or not responded to SMN upregulatory therapy. In poorly responded or unresponsive patients, simultaneous inhibition of myostatin signaling may improve neuromuscular signaling, partly due to enhanced muscle function, thereby increasing the responsiveness of motor neurons innervated by SMN upregulatory agents in unresponsive patients. While we do not wish to be constrained by any particular theory, it is intended that enhancement of the muscle component may affect the neuronal component through positive feedback, and the reverse may also be true due to the bidirectional nature of neuromuscular signaling.

[0144] Patients who have poor and / or no response to SMN upregulatory agents may nevertheless benefit from myostatin inhibition, although the exemplary patient population includes those who have responded to SMN upregulatory agents. It is intended that motor function in these individuals may be further improved by myostatin inhibitor therapy, such as apiteglomab, used in conjunction with motor neuron-targeted therapies, such as SMN upregulatory agent therapy.

[0145] The phrase "in conjunction with..." in the context of a treatment regime for SMA that includes two or more therapeutic agents (e.g., apiteglomab used in conjunction with SMN upregulatory therapy) means that in patients receiving these two or more therapies, the therapeutic effect of the first therapy overlaps temporally and / or spatially with the therapeutic effect of the second and / or additional therapy. The two or more therapies do not have to be administered as a single formulation, nor do they have to be administered simultaneously or via the same route. The first, second, and / or additional compositions may be administered in combination (e.g., simultaneously), individually, or sequentially. Accordingly, the two or more therapies may be formulated as a single formulation for combination administration, or as individual formulations of those therapies for sequential, combination, or simultaneous administration. When a patient treated with a first therapy for SMA (e.g., apiteglomab) is administered a second additional therapy for SMA (e.g., SMN upregulatory therapy), the second additional therapy may be referred to as an "additional" therapy, "adjunct," or "supportive" therapy.

[0146] In some embodiments, the treatment regimens described herein, comprising two or more therapeutic agents (e.g., apiteglomab used in combination with SMN-targeted therapies such as upward-regulating drug therapy), achieve improved clinical benefits in patients compared to monotherapy using each agent alone. Specifically, targeting affected muscles with a myostatin inhibitor therapy such as apiteglomab in combination with motor neuron-targeted therapy such as SMN-targeted drug therapy may produce beneficial clinical outcomes compared to myostatin inhibitor therapy or motor neuron-targeted therapy alone. Such effects may be additive or synergistic compared to each monotherapy. In some embodiments, the combined effect of 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 those therapies used independently. In some embodiments, the combined effect of two or more therapies is synergistic, i.e., hyperadditive, i.e., the effect of the therapies used together is greater than the sum of the effects of those therapies used independently.

[0147] In some embodiments, one or more beneficial therapeutic effects (e.g., effects on at least one symptom or disease progression risk / rate) of using apiteglomab in combination with SMN upregulating therapy are additive. In some embodiments, one or more beneficial therapeutic effects (e.g., effects on at least one symptom or disease progression risk / rate) of using apiteglomab in combination with SMN upregulating therapy are synergistic. In some embodiments, apiteglomab used in combination with SMN upregulating therapy provides additive, synergistic, and / or one or more additional combination benefits. In some embodiments, apiteglomab used in combination with SMN upregulating therapy provides an additive or synergistic effect on at least one efficacy parameter of SMA (e.g., HFMSE score). In some embodiments, apiteglomab used in combination with SMN upregulating therapy provides an additive or synergistic effect on the HFMSE score of SMA patients and / or SMA patient populations. In some embodiments, apiteglomab used in combination with SMN upregulatory therapy provides a further increase in HFMSE scores compared to SMN upregulatory therapy alone (see, for example, Example 1; also see Figure 8 and Darras et al. (2019) Neurology. 92(21)e2492-e2506). In some embodiments, the further improvement in HFMSE scores is additive. In some embodiments, the further improvement in HFMSE scores is synergistic.

[0148] Patient Selection This disclosure includes identifying or selecting human subjects suitable for treatment with selective myostatin inhibitors, such as apiteglomab. Suitable human subjects are patients who are likely to benefit from apiteglomab therapy, either as monotherapy or in combination with (or in combination with) another therapy.

[0149] SMA patients who are likely to benefit from such therapy include those who meet one or more of the following criteria: having a record of a 5q SMA and late-onset (e.g., type 2 or 3) SMA diagnosis prior to receiving therapy for SMA; being unable to walk but able to sit independently as defined by the WHO Motor Milestones; being able to walk independently and walk 10 meters without support in 30 seconds; having a Revised Hammersmith Scale (RHS) score of 63 or less and / or an extended Hammersmith Functional Motor Scale score. Subjects with an Expanded score of 10 or higher; subjects who do not use positive pressure ventilation under tracheostomy or chronic daytime non-invasive ventilatory support for more than 16 hours daily within two weeks prior to treatment; subjects who do not have any acute or co-existing conditions that impair the subject's well-being within two weeks prior to treatment; subjects who do not have severe scoliosis or contracture; and / or subjects who have not used any systemic corticosteroids, valproic acid, or therapies that may have muscle or neuromuscular effects other than approved SMN upregulatory agents (also known as SMN modifiers) within the past 60 days. Therapies that may have muscle or neuromuscular effects include androgens, insulin-like growth factor, growth hormone, systemic β-agonists, botulinum toxin, muscle relaxants, muscle-building supplements, or acetylcholinesterase inhibitors. In some embodiments, the patient has a diagnostic record 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 patients with type 2 SMA, there is a positive correlation between age-normalized changes in motor function and age-normalized multipliers of change in latent myostatin levels. In various embodiments, the methods disclosed herein involve selecting one or more such patients or patient populations for treatment with a myostatin inhibitor, such as apiteglomab, for example, according to the dosage or regimen disclosed herein.

[0150] SMA patients who may respond particularly well to apiteglomab therapy, either as monotherapy or in combination with other therapies, include those under 2 years of age with any type of SMA, and those exhibiting the SMA1 phenotype or having 3 copies or less of SMN2. In some embodiments, apiteglomab may have enhanced therapeutic efficacy in younger patients, e.g., those under 21 years of age, because such patients have higher background anabolic activity. In some embodiments, younger patients, e.g., those under 21 years of age, or those with anabolic activity receive apiteglomab therapy. In some embodiments, patients are 2 years of age or younger, e.g., from birth to 24 months of age. In some embodiments, patients are 6 weeks of age or younger, e.g., from birth to 6 weeks of age. In some embodiments, patients are 2 to 21 years of age. In some embodiments, patients are 13 to 21 years of age. In some embodiments, patients are 12 years of age or younger. In some embodiments, the patient is 2–12 years old. In some embodiments, the patient is 5–12 years old. In some embodiments, apiteglomab may be particularly effective in patients before the onset of puberty (e.g., before the age of 12). In some embodiments, apiteglomab treatment may be effective in preventing the dramatic deterioration of motor function associated with the onset of puberty in younger patients (e.g., patients younger than the age of 12). In some embodiments, the patient is about 2 years old. In some embodiments, the patient is younger than the age of 2. In some embodiments, the patient exhibits the SMA1 type phenotype. In some embodiments, the patient has 3 copies or less of SMN2. In various embodiments, the methods disclosed herein involve the selection of one or more such patients or patient populations for treatment with a myostatin inhibitor, such as apiteglomab, for example, according to the dosage or regimen disclosed herein.

[0151] Patients who may respond particularly well to apiteglomab therapy, either as monotherapy or in combination with another therapy, include patients with type 2 SMA whose baseline (i.e., before initiation of apiteglomab therapy) serum latent myostatin (LM) concentration is at least 1 ng / mL (e.g., higher than 1.5 ng / mL, higher than 2 ng / mL, higher than 2.5 ng / mL, higher than 3 ng / mL, or higher). In some embodiments, apiteglomab therapy, either as monotherapy or in combination with another therapy, may be even 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 younger than 2 years of age. In some embodiments, type 2 SMA patients under 12 years of age with a baseline serum LM concentration of at least 1 ng / mL (e.g., higher than 1.5 ng / mL, higher than 2 ng / mL, higher than 2.5 ng / mL, higher than 3 ng / mL, or higher) may show a particularly high response to apiteglomab therapy. In some embodiments, type 2 SMA patients under 2 years of age with a baseline serum LM concentration of at least 1 ng / mL (e.g., higher than 1.5 ng / mL, higher than 2 ng / mL, higher than 2.5 ng / mL, higher than 3 ng / mL, or higher) may show a particularly high response to apiteglomab therapy. In some embodiments, apiteglomab therapy includes administering apiteglomab at a dose greater than 2 mg / kg, for example, 10 mg / kg or 20 mg / kg.

[0152] In some embodiments, a method for treating SMA includes administering apiteglomab therapy as monotherapy or in combination with another therapy to patients with a baseline serum LM concentration of at least 1 ng / mL (e.g., higher than 1.5 ng / mL, higher than 2 ng / mL, higher than 2.5 ng / mL, higher than 3 ng / mL, or higher). In some embodiments, a method for treating SMA includes administering apiteglomab therapy as monotherapy or in combination with another therapy to patients under 12 years of age with a baseline serum LM concentration of at least 1 ng / mL (e.g., higher than 1.5 ng / mL, higher than 2 ng / mL, higher than 2.5 ng / mL, higher than 3 ng / mL, or higher). In some embodiments, a method for treating SMA includes administering apiteglomab therapy, either as monotherapy or in combination with another therapy, to patients under 2 years of age with a baseline serum LM concentration of at least 1 ng / mL (e.g., higher than 1.5 ng / mL, higher than 2 ng / mL, higher than 2.5 ng / mL, higher than 3 ng / mL, or higher). In some embodiments, apiteglomab therapy includes administering apiteglomab in a dose greater than 2 mg / kg, for example, 10 mg / kg or 20 mg / kg.

[0153] In some embodiments, apiteglomab is used to treat SMA either as monotherapy or in combination with another therapy in patients with a baseline serum LM concentration of at least 1 ng / mL (e.g., higher than 1.5 ng / mL, higher than 2 ng / mL, higher than 2.5 ng / mL, higher than 3 ng / mL, or higher). In some embodiments, apiteglomab is used to treat SMA either as monotherapy or in combination with another therapy in patients under 12 years of age with a baseline serum LM concentration of at least 1 ng / mL (e.g., higher than 1.5 ng / mL, higher than 2 ng / mL, higher than 2.5 ng / mL, higher than 3 ng / mL, or higher). In some embodiments, apiteglomab is used to treat SMA either as monotherapy or in combination with another therapy in patients under 2 years of age with a baseline serum LM concentration of at least 1 ng / mL (e.g., higher than 1.5 ng / mL, higher than 2 ng / mL, higher than 2.5 ng / mL, higher than 3 ng / mL, or higher). In some embodiments, apiteglomab is preferred at doses greater than 2 mg / kg, for example, 10 mg / kg or 20 mg / kg.

[0154] In various embodiments, the SMA patient (e.g., any of the exemplary SMA patients described above) is either currently receiving or has a history of SMN-directed therapy. In some embodiments, the SMN-directed therapy includes nusinersen and / or onasemnogene abeparvovec. In some embodiments, the patient is either currently receiving or has a history of nusinersen. In some embodiments, the patient has a history of past treatment with nusinersen. In some embodiments, the patient has a history of past administration of onasemnogene abeparvovec.

[0155] In various embodiments, the Disclosure provides methods for treating one or more patients or patient populations with a myostatin inhibitor such as apiteglomab, either alone or in combination with (or in combination with) SMN-targeted therapy, wherein one or more patients or patient populations meet one or more of the following criteria: having any type of SMA at an age of 2 years or less, exhibiting an SMA1 type phenotype, and / or having 3 copies or less of SMN2. In some embodiments, the treatment includes apiteglomab therapy as monotherapy, for example, according to the dosage or regimen disclosed herein. In some embodiments, the treatment includes apiteglomab therapy in combination with (or in combination with) SMN-targeted therapy, such as nusinersen or onasemnogene abeparvovec, for example, according to the dosage or regimen disclosed herein. In some embodiments, the patient is currently receiving (or has a history of) nusinersen. In some embodiments, the patient has a history of treatment with nusinersen. In some embodiments, the patient has a history of receiving onasemnogene abeparvovec.

[0156] In some mechanisms, the patient is symptomatic or pre-symptomatic.

[0157] Pre-symptomatic patients include those 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 gene modifications (e.g., determination of SMN2 copy number). Genetic identification of SMA patients may be performed as part of newborn screening. At the time of identification (e.g., diagnosis), the patient (e.g., a newborn) may not be showing obvious / obvious symptoms (asymptomatic), but based on genetic characteristics and possibly other factors, the patient may be expected to develop the disease.

[0158] In severe cases, newborns may already show signs of the disease (i.e., it is symptomatic). Typically, such patients are likely to have type 1 SMA based on the natural history of SMA, and are generally expected to be unable to sit up independently without intervention.

[0159] In some embodiments, the patient is a neonatal patient (age 0-6 months). In some embodiments, the patient is a pediatric patient, age 6 months to 17 years. In some embodiments, the patient is under 5 years old. In some cases, the patient is 5 years old or younger, for example, 2-5 years old. In some embodiments, the patient is 2 years old or younger, for example, from birth to 24 months old. In some embodiments, the patient is 6 weeks old or younger, for example, from birth to 6 weeks old. In some embodiments, the patient is 2 years old or older. In some embodiments, the patient is 2-12 years old. In some embodiments, the patient is 2-12 years old. In some embodiments, the patient is 13-21 years old. In some embodiments, the patient is 5 years old or older, for example, 5-17 years old. In some embodiments, the patient is 5-21 years old. In some embodiments, the patient is an adult.

[0160] In some embodiments, the patient has not received or will not be treated with SMN corrective therapy, such as SMN2 upregulatory therapy and / or SMN1 gene therapy. In some embodiments, the patient has received or will be treated with SMN corrective therapy, such as SMN2 upregulatory therapy and / or SMN1 gene therapy. In some embodiments, the patient initiated or was initiated SMN corrective therapy at an age of less than 5 years. In some embodiments, the patient initiated or was initiated SMN corrective therapy at an age of 5 years or older.

[0161] In some embodiments, patients exhibit disease progression, such as worsening motor function, indicated by a decrease of one or more points in motor function assessment test scores (e.g., HFMSE and RHS scores) during the 12 months prior to treatment with a selective myostatin inhibitor such as apiteglomab.

[0162] In some embodiments, patients treated herein are in a period of disease stabilization, such as when the rate of deterioration of motor function (e.g., as measured by HFMSE and RHS scores) has not changed significantly for at least 6 months prior to the initiation of treatment with a selective myostatin inhibitor (e.g., apiteglomab). In some embodiments, patients exhibit disease stabilization, such as when the patient's motor function (e.g., as measured by HFMSE and RHS scores) has not changed significantly for at least 6 months prior to the initiation of treatment with a selective myostatin inhibitor (e.g., apiteglomab). In some embodiments, patients have non-walking SMA. In some embodiments, patients have type 2 or type 3 non-walking SMA. In some embodiments, patients have walking SMA. In some embodiments, patients have type 3 walking SMA. In some embodiments, patients initiated SMN upregulator / corrective therapy at an age of less than 5 years. In some embodiments, patients initiated SMN upregulator / corrective therapy at an age of 5 years or older. In some embodiments, patients are 2 years of age or younger, e.g., birth to 24 months of age. In some embodiments, the patient is 2 to 12 years old. In some embodiments, the patient is 6 weeks old or younger, e.g., from birth to 6 weeks old. In some embodiments, the patient is 2 to 12 years old and SMN upregulatory / corrective therapy (e.g., nusinersen) is initiated at an age of less than 5 years. In some embodiments, the patient is 2 to 12 years old and SMN upregulatory / corrective therapy (e.g., nusinersen) is initiated at an age of 5 years or older. In some embodiments, the patient is 5 to 12 years old and SMN upregulatory / corrective therapy (e.g., nusinersen) is initiated at an age of 5 years or older.

[0163] In some embodiments, the patient is a patient with 5q spinal muscular atrophy (SMA) with a biallelemic mutation in the SMN1 gene and a clinical diagnosis of SMA1 type, or the patient is a patient with 5q SMA with a biallelemic mutation in the SMN1 gene and three or fewer copies of the SMN2 gene. Such patients may be treated with selective myostatin inhibitors 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 their head up, rolling over from supine to lateral, sitting unsupported for 30 seconds, and sitting unsupported for at least 10 seconds.

[0164] In some embodiments, the patient is a type 2 SMA patient who is able to sit but has never walked, and is aged 2 to 18 years. In some embodiments, SMN1 gene therapy is used to treat type 2 SMA in a patient aged 2 to 18 years who is able to sit but has never acquired the ability to walk, and is treated with a myostatin inhibitor, where optionally, the myostatin inhibitor is a myostatin selective inhibitor such as apiteglomab, GYM329, trevoglumab, or any one of the aforementioned variants. In some embodiments, the myostatin inhibitor is used to treat type 2 SMA in a patient aged 2 to 18 years who is able to sit but has never acquired the ability to walk, and is treated with SMN1 gene therapy, where optionally, the SMN1 gene therapy includes onasemnogene abeparvovec. In preferred embodiments, the myostatin inhibitor is a myostatin-selective inhibitor, such as apiteglomab, GYM329, trevoglumab, or any one of the aforementioned variants. In some embodiments, SMN1 gene therapy and a myostatin inhibitor are used as a 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 herein, this patient is treated with a myostatin inhibitor, where optionally, the myostatin inhibitor is a myostatin-selective inhibitor, such as apiteglomab, GYM329, trevoglumab, or any one of the aforementioned variants, and herein optionally, the SMN1 gene therapy comprises onasemnogene abeparvovec. In some embodiments, the antibody variant may have nucleic acid and / or amino acid sequences with significant homology (e.g., >90% sequence identity) when compared to a known antibody and retain one or more physical and / or functional properties.

[0165] In some embodiments, patients exhibit disease stability as assessed by motor function, such as having no significant change in motor function assessment test scores (e.g., HFMSE and RHS scores) for at least six months prior to treatment with a selective myostatin inhibitor such as apiteglomab. In some embodiments, patients have previously received or are being treated with SMN modification therapy.

[0166] In some embodiments, the patient has previously undergone spinal fusion, such as primary posterior spinal fusion.

[0167] According to this disclosure, patient selection or classification may be based on the highest motor milestone achieved compared to the SMN2 gene copy number. Accordingly, this disclosure includes the therapeutic use of a myostatin selective inhibitor (such as apiteglomab, GYM329, or trevoglumab) in the treatment of a patient's SMA, wherein the treatment includes the administration of a composition comprising the myostatin selective inhibitor. In a preferred embodiment, the myostatin selective inhibitor is apiteglomab, 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) lifting / supporting the head (i.e., head control, e.g., being able to lift or keep the head lifted while lying supine); 2) rolling over; 3) sitting on tripod (e.g., using hands to support the body while sitting) or sitting with support; 4) sitting without support; 5) standing with support / assistance; 6) crawling on all fours; 7) standing with support. 8) Walk with assistance (e.g., walk while holding onto furniture); 9) Stand without support; 10) Take a few steps on one's own but fall; 11) Walk alone (e.g., walk on one's own, walk without support); 12) Squat down to pick up an object (e.g., a toy); 13) Walk / crawl up and down stairs; 14) Run; 15) Jump; 16) Step up stairs by stepping one leg at a time; 17) Jump on one leg; 18) Step down stairs by stepping one leg at a time.

[0168] In some embodiments, the patient has one copy of the smn2 gene, and the highest motor milestone achieved is raising or keeping the head raised 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 with support. 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 by alternating legs. In some embodiments, the patient has one copy of the smn2 gene, and the highest motor milestone achieved is jumping on one leg. In some embodiments, the patient has one copy of the smn2 gene, and the highest motor milestone achieved is descending stairs by alternating legs.

[0169] In some embodiments, the patient has two copies of the smn2 gene, and the highest motor milestone achieved is raising or keeping the head raised 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 with support. 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 by alternating legs. In some embodiments, the patient has two copies of the smn2 gene, and the highest motor milestone achieved is jumping on one leg. In some embodiments, the patient has two copies of the smn2 gene, and the highest motor milestone achieved is descending stairs by alternating legs.

[0170] In some embodiments, the patient has three copies of the smn2 gene, and the highest motor milestone achieved is raising or keeping the head raised 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 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 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 independently (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 by alternating legs. In some embodiments, the patient has three copies of the smn2 gene, and the highest motor milestone achieved is hopping on one leg. In some embodiments, the patient has three copies of the smn2 gene, and the highest motor milestone achieved is descending stairs by alternating legs.

[0171] 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 with support. 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 motor milestone achieved is running. In some embodiments, the patient has four copies of the smn2 gene, and the highest motor milestone achieved is jumping. In some embodiments, the patient has four copies of the smn2 gene, and the highest motor milestone achieved is climbing stairs by alternating legs. In some embodiments, the patient has four copies of the smn2 gene, and the highest motor milestone achieved is jumping on one leg. In some embodiments, the patient has four copies of the smn2 gene, and the highest motor milestone achieved is descending stairs by alternating legs.

[0172] 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 two 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 independently (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 by alternating legs. In some embodiments, the patient has more than four copies of the smn2 gene, and the highest motor milestone achieved is hopping on one leg. In some embodiments, the patient has more than four copies of the smn2 gene, and the highest motor milestone achieved is descending stairs by alternating legs.

[0173] In some embodiments, the patient has one copy of the smn2 gene and achieves the WHO motor development milestone of walking independently. In some embodiments, the patient has one copy of the smn2 gene and achieves the WHO motor development milestone of standing independently. In some embodiments, the patient has one copy of the smn2 gene and achieves the WHO motor development milestone of standing with assistance. In some embodiments, the patient has one copy of the smn2 gene and achieves the WHO motor development milestone of crawling on hands and knees. In some embodiments, the patient has one copy of the smn2 gene and achieves the WHO motor development milestone of walking with assistance.

[0174] In some embodiments, the patient has two copies of the smn2 gene and achieves the WHO motor development milestone of walking independently. In some embodiments, the patient has two copies of the smn2 gene and achieves the WHO motor development milestone of standing independently. In some embodiments, the patient has two copies of the smn2 gene and achieves the WHO motor development milestone of standing with assistance. In some embodiments, the patient has two copies of the smn2 gene and achieves the WHO motor development milestone of crawling on hands and knees. In some embodiments, the patient has two copies of the smn2 gene and achieves the WHO motor development milestone of walking with assistance.

[0175] In some embodiments, the patient has three copies of the smn2 gene and achieves the WHO motor development milestone of walking independently. In some embodiments, the patient has three copies of the smn2 gene and achieves the WHO motor development milestone of standing independently. In some embodiments, the patient has three copies of the smn2 gene and achieves the WHO motor development milestone of standing with assistance. In some embodiments, the patient has three copies of the smn2 gene and achieves the WHO motor development milestone of crawling on hands and knees. In some embodiments, the patient has three copies of the smn2 gene and achieves the WHO motor development milestone of walking with assistance.

[0176] In some embodiments, the patient has four copies of the smn2 gene and achieves the WHO motor development milestone of walking independently. In some embodiments, the patient has four copies of the smn2 gene and achieves the WHO motor development milestone of standing independently. In some embodiments, the patient has four copies of the smn2 gene and achieves the WHO motor development milestone of standing with assistance. In some embodiments, the patient has four copies of the smn2 gene and achieves the WHO motor development milestone of crawling on hands and knees. In some embodiments, the patient has four copies of the smn2 gene and achieves the WHO motor development milestone of walking with assistance.

[0177] In some embodiments, patients have more than four copies of the smn2 gene and achieve the WHO motor development milestone of walking independently. In some embodiments, patients have more than four copies of the smn2 gene and achieve the WHO motor development milestone of standing independently. In some embodiments, patients have more than four copies of the smn2 gene and achieve the WHO motor development milestone of standing with assistance. In some embodiments, patients have more than four copies of the smn2 gene and achieve the WHO motor development milestone of crawling on their hands and knees. In some embodiments, patients have more than four copies of the smn2 gene and achieve the WHO motor development milestone of walking with assistance.

[0178] [Table 13]

[0179] In some embodiments, the subject can raise or support the head of an infant under 3 months, 6 months, 9 months, or 12 months of age.

[0180] In some embodiments, the subject can roll over at an age of 6 months, 9 months, or less than 12 months.

[0181] In some embodiments, the subject is able to sit with support or in a tripod position at an age of 6 months, 9 months, or 12 months.

[0182] In some embodiments, the subject is able to sit without support at an age of 6 months, 9 months, or 12 months.

[0183] In some embodiments, the subject is able to stand with support at an age of 9 months or less than 12 months.

[0184] In some embodiments, the subject is able to stand without support at an age of less than 12 months.

[0185] In some embodiments, the subjects are infants who are under 6 months, 9 months, or 12 months old and can crawl or walk on all fours.

[0186] In some embodiments, the subject is a child who can stand while holding on to something at an age of 9 or 12 months.

[0187] In some embodiments, the subject is able to walk with assistance at an age of 12 or 15 months.

[0188] In some embodiments, the subject is able to walk without assistance at an age of 12 months or less than 15 months.

[0189] In some embodiments, the subjects can run at an age of 15 months, 18 months, or less than 24 months.

[0190] In some embodiments, the subjects are able to jump at an age of 15 months, 18 months, or less than 24 months.

[0191] In some embodiments, the subject is able to squat down and pick up objects at an age of 15 months, 18 months, or less than 24 months.

[0192] In some embodiments, the subject is able to walk or crawl up and down stairs at an age of 15 months, 18 months, or 24 months.

[0193] In some embodiments, the subject is able to climb stairs by stepping with one foot at a time, at an age of 30 or less than 36 months.

[0194] In some embodiments, the subject is under 36 months (3 years) old and can descend stairs by alternating their feet.

[0195] In some embodiments, the subjects are under the age of 4 or 5 and are able to jump on one leg.

[0196] This disclosure provides the therapeutic use of apiteglomab in the treatment of a patient’s SMA, wherein this treatment comprises intravenous administration of a composition comprising a therapeutic dose of apiteglomab, wherein the therapeutic dose is greater than 2 mg / kg and less than or equal to 20 mg / kg (e.g., 10 mg / kg), and wherein optionally, the patient may be selected from one or more of the following classifications, or the patient is characterized by the following:

[0197] The patient is under 2 years old, for example, between birth and 24 months of age.

[0198] The patient is under 6 weeks old, for example, between birth and 6 weeks of age.

[0199] The patient is 2 years of age or older.

[0200] The patients are between 2 and 21 years old.

[0201] The patients are between 2 and 12 years old.

[0202] The patients are between 2 and 5 years old.

[0203] The patients are between 5 and 12 years old.

[0204] The patients are between 13 and 21 years old.

[0205] The patient has late-onset SMA.

[0206] The patient has type 2 SMA.

[0207] The patient has type 3 SMA, and optionally, the patient has type 3 SMA that prevents them from walking.

[0208] The patient has type 3 SMA, and optionally, the patient has a walkable type 3 SMA.

[0209] 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, herein optional, the patient has 2 to 4 copies of the SMN2 gene.

[0210] 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, and optionally, the patient has type 2 SMA or type 3 SMA that renders the patient unable to walk.

[0211] The patient has at least three copies of the SMN2 gene, for example, three, four, five, or six copies of the SMN2 gene; or, herein optional, the patient has three to five copies of the SMN2 gene, herein optional, the patient has a walkable SMA, herein optional, the walkable SMA is type 4 SMA.

[0212] The patient has SMA (e.g., any type of SMA), is under 2 years of age, and optionally, the patient has a history of SMN therapy, and optionally, the SMN therapy includes an SMN2 upregulator (such as nusinersen) or SMN1 gene therapy.

[0213] The patient has type 1 SMA with 3 or fewer copies of the SMN2 gene, and optionally, the patient has a history of SMN therapy, and optionally, the SMN therapy includes an SMN2 upregulator (such as nusinersen) or SMN1 gene therapy.

[0214] The patient has symptomatic SMA.

[0215] The patient has pre-symptomatic SMA.

[0216] Patients are identified as carriers of one or more SMA mutations, but are asymptomatic (pre-symptomatic).

[0217] The patient has no prior history of SMN-directed therapy.

[0218] The patient is currently receiving or has a history of SMN-targeted therapy, where optionally, SMN-targeted therapy is gene therapy, splicing modifiers, or a combination thereof, where optionally, splicing modifiers are nucleic acid-based drugs or low molecular weight compounds that modify SMN2 splicing.

[0219] The patient is currently receiving or has a history of SMN-targeted therapy, wherein the SMN-targeted therapy is, optionally, gene therapy, splicing modifiers, or a combination thereof, wherein the splicing modifiers are nucleic acid-based drugs or low molecular weight compounds that modify SMN2 splicing; and the patient initiated SMN-targeted therapy at an age of less than 5 years.

[0220] The patient is currently receiving or has a history of SMN-targeted therapy, wherein the SMN-targeted therapy is optionally gene therapy, splicing modifiers, or a combination thereof, wherein the splicing modifiers are optionally nucleic acid-based drugs or low molecular weight compounds that modify SMN2 splicing, and the patient initiated SMN-targeted therapy at an age of 5 years or older.

[0221] The patient has been continuing SMN-targeted therapy for at least 12 months prior to the initiation of apiteglomab therapy (e.g., before receiving the first dose of apiteglomab).

[0222] The patient has been receiving SMN-targeted therapy for at least 15 months prior to the initiation of apiteglomab therapy (e.g., before receiving the first dose of apiteglomab).

[0223] The patient has been receiving SMN-targeted therapy for at least 24 months prior to the initiation of apiteglomab therapy (e.g., before receiving the first dose of apiteglomab).

[0224] The patient is 5 years of age or younger at the start of apiteglomab therapy.

[0225] The patient is 2 years of age or younger at the start of apiteglomab therapy.

[0226] Patients are 6 weeks old or younger at the start of apiteglomab therapy.

[0227] The patient is under 5 years old at the time of receiving the first dose of apiteglomab.

[0228] The patient has a baseline HFMSE score of at least 10 points, for example, at least 13 points, for example, between 13 and 39 points, for example, 39 points or less.

[0229] In some embodiments, this disclosure provides the therapeutic use of apiteglomab in the treatment of SMA in patients aged 2 to 12 years who have received SMN upregulatory / corrective therapy (e.g., nusinersen or risdiplam) for at least 6 months prior to initiation of apiteglomab treatment, wherein the apiteglomab treatment comprises intravenous administration, for example, once every 4 weeks or once a month, of a composition comprising 10 mg / kg or 20 mg / kg of apiteglomab. In some embodiments, patients initiated SMN upregulatory / corrective therapy at an age of less than 5 years. In some embodiments, patients initiated SMN upregulatory / corrective therapy at an age of 5 years or older. In some embodiments, the disclosure provides a therapeutic use of apiteglomab in the treatment of SMA in patients aged 2 to 12 years who have received risdiplam for at least 6 months prior to initiation of apiteglomab treatment, wherein the apiteglomab treatment comprises intravenous administration of a composition containing 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or once a month. In some embodiments, the disclosure provides a therapeutic use of apiteglomab in the treatment of SMA in patients aged 2 to 12 years who have received nusinersen for at least 10 months prior to initiation of apiteglomab treatment, wherein the apiteglomab treatment comprises intravenous administration of a composition containing 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or once a month.

[0230] In some embodiments, this disclosure provides the therapeutic use of apiteglomab in the treatment of SMA in patients aged 5 to 12 years who have received SMN upregulatory / corrective therapy (e.g., nusinersen or risdiplam) for at least 6 months prior to initiation of apiteglomab treatment, wherein the apiteglomab treatment comprises intravenous administration, for example, once every 4 weeks or once a month, of a composition comprising 10 mg / kg or 20 mg / kg of apiteglomab. In some embodiments, patients initiated SMN upregulatory / corrective therapy at an age of less than 5 years. In some embodiments, patients initiated SMN upregulatory / corrective therapy at an age of 5 years or older. In some embodiments, the disclosure provides a therapeutic use of apiteglomab in the treatment of SMA in patients aged 5 to 12 years who have received risdiplam for at least 6 months prior to initiation of apiteglomab treatment, wherein the apiteglomab treatment comprises intravenous administration of a composition containing 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or once a month. In some embodiments, the disclosure provides a therapeutic use of apiteglomab in the treatment of SMA in patients aged 5 to 12 years who have received nusinersen for at least 10 months prior to initiation of apiteglomab treatment, wherein the apiteglomab treatment comprises intravenous administration of a composition containing 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or once a month.

[0231] In some embodiments, the disclosure provides a therapeutic use of apiteglomab in the treatment of SMA in patients aged 13–21 years who have received SMN upregulatory / corrective therapy (e.g., nusinersen or risdiplam) for at least 6 months prior to initiation of apiteglomab treatment, wherein the apiteglomab treatment comprises intravenous administration, for example, once every 4 weeks or once a month, of a composition containing 20 mg / kg of apiteglomab. In some embodiments, the patient initiated SMN upregulatory / corrective therapy at an age of less than 5 years. In some embodiments, the patient initiated SMN upregulatory / corrective therapy at an age of 5 years or older. In some embodiments, the disclosure provides a therapeutic use of apiteglomab in the treatment of SMA in patients aged 13–21 years who have received risdiplam for at least 6 months prior to initiation of apiteglomab treatment, wherein the apiteglomab treatment comprises intravenous administration, for example, once every 4 weeks or once a month, of a composition containing 20 mg / kg of apiteglomab. In some embodiments, the present disclosure provides therapeutic use of apiteglomab in the treatment of SMA in patients aged 13–21 years who have received nusinersen for at least 10 months prior to initiation of apiteglomab treatment, wherein the apiteglomab treatment comprises intravenous administration of a composition comprising 20 mg / kg of apiteglomab every four weeks or once a month.

[0232] In some embodiments, this disclosure provides the therapeutic use of apiteglomab in the treatment of SMA in patients aged 5 years or younger, wherein the patient has not received SMN upregulatory / corrective therapy prior to the initiation of apiteglomab treatment, wherein the treatment comprises the combined administration (e.g., concurrent, separate, or sequential) of a composition comprising apiteglomab and a composition comprising an SMN upregulatory / corrective therapy (e.g., nusinersen or risdiplam). In some embodiments, the composition comprising apiteglomab is administered intravenously. In some embodiments, the composition comprising apiteglomab is administered at a frequency of once every four weeks or once a month.

[0233] In some embodiments, the present disclosure provides the therapeutic use of apitegromab in the treatment of SMA in patients aged 2 years or younger, for example, from birth to 24 months after birth, wherein the patient has not received SMN up-regulator / modifier therapy before the initiation of apitegromab treatment, and wherein the treatment comprises combined (for example, simultaneous, separate, or sequential) administration of a composition comprising apitegromab and a composition comprising SMN up-regulator / modifier therapy (for example, nusinersen or risdiplam). In some embodiments, the present disclosure provides the therapeutic use of apitegromab in the treatment of SMA in patients aged 6 weeks or younger after birth, for example, from birth to 6 weeks after birth, wherein the patient has not received SMN up-regulator / modifier therapy before the initiation of apitegromab treatment, and wherein the treatment comprises combined (for example, simultaneous, separate, or sequential) administration of a composition comprising apitegromab and a composition comprising SMN up-regulator / modifier therapy (for example, nusinersen or risdiplam). In some embodiments, the patient has pre-symptomatic SMA. In some embodiments, the patient has 2 copies of the SMN2 gene. In some embodiments, the composition comprising apitegromab is administered intravenously. In some embodiments, the composition comprising apitegromab is administered at a frequency of once every 4 weeks or once a month.

[0234] In some embodiments, this disclosure provides therapeutic use of myostatin-selective inhibitors, e.g., apiteglomab, GYM329, or trevoglumab, in the treatment of pre-symptomatic SMA in human patients. In some embodiments, the patient has not previously received SMN upregulatory / corrective therapy (e.g., SMN1 gene therapy) prior to the initiation of myostatin-selective inhibitor treatment. In some embodiments, the patient has previously received or is currently receiving SMN upregulatory / corrective therapy (e.g., SMN1 gene therapy). In some embodiments, the treatment involves the combined administration (e.g., concurrent, separate, or sequential) of a composition comprising a myostatin-selective inhibitor, e.g., apiteglomab, GYM329, or trevoglumab, and a composition comprising SMN upregulatory / corrective 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 apiteglomab, GYM329, or trevoglumab, is administered intravenously. In some embodiments, a composition comprising a myostatin selective inhibitor, such as apiteglomab, 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 apiteglomab.

[0235] In some embodiments, the present disclosure provides the therapeutic use of a myostatin selective inhibitor, such as apitegromab, GYM329, or trevogrumab, in the treatment of SMA in patients 5 years of age or younger. In some embodiments, the patient has not previously received SMN upregulator / modifier therapy (e.g., SMN1 gene therapy) prior to the initiation of myostatin selective inhibitor treatment. In some embodiments, the patient has previously received or is currently receiving SMN upregulator / modifier therapy (e.g., SMN1 gene therapy). In some embodiments, the patient is administered SMN upregulator / modifier therapy (e.g., SMN1 gene therapy) at 5 years of age or younger. In some embodiments, treatment of SMA comprises combination (e.g., simultaneous, separate, or sequential) administration of a composition comprising a myostatin selective inhibitor, such as apitegromab, GYM329, or trevogrumab, and a composition comprising SMN upregulator / modifier therapy, such as SMN1 gene therapy. In some embodiments, the composition comprising a myostatin selective inhibitor, such as apitegromab, GYM329, or trevogrumab, is administered intravenously. In some embodiments, the patient has pre-symptomatic SMA. In some embodiments, the patient has 2 copies of the SMN2 gene. In some embodiments, the composition comprising a myostatin selective inhibitor, such as apitegromab, GYM329, or trevogrumab, is administered at a frequency of once every 4 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.

[0236] In some embodiments, this disclosure provides the therapeutic use of myostatin-selective inhibitors, e.g., apiteglomab, GYM329, or trevoglumab, in the treatment of SMA in patients aged 2 years or younger, e.g., from birth to 24 months of age. In some embodiments, the patient has not previously received SMN upregulatory / corrective therapy (e.g., SMN1 gene therapy) prior to the initiation of myostatin-selective inhibitor therapy. In some embodiments, the patient has previously received or is currently receiving SMN upregulatory / corrective therapy (e.g., SMN1 gene therapy). In some embodiments, the patient is administered SMN upregulatory / corrective therapy (e.g., SMN1 gene therapy) at an age of 2 years or younger (e.g., from birth to 24 months of age). In some embodiments, treatment involves the combined administration (e.g., concurrently, individually, or sequentially) of a composition comprising a myostatin-selective inhibitor, e.g., apiteglomab, GYM329, or trevoglumab, with a composition comprising an SMN upregulator / corrective 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 the myostatin-selective inhibitor, e.g., apiteglomab, GYM329, or trevoglumab, is administered intravenously. In some embodiments, the composition comprising the myostatin-selective inhibitor, e.g., apiteglomab, 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 apiteglomab.

[0237] In some embodiments, the disclosure provides therapeutic use of myostatin-selective inhibitors, e.g., apiteglomab, GYM329, or trevoglumab, in the treatment of SMA in patients aged 6 weeks or less, e.g., birth to 6 weeks postnatally, wherein the treatment comprises the combined administration (e.g., concurrent, separate, or sequential) of a composition comprising a myostatin-selective inhibitor, e.g., apiteglomab, GYM329, or trevoglumab, and a composition comprising SMN upregulatory / corrective therapy (e.g., SMN1 gene therapy). In some embodiments, the patient has not previously received SMN upregulatory / corrective therapy (e.g., SMN1 gene therapy) prior to the initiation of myostatin-selective inhibitor treatment. In some embodiments, the patient has previously received or is currently receiving SMN upregulatory / corrective 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 apiteglomab, GYM329, or trevoglumab, is administered intravenously. In some embodiments, a composition comprising a myostatin selective inhibitor, such as apiteglomab, 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 apiteglomab.

[0238] In some embodiments, the disclosure provides myostatin-selective inhibitors and SMN upregulator / corrective therapies (e.g., SMN1 gene therapy) for use in the treatment of pre-symptomatic SMA in patients, wherein the therapy comprises administering the myostatin-selective inhibitors and SMN upregulator / corrective therapies (e.g., SMN1 gene therapy) to a pre-symptomatic patient in a dose effective to treat SMA. In some embodiments, the patient has two copies of the SMN2 gene and / or herein the patient is 6 weeks old or younger at the time of administration of the SMN upregulator / corrective therapies (e.g., SMN1 gene therapy). In some embodiments, the myostatin-selective inhibitor is apiteglomab, GYM329, or trevoglumab.

[0239] In some embodiments, the Disclosure provides myostatin-selective inhibitors and SMN upregulator / corrective therapies (e.g., SMN1 gene therapy) for use in the treatment of pre-symptomatic SMA in patients, wherein the therapy comprises administering a myostatin-selective inhibitor and SMN upregulator / corrective therapies (e.g., SMN1 gene therapy) to a pre-symptomatic patient in an amount effective to treat SMA, wherein the patient has two copies of the SMN2 gene, wherein the patient is 6 weeks old or younger at the time of administration of the SMN upregulator / corrective therapies (e.g., SMN1 gene therapy), and wherein the myostatin-selective inhibitor is apiteglomab, GYM329, or trevoglumab.

[0240] In some embodiments, the disclosure provides myostatin-selective inhibitors for use in the treatment of pre-symptomatic SMA in patients, wherein the treatment comprises administering the myostatin-selective inhibitor to the pre-symptomatic patient in a dose effective to treat SMA. In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, the patient is administered SMN upregulatory / corrective therapy (e.g., SMN1 gene therapy) at or below 6 weeks of age. In some embodiments, the myostatin-selective inhibitor is apiteglomab, GYM329, or trevoglumab.

[0241] In some embodiments, the present disclosure provides a myostatin-selective inhibitor for use in the treatment of pre-symptomatic SMA in patients, wherein the treatment comprises administering the myostatin-selective inhibitor to a pre-symptomatic patient in an amount effective to treat SMA, wherein the patient has two copies of the SMN2 gene, wherein the patient has been administered SMN upregulatory / corrective therapy (e.g., SMN1 gene therapy) at least six weeks of age, and wherein the myostatin-selective inhibitor is apiteglomab, GYM329, or trevoglumab.

[0242] In some embodiments, this disclosure provides therapeutic use of SMN upregulatory / corrective therapy (e.g., SMN1 gene therapy) in the treatment of pre-symptomatic SMA in human patients, wherein the therapy includes the combined (e.g., concurrent, separate, or sequential) administration of a composition comprising SMN upregulatory / corrective therapy (e.g., SMN1 gene therapy) and a composition comprising a myostatin selective inhibitor, e.g., apiteglomab, GYM329, or trevoglumab. In some embodiments, the patient has not previously received a myostatin selective inhibitor, e.g., apiteglomab, GYM329, or trevoglumab prior to the initiation of SMN upregulatory / corrective therapy. In some embodiments, the patient has previously received or is currently receiving a myostatin selective inhibitor, e.g., apiteglomab, GYM329, or trevoglumab. In some embodiments, patients receive SMN upregulatory / corrective therapy (e.g., SMN1 gene therapy) at an age of 5 years or younger. In some embodiments, patients receive SMN upregulatory / corrective therapy (e.g., SMN1 gene therapy) at an age of 2 years or younger (e.g., birth to 24 months of age). In some embodiments, patients receive SMN upregulatory / corrective therapy (e.g., SMN1 gene therapy) at an age of 6 weeks or younger (e.g., birth to 6 weeks of age). In some embodiments, patients have two copies of the SMN2 gene. In some embodiments, a composition comprising a myostatin selective inhibitor, e.g., apiteglomab, GYM329, or trevoglumab, is administered intravenously. In some embodiments, a composition comprising a myostatin selective inhibitor, e.g., apiteglomab, GYM329, or trevoglumab, is administered every 4 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 apiteglomab.

[0243] In some embodiments, myostatin selective inhibitors are used to treat SMA in patients aged 2 months or older who are being treated with SMN2 upregulators such as risdiplam.

[0244] In some embodiments, myostatin selective inhibitors are used to treat pre-symptomatic SMA in patients with three or fewer copies of the SMN2 gene (e.g., two or three copies) or in patients diagnosed with type 1 SMA, where the patient receives gene therapy such as onasemnogene abeparvovec. Optionally, the patient is less than six weeks old. Further optional, the patient weighs between 2.6 kg and 21.0 kg.

[0245] In some embodiments, the Disclosure provides an SMN1 upregulator / corrective therapy (e.g., SMN1 gene therapy) for use in the treatment of pre-symptomatic SMA in patients, wherein the therapy comprises administering the SMN1 upregulator / corrective 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 / corrective therapy (e.g., SMN1 gene therapy) at least 6 weeks of age, wherein the patient is further treated with a myostatin selective inhibitor, wherein the myostatin selective inhibitor is apiteglomab, GYM329, or trevoglumab.

[0246] Further indications The data presented herein indicate that the disclosed treatment regimens for apiteglomab, including, for example, dose selection, may provide clinical benefits to human patients other than those with SMA. Apiteglomab may provide clinical benefits to human patients diagnosed with other indications that share certain attributes of SMA. Such attributes include one or more criteria such as disease in a relatively young patient population, disease in which the muscle is structurally intact or functionally preserved, disease affecting fast-twitch muscle fibers, and availability of established endpoints that rely on fast-twitch muscle fibers.

[0247] Further indications other than SMA that may benefit from treatment with the antibodies disclosed herein (e.g., apiteglomab) include, but are not limited to, dystrophies such as Becker muscular dystrophy, Duchenne muscular dystrophy, and other muscular dystrophy, as well as late-onset Pompe disease, muscle strength recovery after cancer treatment, and glucocorticoid-induced myopathy (e.g., some patients who cannot discontinue steroid therapy). Becker muscular dystrophy may be particularly suitable for treatment with the antibodies disclosed herein (e.g., apiteglomab). 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; Mariott et al. (2017) Nat Commun. 8:1859). In other embodiments, the indications for treatment are muscle strength recovery after cancer treatment, for example, muscle strength recovery after cancer treatment in pediatric patients (because some children may develop severe muscle wasting from chemotherapy). The antibodies disclosed herein (e.g., apiteglomab) can be used as monotherapy or as add-on therapy to provide muscle-directed approaches that enhance other stabilizing treatments (e.g., gene therapy in Duchenne muscular dystrophy or enzyme replacement therapy in lysosomal storage disorders).

[0248] Selection and administration of medication dosage In various embodiments of the methods, uses, and compositions disclosed herein, an effective dose of an anti-promyostatin / anti-latent myostatin antibody (e.g., apiteglomab) is administered intravenously to a human subject in need of treatment, for example, by continuous infusion over a period of time.

[0249] The terms “administer,” “dosage,” and “administer” include any method of delivering a therapeutic agent, such as an anti-promyostatin / anti-latent myostatin antibody (e.g., apiteglomab), to the whole body of a subject or to a specific area inside or on the body of a subject (systemic administration and local administration, respectively). In some embodiments, the therapeutic agent is apiteglomab. In some embodiments, apiteglomab is formulated for administration as a composition, e.g., a pharmaceutical composition. In some embodiments, apiteglomab is formulated for intravenous administration. For example, in some embodiments, apiteglomab is administered by intravenous injection / infusion, e.g., intravenous infusion. In some embodiments, apiteglomab is administered by intravenous infusion over, for example, about 1 to 2 hours. In some embodiments, apiteglomab is administered by intravenous infusion over about 2 hours. In some embodiments, the infusion time is less than 2 hours but not less than 1 hour.

[0250] In some embodiments, apiteglomab is administered to the patient as a body weight-based dose, i.e., a dose dependent on the patient's body weight. In some embodiments, preferred doses of apiteglomab include, optionally, about 5, 10, 15, or 20 mg / kg, with a dose greater than 2 and no more than 20 mg / kg. In some embodiments, the therapeutic dose of apiteglomab is 10 mg / kg. In some embodiments, the therapeutic dose of apiteglomab is 20 mg / kg. In some embodiments, doses greater than 20 mg / kg may be used while maintaining a similar safety profile; however, given, for example, 20 mg / kg and 2 mg / kg, respectively, the need for higher doses may be reduced if surprisingly good therapeutic and PK profiles are provided.

[0251] Targeted meeting analyses in 6-month and 12-month studies (see examples in this specification) indicate that 20 mg / kg of apiteglomab achieved targeted saturation, while 2 mg / kg showed partial targeted meeting. These observations support the possibility that the therapeutic dose of intravenously administered apiteglomab may be between 20 mg / kg and 2 mg / kg.

[0252] PK analysis of apiteglomab shows a correlation between drug clearance and age (see Figure 18) or body weight (see Figure 17). These data suggest that younger patients (lighter body weight) exhibit slower clearance of apiteglomab compared to older patients (heavier body weight). This finding may indicate that suitable intermediate dose selections are, for example, 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12 mg / kg, 15 mg / kg, etc.

[0253] In some embodiments, a preferred dose of apiteglomab is 20 mg / kg. In some embodiments, a preferred dose of apiteglomab is 10 mg / kg. In some embodiments, apiteglomab is administered intravenously to the patient every four weeks or monthly at doses of 5 mg / kg, 7.5 mg / kg, 10 mg / kg, or 12 mg / kg.

[0254] In some embodiments, apiteglomab is administered to the patient at a dose of 20 mg / kg. In some embodiments, due to its favorable safety profile at a dose of 20 mg / kg, apiteglomab may be administered to the patient at a dose higher than 20 mg / kg, for example, 30 mg / kg or less, e.g., 25 mg / kg. In some embodiments, apiteglomab is administered to the patient at a dose higher than 20 mg / kg (e.g., about 25 mg / kg, about 30 mg / kg). In some embodiments, apiteglomab is administered to the patient intravenously every four weeks or monthly at a dose of 10–20 mg / kg.

[0255] In some embodiments, apitegromab is administered to a patient once every about 4 weeks, once a month, or the like. Such an antibody may be administered via intravenous injection / infusion, for example, by intravenous infusion, or by another suitable route of administration (for example, subcutaneously (for example, under the skin) or intrathecally (for example, into the spinal cord)). Similarly, an SMN up-regulator, for example, a splicing modifier, may be administered orally, for example, via the oral route, or by another suitable route of administration.

[0256] In some embodiments, the subject has received administration of an SMN up-regulator prior to administration of apitegromab. In some embodiments, the subject is receiving concomitant administration of an SMN up-regulator at the same time point as administration of apitegromab. In some embodiments, the subject will receive administration of an SMN up-regulator after administration of apitegromab.

[0257] In some embodiments, apitegromab is administered to a subject receiving an SMN up-regulator at least 24 hours (for example, at least 36 hours, at least 48 hours, or more) before a dose (for example, a maintenance dose) of the SMN up-regulator (for example, nusinersen). In some embodiments, apitegromab is administered to a subject receiving an SMN up-regulator at least 14 days (for example, at least 21 days, or more) after a dose (for example, a maintenance dose) of the SMN up-regulator (for example, nusinersen).

[0258] In some embodiments, the subject has received administration of an SMN up-regulator within 6 months after administration of apitegromab. In some embodiments, the subject has received administration of an SMN up-regulator within 3 months after administration of apitegromab. In some embodiments, the subject has received administration of an SMN up-regulator within 6 months, 5 months, 4 months, 3 months, 2 months, or 1 month after administration of apitegromab. In some embodiments, the subject has received administration of an SMN up-regulator within 4 weeks, 3 weeks, 2 weeks, or 1 week after administration of apitegromab. In some embodiments, the subject has received administration of an SMN up-regulator on the same day as administration of apitegromab.

[0259] In some embodiments, subjects are expected to receive an SMN upcontrol agent within 6 months of apiteglomab administration. In some embodiments, subjects are expected to receive an SMN upcontrol agent within 3 months of apiteglomab administration. In some embodiments, subjects are expected to receive an SMN upcontrol agent within 6 months, 5 months, 4 months, 3 months, 2 months, or 1 month of apiteglomab administration. In some embodiments, subjects are expected to receive an SMN upcontrol agent within 4 weeks, 3 weeks, 2 weeks, or 1 week of apiteglomab administration.

[0260] In some embodiments, the SMN upregulator is an antisense nucleotide, administered intrathecally to the target central nervous system. In some embodiments, the antisense nucleotide is administered to the subject every few months, for example, monthly, every two months, every three months, every four months, every five months, every six months, or every twelve months. In other embodiments, initial treatment may involve more frequent doses, followed by less frequent maintenance doses.

[0261] In some embodiments, the SMN upregulator is a small molecule administered orally to the subject. In some embodiments, the small molecule is administered daily to the subject. In other embodiments, the small molecule is administered weekly, bi-weekly, or monthly to the subject.

[0262] In some embodiments, the SMN upregulator is a gene therapy administered by intravenous injection. In some embodiments, the SMN upregulator is a gene therapy administered by intrathecal injection. In some embodiments, initial treatment may involve more frequent doses followed by less frequent maintenance doses. Less frequent maintenance doses may be preferable to avoid inappropriate immune responses to gene therapy.

[0263] In some embodiments, apiteglomab is administered to the subject intravenously, for example, by intravenous infusion. In some embodiments, apiteglomab is administered to the subject once every four weeks or monthly. In some embodiments, initial treatment may involve more frequent doses followed by less frequent maintenance doses. In some embodiments, apiteglomab may be administered initially at a 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 apiteglomab 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), for example, four weeks or one month after the initial 20 mg / kg dose, where the one or more lower doses are then administered every four weeks or once a month, or at longer intervals than those used for the loading dose.

[0264] The “effective dose” of treatment for SMA, as used herein, may be a dose that achieves clinical efficacy, including, but is not limited to, preserving motor function compared to deterioration of a control, delaying disease progression, delaying or preventing ambulation in a walkable type 3 SMA patient, 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 net zero change in one or more motor function scores compared to baseline.

[0265] The clinical benefits of SMA therapy may include 1) improved motor function, 2) maintenance of motor function (disease stabilization), or 3) delay of disease progression.

[0266] Motor function may be assessed by preferred means, such as HFMSE and / or RHS, the latter of which RHS is often used to assess motor function in patients who can walk. In some embodiments, HFMSE is more frequently used to assess motor function in patients who cannot walk. An increase in each score compared to a suitable baseline indicates improvement in 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 point or more, 2 points or more, 3 points or more, 4 points or more, or 5 points or more. In some embodiments, the SMA therapy disclosed herein (e.g., SMA therapy including apiteglomab) enhances motor function so that the HFMSE score or RHS score (e.g., HFMSE score) measured at 6 or 12 months after the start of treatment is at least 1, 3, 5, 7, or 10 points above the baseline, where the baseline is obtained at or before the start of treatment. In some embodiments, the SMA therapy disclosed herein (e.g., SMA therapy comprising apiteglomab) produces an increase of at least 5 points in the HFMSE score compared to the baseline score after at least 12 months of treatment. In some embodiments, the SMA therapy disclosed herein (e.g., SMA therapy comprising apiteglomab) produces an increase of 6 to 20 points or more in the HFMSE score compared to the baseline score after at least 12 months of treatment. In some embodiments, the SMA therapy disclosed herein (e.g., SMA therapy comprising apiteglomab) produces an increase of at least 7 points in the HFMSE score compared to the baseline score after at least 12 months of treatment.

[0267] In some embodiments, improvement in motor function scores (e.g., HFMSE or RHS scores) may be positively correlated with the severity of SMA and / or the length of treatment with SMN-modifying therapy (e.g., nusinersen). In some embodiments, improvement in motor function scores (e.g., HFMSE or RHS scores) may be inversely correlated with age and / or characteristics of progressive disease. In some embodiments, characteristics of progressive disease include scoliosis and / or joint contractures. In some embodiments, joint contractures may result from the shortening and deformation of muscles, tendons, and ligaments, and symptoms include pain and loss of joint movement. In some embodiments, a method of treating SMA includes administering apiteglomab therapy either as monotherapy or in combination with another therapy to patients without scoliosis and / or joint contractures. In some embodiments, apiteglomab is used to treat SMA either as monotherapy or in combination with another therapy in patients without scoliosis and / or joint contractures.

[0268] In some embodiments, SMA therapy includes intravenous administration of apiteglomab every four weeks or monthly at doses greater than 2 mg / kg and less than or equal to 20 mg / kg. In some embodiments, SMA therapy includes intravenous administration of approximately 20 mg / kg of apiteglomab every four weeks or monthly. In some embodiments, the SMA therapies disclosed herein (e.g., SMA therapy including apiteglomab) can achieve disease stabilization, such as maintaining the patient's motor function over time, or in other words, preventing exacerbation against the natural history of the disease that predicts progression over time. In some embodiments, a net zero change in motor function score relative to an appropriate baseline reflects disease stabilization. In some embodiments, disease progression is stabilized by the SMA therapy disclosed herein (e.g., SMA therapy including apiteglomab) so that the HFMSE score or RHS score measured at 6 or 12 months after the start of treatment does not fall below baseline, or worsen by more than 0.1, 0.2, 0.3, 0.4, or 0.5 points, where baseline is obtained at or before the start of treatment. In some embodiments, disease progression is stabilized by the SMA therapy disclosed herein (e.g., SMA therapy including apiteglomab) so that the RHS score worsens by less than 1, 2, or 3 points compared to the baseline score after at least 12 months of treatment. In some embodiments, the SMA therapy includes intravenous administration of apiteglomab every four weeks or monthly at a dose greater than 2 mg / kg and less than or equal to 20 mg / kg. In some embodiments, the SMA therapy includes intravenous administration of approximately 20 mg / kg of apiteglomab every four weeks or monthly. In some embodiments, SMA therapy includes administering a therapeutically effective dose of apiteglomab that is sufficient to increase the motor function of the subject by at least one milestone according to the WHO Motor Development Milestones. In some embodiments, SMA therapy includes administering a therapeutically effective dose of apiteglomab that is sufficient to increase the motor function of the subject by one, two, or three milestones according to the WHO Motor Development Milestones.In some embodiments, the WHO motor development milestones include 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.

[0269] In some embodiments, the SMA therapies disclosed herein (e.g., SMA therapies including apiteglomab) may help maintain disease status in a patient population receiving apiteglomab compared to a control group that does not receive it. Maintaining disease status means preventing further exacerbation of the affected muscle, as determined, for example, by changes in motor function over time. In some embodiments, treatment may slow disease progression, as determined, for example, by a slower rate of change in disease function compared to a favorable baseline (e.g., untreated patients). Thus, even if there is no improvement in motor function test scores, apiteglomab may provide clinical benefit by counteracting disease progression. In this way, such clinical benefit may manifest as an observation that, compared to a control group, the patient population treated with apiteglomab maintains pre-test scores for longer periods, or shows a slower rate of decline in scores over time.

[0270] In some embodiments, the SMA therapies disclosed herein (e.g., SMA therapies including apiteglomab) can slow disease progression, for example, by delaying the decline in motor function as measured by a decrease in HFMSE or RHS scores, and / or delaying the transition from being able to walk to being unable to walk, delaying the need for respiratory support or intervention, etc.

[0271] As demonstrated herein, given the surprisingly significant clinical benefits of selective myostatin inhibition in human patients, it is conceivable that different myostatin-selective inhibitors (other than apiteglomab) may be used to treat SMA or other muscle disorders. Accordingly, this disclosure includes myostatin-selective inhibitors for use in the treatment of muscle disorders such as SMA in human subjects, wherein, optionally, the subjects are further treated with motor neuron-directed therapy, wherein, optionally, motor neuron-directed therapy includes SMN upregulatory therapies such as SMN2 upregulatory therapy and SMN1 gene therapy.

[0272] Biological effects of treatment The SMA therapies disclosed herein (e.g., SMA therapies including apiteglomab) may be suitable for the treatment of any type of SMA in human subjects, particularly late-onset SMA.

[0273] The patient populations that may benefit from the therapies described herein include patients with non-walking SMA and patients with walking SMA. In some embodiments, the SMA therapies disclosed herein are considered to be therapies for non-walking SMA, such as type 2 and non-walking type 3 SMA. In other embodiments, the SMA therapies disclosed herein are considered to be therapies for walking SMA, such as walking type 3 SMA.

[0274] Genotype-based diagnosis allows for the identification of patients who carry SMA gene mutations, including those who may be pre-symptomatic (without exhibiting an obvious disease phenotype). In some embodiments, suitable subjects for treatment with the SMA therapies disclosed herein have a direct diagnosis of SMN1 mutation (e.g., direct chromosomal diagnosis of 5q SMA). In some embodiments, subjects have a diagnosis of 5q SMA in addition to a diagnosis based on motor phenotype.

[0275] In some embodiments, subjects with SMA are 2 years of age or older. In some embodiments, subjects with SMA are 5 to 21 years of age. The clinical effects of anti-promyostatin / anti-latent myostatin antibodies (e.g., apiteglomab), administered alone or in combination with SMN upregulators, can be monitored and / or evaluated by various means for efficacy. Exemplary such biologically beneficial effects are provided herein. Beneficial biological effects in subjects can be achieved by administration of anti-promyostatin / anti-latent myostatin antibodies (e.g., apiteglomab) as monotherapy or in combination with SMN upregulators. In some embodiments, apiteglomab, administered as monotherapy or in combination with SMN upregulators, is administered in a dose effective to produce one or more of the biological effects described below.

[0276] The ability to assess functional assessment scales that can be reliably measured in SMA patients may be used to track the progression of the patient's disease over time and the effectiveness of therapy. Muscle function can be assessed by physiological measurements such as muscle strength and force generation, while motor function assessment scales monitor disease progression in a way that is more meaningful and relevant to the patient's function in daily life than scales that quantify muscle strength itself. In some embodiments, patients who require or are receiving treatment for SMA are assessed using one or more motor function assessment tests or functional outcome scales described herein (e.g., one or more of the HFMSE, RHS, 6MWT, WHO Motor Milestones, RULM, 30-second stand-up test, endurance shuttle nine-hole peg test [ESNHPT], and / or endurance shuttle box block test [ESBBT]).

[0277] In some embodiments, patients with SMA (e.g., late-onset SMA) are assessed using the Revised Hammersmith Scale (RHS). In some embodiments, the administration of the RHS includes bed-to-bed time and a 10-meter walk / run test. In some embodiments, the RHS is a 36-item clinical assessment of physical ability in patients with type 2 SMA, as well as in walkable and non-walkable patients with type 3 SMA. The RHS consists of 33 items graded on a scale of 0, 1, and 2, 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 3 items are scored on a scale of 0 and 1, with 0 representing no ability and 1 representing achievable ability. The highest achievable score is 69.

[0278] In some embodiments, patients who will be treated with apiteglomab (e.g., patients with walkable SMA) have a baseline RHS score of 26 or higher prior to treatment. In some embodiments, patients have a baseline RHS score of 63 or lower. In some embodiments, patients have a baseline RHS score in the range of 26 to 63. In some embodiments, patients have walkable SMA, e.g., walkable type 3 SMA.

[0279] 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 a reinforcing function of the RHS used in walkable patients with type 3 SMA. The 10-meter walk / run test measures the time it takes to walk / run 10 meters.

[0280] In some embodiments, patients with SMA (e.g., late-onset SMA) are evaluated using the bed-to-rise time test. In some embodiments, the bed-to-rise time test is a reinforcing function of the RHS used in ambly patients with type 3 SMA. The bed-to-rise time test measures the time it takes to stand up from the floor.

[0281] 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 exercise capacity and fatigue used in clinical studies of walkable late-onset SMA patients (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 per minute and total distance walked in 6 minutes are measured.

[0282] In some embodiments, patients with SMA (e.g., late-onset SMA) are assessed using the 30-second sit-to-stand test. The 30-second sit-to-stand test is used by researchers and clinicians to assess the functional strength of the lower extremities (Jones et al. (1999) Res Q Exerc Sport. 70:113-119). This test is a modified version for the walkable SMA population based on the Modified 30-Second Sit-to-Stand study, a reliable and viable tool used in the general elderly population with low functional levels (McAllister and Palombaro (2019). J Geriatr Phys Ther. 0(0):1-6), and has been associated with the risk of falls 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 change from a sitting to a standing position in 30 seconds.

[0283] In some embodiments, patients with spinal muscular atrophy (e.g., late-onset SMA) are evaluated using the Hammersmith Functional Motor Scale Expanded (HFMSE) (Main M, Kairon H, Mercuri E, Muntoni F. The Hammersmith functional motor scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation. Eur J Paediatr Neurol. 2003;7(4):155-9). In some embodiments, the HFMSE is used to assess the physical ability of patients with type 2 and type 3 SMA (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 patients with SMA who are unable to walk. The HFMSE consists of 33 items that assess an individual's ability to perform a variety of activities, including the following: 1. Sit on a table / chair 2. Long sitting position 3. While seated, raise one arm to your head. 4. While seated, raise both hands to your head. 5. From supine position to lateral position 6. From prone position, rotate clockwise to supine position. 7. From prone position, rotate counterclockwise to supine position. 8. From the supine position, turn clockwise to the prone position. 9. From the supine position, turn counterclockwise to the prone position. 10. From sitting to lying down 11. Support your body with your forearms. 12. Raise the head from the prone position. 13. Extend both arms to support your body. 14. From supine to sitting position 15. On all fours 16. Crawling on all fours 17. Lift your head from a supine position. 18. Standing with support 19. Standing without support 20. Walk 21. Flexion of the right hip joint 22. Flexion of the left hip joint while lying supine. 23. From a kneeling position to a right kneeling position 24. From a kneeling position to a left kneeling position 25. From a kneeling position, step forward with your left leg to stand. 26. From a kneeling position, step forward with your right leg to stand. 27. From standing to sitting 28. Crouch 29. Jump 12 inches forward. 30. Use the handrail when going up the stairs. 31. Use the handrail to descend the stairs. 32. Climbing stairs without using the handrail. 33. Descending the stairs without using the handrail.

[0284] The parameters listed above are evaluated on a scale of 0, 1, and 2, where 0 indicates that the movement cannot be performed, 1 indicates that it was performed with modifications or alterations, and 2 indicates that it was performed without modifications or alterations. The highest achievable score is 66 points.

[0285] In some embodiments, patients who will be treated with apiteglomab (e.g., patients with immobile SMA, such as type 2 or immobile type 3 SMA) have a baseline HFMSE score of 12 or higher before treatment. In some embodiments, patients have a baseline HFMSE score of 44 or lower. In some embodiments, patients have a baseline HFMSE score in the range of 12 to 44. In some embodiments, patients have immobile SMA. In some embodiments, patients have type 2 SMA. In some embodiments, patients have immobile type 3 SMA.

[0286] 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 patients with non-walking SMA (young children and adults) (Mazzone et al. (2017) Muscle Nerve. 55(6):869-874). Nineteen items are scored to examine functions related to daily living, such as placing hands on the knees, pressing buttons, and picking up tokens. Items are scored on a scale of 0, 1, and 2, with 0 indicating inability, 1 indicating ability with modifications, and 2 indicating ability without difficulty. The highest achievable score is 37. In some embodiments, the RULM is used to evaluate patients with non-walking SMA. In some embodiments, the RULM is performed on all items by patients aged 30 months or older, for example, at the baseline assessment.

[0287] In some embodiments, patients with SMA (e.g., late-onset SMA) are assessed using the World Health Organization (WHO) Motor Development Milestones. The WHO Multicenter Growth Reference Study (MGRS) developed growth curves for assessing the growth and development of infants and young children worldwide (de Onis et al. (2004) Food Nutr Bull. 25 Suppl: S1-89). The primary objective of the MGRS was to develop curves and related tools for assessing the growth and development of children from birth to 5 years of age. Another feature of the MGRS is that it includes the collection of ages for achieving motor milestones, including gross motor development milestones such as sitting without support, crawling on all fours with hands and knees, standing with assistance, walking with assistance, standing independently, and walking independently (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 used to determine motor development milestones, for example, in patients with type 2 and ham-less type 3 SMA.

[0288] In some embodiments, patients with SMA (e.g., late-onset SMA) are evaluated 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 9-hole peg test at 75% of their maximum speed. The round-trip motion is based on a set speed indicated by auditory cues, and the test ends if the patient fails to respond to two consecutive beeps. The primary outcome parameter is "Tlim," the time the patient can maintain the task at a predetermined 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 patients with non-walking SMA. In some embodiments, the ESNHPT is performed by patients aged 8 years or older.

[0289] In some embodiments, patients with SMA (e.g., late-onset SMA) are evaluated using the Endurance Shuttle Box and Block Test (ESBBT). The ESBBT is an endurance test for patients with moderate SMA. Patients are instructed to repeat the original box and block test at 75% of their maximum speed. The round trip motion is based on a set speed indicated by auditory cues, and the test ends if the patient fails to respond to two consecutive beeps. The primary outcome parameter is "Tlim," the time the patient can maintain the task at a predetermined intensity. The maximum test duration is 20 minutes (Stam et al. (2018) BMJ Open. 8(7):e019932). In some embodiments, the ESBBT is used to evaluate patients with non-walking SMA. In some embodiments, the ESBBT is performed by patients aged 8 years or older.

[0290] In some embodiments, patients with SMA (e.g., late-onset SMA) are evaluated using the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDICAT). In some embodiments, a caregiver (who may or may not be a parent and / or legal guardian) completes all items of the PEDICAT assessment. In some embodiments, the PEDICAT assessment is not administered to the patient, or is not administered if a caregiver is not present. PEDICAT is a questionnaire in which a caregiver completes all items to assess a patient's ability to perform daily functions (Haley et al. (2005) Arch Phys Med Rehabil. 86(5):932-939). In some embodiments, the caregiver inputs the PEDICAT in a location where the caregiver cannot see the patient performing any function assessment test. Responses are scored on a four-point scale (cannot do ~ easy). This test is suitable for assessing function from birth to 21 years of age. The characteristics of PEDICAT have been studied in the SMA population. According to the Rasch analysis, whose results were published in 2016, the distribution of PEDICAT's motor and daily activity domain abilities is best represented in type 2 and type 3 groups (Pasternak et al. (2016) Muscle Nerve. 54(6):1097-1107).

[0291] In some embodiments, patients with SMA (e.g., late-onset SMA) are assessed using the Patient-reported Outcomes Measurement Information System (PROMIS). PROMIS is a human-centered scale intended to be completed entirely by the patient or surrogate parent without assistance (Ader (2007) Med Care. 5(5): S1-S2). The fatigue profile domain measures symptoms ranging from mild subjective fatigue to uncontrollable, debilitating, persistent weakness. This self-report scale is suitable for children aged 8–17 years, while the parent / surrogate-reported scale is suitable for children aged 5–17 years. Patients aged 18–21 years may complete all items of the adult version of PROMIS. In some embodiments, PROMIS is completed entirely by patients aged 5 years or older.

[0292] Methods, uses, and compositions for treating SMA In various embodiments, apiteglomab therapy delivers an average serum concentration of approximately 25-250 micrograms per milliliter (C). trough It is administered (alone or in combination with at least one additional therapy) in an amount that achieves a mean serum concentration (C) of approximately 25–700 micrograms per milliliter. In some embodiments, apiteglomab therapy is administered in an amount that achieves a mean serum concentration (C) of approximately 25–700 micrograms per milliliter. max It is administered (alone or in combination with at least one additional therapy) in an amount that achieves the desired effect.

[0293] In some embodiments, the Disclosure provides a method for treating SMA in a human subject, comprising administering to the subject by intravenous infusion of a composition comprising apiteglomab every four weeks or monthly for at least six or twelve months in an amount sufficient to prevent or delay a decline in the Revised Hammersmith Score (RHS) score compared to a baseline score before treatment. In some embodiments, the Disclosure provides a composition comprising apiteglomab for use in the treatment of SMA in a human subject, wherein the subject is administered by intravenous infusion of apiteglomab every four weeks or monthly for at least six or twelve months in an amount sufficient to prevent or delay a decline in the RHS score compared to a baseline score before treatment. In some embodiments, the Disclosure provides the use of a composition comprising apiteglomab for the treatment of SMA in a human subject, wherein the subject is administered by intravenous infusion of apiteglomab every four weeks or monthly for at least six or twelve months in an amount sufficient to prevent or delay a decline in the RHS score compared to a baseline score before treatment. In some embodiments, the disclosure provides the use of apiteglomab in the manufacture of a therapeutic composition for SMA in human subjects, wherein apiteglomab is administered intravenously every four weeks or monthly for at least six or twelve months in an amount sufficient to prevent or delay the decline in RHS score compared to a baseline score before treatment.

[0294] In some embodiments, the SMA is a late-onset SMA. In some embodiments, the SMA is a walkable type 3 SMA. In some embodiments, the subjects are 5 to 21 years of age. In some embodiments, a sufficient dose is a dose of approximately 5, 10, 15, or 20 mg / kg, with the option being greater than 2 mg / kg and less than or equal to 20 mg / kg. In some embodiments, a sufficient dose is a dose of 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or monthly.

[0295] In some embodiments, apiteglomab is administered in a dose that stabilizes the RHS score or causes a decrease of less than 0.4 points after, for example, at least 12 months of treatment. In some embodiments, apiteglomab is administered in a dose that causes a mean increase of at least 0.2 points in the RHS score compared to the baseline score before treatment, or optionally a mean increase 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 in the RHS score compared to baseline, for example, a mean increase in a cohort of at least 11 subjects. In some embodiments, apiteglomab is administered in a dose that causes a mean increase of at least 1 point in the RHS score compared to baseline, for example, a mean increase in a cohort of at least 11 subjects. In some embodiments, apiteglomab is administered in a dose that causes a mean increase of at least 3 points in the RHS score compared to baseline, for example, a mean increase in a cohort of at least 11 subjects. In some embodiments, apiteglomab is administered in a dose that stabilizes the RHS score when evaluated against baseline after at least 12 months of treatment. In some embodiments, apiteglomab is administered in a dose that prevents a decrease in the RHS score of approximately 0.5, 0.4, 0.3, 0.2, or 0.1 when evaluated against baseline after at least 12 months of treatment.

[0296] In some embodiments, subjects are treated with SMN upregulatory therapy. In some embodiments, the SMN upregulatory therapy is nusinersen, risdiplam, and / or onasemnogene abeparvovec. In some embodiments, the SMN control therapy is nusinersen. In some embodiments, subjects initiated SMN upregulatory therapy at an age of 5 years or older. In some embodiments, apiteglomab is administered in a dose that stabilizes the RHS score when evaluated against baseline, for example, after at least 12 months of treatment. In some embodiments, apiteglomab is administered in a dose that prevents a decrease in the RHS score of approximately 0.5, 0.4, 0.3, 0.2, or 0.1 when evaluated against baseline, for example, after at least 12 months of treatment. In some embodiments, apiteglomab is administered in a dose that produces a mean increase of at least 0.3 points in the RHS score compared to baseline, for example, a mean increase in a cohort of at least 11 subjects. In some embodiments, apiteglomab is administered in a dose that produces a mean increase of at least 0.3 points in the RHS score compared to baseline after 8 weeks, for example, a mean increase in a cohort of at least 11 subjects. In some embodiments, this dose is 20 mg / kg of apiteglomab every 4 weeks or monthly.

[0297] In some embodiments, subjects are not treated with SMN upregulatory therapy. In some embodiments, apiteglomab is administered in a dose that stabilizes the RHS score when evaluated against baseline after, for example, at least 12 months of treatment. In some embodiments, apiteglomab is administered in a dose that prevents a decrease in the RHS score of approximately 0.5, 0.4, 0.3, 0.2, or 0.1 when evaluated against baseline after, for example, at least 12 months of treatment. In some embodiments, apiteglomab is administered in a dose that produces a mean increase of at least 0.7 points in the RHS score compared to baseline, for example, a mean increase in a cohort of at least 11 subjects. In some embodiments, apiteglomab is administered in a dose that produces a mean increase of at least 0.7 points in the RHS score compared to baseline after 8 weeks, for example, a mean increase in a cohort of at least 11 subjects. In some embodiments, this dose is 20 mg / kg of apiteglomab every 4 weeks or monthly.

[0298] In some embodiments, apiteglomab, when determined by the mean value over a treatment course of at least 12 months, delivers serum concentrations (C) of at least about 100 micrograms per milliliter, for example, about 100 to 500 micrograms per milliliter (e.g., about 100, 200, 300, 400, or 500 micrograms per milliliter). trough It is administered in an amount that achieves the serum concentration (C). In some embodiments, the serum concentration (C) is trough This is approximately 100-450 micrograms per milliliter. In some embodiments, this amount corresponds to a dose of 20 mg / kg of apiteglomab every four weeks or monthly.

[0299] In some embodiments, apiteglomab, when determined by the mean value over a treatment course of at least 12 months, delivers at least about 300 micrograms per milliliter of serum (C max It is administered in an amount that achieves the serum concentration (C). In some embodiments, the serum concentration (C) is maxThe concentration is at least about 300-1100 micrograms per milliliter, for example, 300-800. In some embodiments, serum concentration (C max The dose is at least 600 micrograms of apiteglomab 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 the steady-state serum concentration. In some embodiments, apiteglomab is administered in a dose that achieves a steady-state serum concentration after about 112 days. In some embodiments, this dose is 20 mg / kg of apiteglomab every four weeks or monthly.

[0300] In some embodiments, apiteglomab is administered in an amount sufficient to achieve target association as measured by a serum latent myostatin concentration of at least about 100 nanograms per milliliter when determined at steady state over a treatment course of at least 12 months. In some embodiments, apiteglomab is administered in an amount sufficient to achieve target association as measured by a serum latent myostatin concentration of at least about 250 nanograms per milliliter when determined at steady state over a treatment course of at least 12 months. In some embodiments, apiteglomab is administered in an amount sufficient to achieve target association as measured by a serum latent myostatin concentration of at least about 400 nanograms per milliliter. In some embodiments, apiteglomab is administered in an amount sufficient to achieve target aggregation as measured by serum latent myostatin concentrations 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, serum latent myostatin concentrations are approximately 550 to 2400 nanograms per milliliter. In some embodiments, serum latent myostatin concentrations are steady-state concentrations measured in the trough. In some embodiments, this amount is a dose of 20 mg / kg of apiteglomab every four weeks or monthly.

[0301] In some embodiments, apiteglomab is administered in a dose 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 ambulation in walkable 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 a control; and / or maintaining at least a net zero change in one or more motor function scores compared to baseline. In some embodiments, this dose is 20 mg / kg of apiteglomab every four weeks or monthly.

[0302] In some embodiments, the Disclosure provides a method for treating SMA in human subjects, comprising administering to a subject a composition comprising apiteglomab and a composition comprising an SMN upregulator, wherein the subject is administered by intravenous infusion every four weeks or monthly for at least six or twelve months in an amount sufficient to produce a mean increase of at least 0.5 or 1 point in the Hammersmith Functional Motor Scale Expanded (HFMSE) score compared to a baseline score before treatment, for example, a mean increase in a cohort of at least 13 or 14 subjects. In some embodiments, the Disclosure provides a composition comprising apiteglomab for use in the treatment of SMA in human subjects receiving SMN upcontrolling agents, wherein the subjects are administered by intravenous infusion every four weeks or monthly for at least six or twelve months in an amount sufficient to produce a mean increase of at least 0.5 or 1 point in the HFMSE score compared to a baseline score before treatment, for example, a mean increase in a cohort of at least 13 or 14 subjects. In some embodiments, the Disclosure provides the use of apiteglomab in the manufacture of a therapeutic composition for SMA in human subjects receiving SMN upcontrolling agents, wherein apiteglomab is administered intravenously every four weeks or monthly for at least six or twelve months in an amount sufficient to produce a mean increase of at least 0.5 or 1 point in the HFMSE score compared to the baseline score before treatment, for example, a mean increase in a cohort of at least 13 or 14 subjects.

[0303] In some embodiments, SMA is late-onset SMA. In some embodiments, SMA is type 2 SMA. In some embodiments, SMA is type 3 SMA that causes ambulation. In some embodiments, the subjects are 5 to 21 years old. In some embodiments, the SMN upregulatory therapy is nusinersen, risdipram, and / or onasemnogene abeparvovec. In some embodiments, the SMN upregulatory therapy is nusinersen. In some embodiments, a sufficient dose is a dose of approximately 5, 10, 15, or 20 mg / kg, optionally greater than 2 mg / kg and less than or equal to 20 mg / kg. In some embodiments, a sufficient dose is a dose of 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or monthly.

[0304] In some embodiments, apiteglomab is administered at a dose that, after 16 weeks, produces an increase of at least 0.5 or 1 point in the HFMSE score compared to baseline, for example, a mean increase in a cohort of at least 13 or 14 subjects. In some embodiments, apiteglomab is administered at a dose that produces an increase of at least 2, at least 3, at least 4, or at least 5 points in the HFMSE score compared to baseline, for example, a mean increase in a cohort of at least 13 or 14 subjects. In some embodiments, apiteglomab is administered at a dose that produces an increase of at least 3 points in the HFMSE score compared to baseline, for example, a mean increase in a cohort of at least 13 or 14 subjects. In some embodiments, apiteglomab is administered at a dose that produces an increase of at least 5 points in the HFMSE score compared to baseline, for example, a mean increase in a cohort of at least 13 or 14 subjects. In some embodiments, this dose is 20 mg / kg of apiteglomab every four weeks or monthly.

[0305] In some embodiments, apiteglomab is administered at a dose of at least about 300 micrograms per milliliter, for example, at a serum concentration of at least about 400, 500, 600, 700, 800, 900, 1000, or 1100 (C)max It is administered in an amount that achieves the following: In some embodiments, apiteglomab is administered in an amount that achieves a serum concentration of at least 600 micrograms of apiteglomab 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 to 1000 micrograms per milliliter. In some embodiments, the serum concentration is the steady-state serum concentration. In some embodiments, apiteglomab is administered in an amount that achieves the steady-state serum concentration after about 112 days. In some embodiments, this amount is a dose of 20 mg / kg of apiteglomab every four weeks or monthly.

[0306] In some embodiments, apiteglomab is administered at a serum concentration of at least about 100 micrograms per milliliter, for example, at at least about 200, 300, or 400 micrograms per milliliter (C trough It is administered in an amount that achieves the desired result. In some embodiments, this amount is a dose of 20 mg / kg of apiteglomab every four weeks or monthly.

[0307] In some embodiments, apiteglomab is administered in an amount sufficient to achieve target aggregation as measured by serum latent myostatin concentrations of at least about 250 nanograms per milliliter, for example, at least about 400 or 500 nanograms per milliliter (e.g., at least 500, 550, 600, or 650 nanograms per milliliter). In some embodiments, serum latent myostatin concentrations are about 550 to 1650 nanograms per milliliter. In some embodiments, serum latent myostatin concentrations are steady-state concentrations measured in the trough. In some embodiments, this amount is a dose of 20 mg / kg of apiteglomab every four weeks or monthly.

[0308] In some embodiments, apiteglomab is administered in a dose 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 ambulation in walkable 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 a control; and / or maintaining at least a net zero change in one or more motor function scores compared to baseline. In some embodiments, this dose is 20 mg / kg of apiteglomab every four weeks or monthly.

[0309] In some embodiments, the Disclosure provides a method for treating SMA in human subjects, comprising administering to a subject a composition comprising apiteglomab and a composition comprising an SMN upregulator, wherein the subject is administered by intravenous infusion every four weeks or monthly for at least six or twelve months in an amount sufficient to produce a mean increase of at least two points in the HFMSE score compared to a baseline score before treatment, e.g., a mean increase in a cohort of at least eight or nine subjects, and wherein the subject initiated SMN upregulator therapy at an age of less than five years. In some embodiments, the Disclosure provides a composition comprising apiteglomab for use in the treatment of SMA in human subjects receiving SMN upregulatory therapy, wherein the subjects are administered by intravenous infusion every four weeks or monthly for at least six or twelve months in an amount sufficient to produce a mean increase of at least two points in the HFMSE score compared to the baseline score before treatment, e.g., a mean increase in a cohort of at least eight or nine subjects, and wherein the subjects initiated SMN upregulatory therapy at an age of less than five years. In some embodiments, the Disclosure provides the use of a composition comprising apiteglomab for the treatment of SMA in human subjects receiving SMN upregulatory therapy, wherein the subjects are administered a dose sufficient to produce a mean increase of at least 2 points in the HFMSE score compared to the baseline score before treatment, e.g., a mean increase in a cohort of at least 9 subjects, by intravenous infusion every 4 weeks or monthly for at least 6 or 12 months, and wherein the subjects initiated SMN upregulatory therapy at an age of less than 5 years. In some embodiments, the disclosure provides the use of apiteglomab in the manufacture of a therapeutic composition for SMA in human subjects receiving SMN upregulatory therapy, wherein the subjects are administered apiteglomab by intravenous infusion every four weeks or monthly for at least six or twelve months in an amount sufficient to produce a mean increase of at least two points in the HFMSE score compared to the baseline score before treatment, e.g., a mean increase in a cohort of at least eight or nine subjects, wherein the subjects initiated SMN upregulatory therapy at an age of less than five years.

[0310] In some embodiments, SMA is late-onset SMA. In some embodiments, SMA is type 2 SMA. In some embodiments, the subjects are aged 2 years or older. In some embodiments, the SMN upregulatory therapy is nusinersen, risdipram, and / or onasemnogene abeparvovec. In some embodiments, the SMN upregulatory therapy is nusinersen. In some embodiments, a sufficient dose is a dose of approximately 5, 10, 15, or 20 mg / kg, optionally greater than 2 mg / kg and less than or equal to 20 mg / kg. In some embodiments, a sufficient dose is a dose of 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or monthly.

[0311] In some embodiments, apiteglomab is administered at a dose that produces a mean increase of at least 2 points in the HFMSE score compared to baseline, for example, a mean increase in a cohort of at least 8 or 9 subjects, after 8 weeks or 12 months. In some embodiments, apiteglomab is administered at a dose that produces a mean increase of at least 3, at least 4, at least 5, at least 6, or at least 7 points in the HFMSE score compared to baseline, for example, after at least 12 months of treatment. In some embodiments, apiteglomab is administered at a dose that produces a mean increase of at least 3 points in the HFMSE score compared to baseline, for example, a mean increase in a cohort of at least 8 or 9 subjects. In some embodiments, apiteglomab is administered at a dose that produces a mean increase of at least 5 points in the HFMSE score compared to baseline, for example, a mean increase in a cohort of at least 8 or 9 subjects. In some embodiments, apiteglomab is administered in a dose that produces a mean increase of at least 6 points in the HFMSE score compared to baseline, for example, in a cohort of at least 8 or 9 subjects. In some embodiments, apiteglomab is administered in a dose that produces a mean increase of at least 7 points in the HFMSE score compared to baseline, for example, in a cohort of at least 8 or 9 subjects. In some embodiments, this dose is 20 mg / kg of apiteglomab every four weeks or monthly.

[0312] In some embodiments, apiteglomab is used to deliver at least about 25-1100 micrograms of apiteglomab per milliliter of serum concentration (C maxIt is administered in an amount that achieves the steady-state serum concentration. In some embodiments, apitegromab is administered at 2 mg / kg, achieving a serum concentration of approximately 25–55 micrograms per milliliter. In some embodiments, apitegromab is administered at a dose greater than 2 mg / kg and less than or equal to 20 mg / kg, achieving a serum concentration of approximately 250–1100 micrograms per milliliter. In some embodiments, the serum concentration is 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 approximately 600–1000 micrograms per milliliter. In some embodiments, the serum concentration is the steady-state serum concentration. In some embodiments, apitegromab is administered in an amount that achieves the steady-state serum concentration after approximately 112 days or approximately 5 half-lives. In some embodiments, a dose greater than 2 mg / kg and less than or equal to 20 mg / kg is a dose of apiteglomab administered every four weeks or monthly at a dose of 20 mg / kg. In some embodiments, increasing the dose of apiteglomab leads to a serum concentration (C max A dose-response occurs, for example, when the dose is increased tenfold from 2 mg / kg to 20 mg / kg, C max This results in a tenfold increase.

[0313] In some embodiments, apiteglomab is administered at a concentration of at least about 25 micrograms per milliliter of serum, for example, at least about 50, 100, 200, 300, or 400 micrograms per milliliter of serum (C troughIt is administered in an amount that achieves (C). In some embodiments, apitegromab is administered at 2 mg / kg, achieving a serum concentration of approximately 25-55 micrograms per milliliter. In some embodiments, apitegromab is administered at a dose greater than 2 mg / kg but less than or equal to 20 mg / kg, achieving a serum concentration of approximately 100-400 micrograms per milliliter. In some embodiments, the dose greater than 2 mg / kg but less than or equal to 20 mg / kg is a dose of 20 mg / kg of apitegromab every four weeks or monthly. In some embodiments, increasing the dose of apitegromab leads to a serum concentration (C). trough A dose-response occurs, for example, when the dose is increased tenfold from 2 mg / kg to 20 mg / kg, C trough This results in a tenfold increase.

[0314] In some embodiments, apiteglomab is administered in an amount sufficient to achieve target aggregation as measured by serum latent myostatin concentrations of at least about 250 nanograms per milliliter, for example, 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, serum latent myostatin concentrations are about 550–1100 or 600–1000 nanograms per milliliter. In some embodiments, serum latent myostatin concentrations are steady-state concentrations measured in the trough. In some embodiments, this amount is a dose of 20 mg / kg of apiteglomab every four weeks or monthly.

[0315] In some embodiments, apiteglomab is administered in a dose 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 ambulation in walkable 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 a control; and / or maintaining at least a net zero change in one or more motor function scores compared to baseline. In some embodiments, this dose is 20 mg / kg of apiteglomab every four weeks or monthly.

[0316] In some embodiments, the Disclosure provides a method for treating SMA, comprising administering to a patient population a composition comprising apieglomab, wherein the patient population is administered by intravenous infusion every four weeks or monthly for at least six or twelve months in an amount sufficient to increase the clinical response rate (ratio of responders) in the patient population, wherein the clinical response rate is measured by a six-minute walk test and / or a 30-second stand-up test. In some embodiments, the Disclosure provides a composition comprising apieglomab for use in the treatment of SMA, wherein the patient population is administered by intravenous infusion every four weeks or monthly for at least six or twelve months in an amount sufficient to increase the clinical response rate (ratio of responders) in the patient population, wherein the clinical response rate is measured by a six-minute walk test and / or a 30-second stand-up test. In some embodiments, the Disclosure provides the use of a composition comprising apiteglomab for the treatment of SMA, wherein a patient population is administered by intravenous infusion every four weeks or monthly for at least six or twelve months in an amount sufficient to increase the clinical response rate (ratio of responders) in the patient population, wherein the clinical response rate is measured by a six-minute walk test and / or a 30-second stand-up test. In some embodiments, the Disclosure provides the use of apiteglomab in the manufacture of a therapeutic composition for SMA, wherein a patient population is administered by intravenous infusion every four weeks or monthly for at least six or twelve months in an amount sufficient to increase the clinical response rate (ratio of responders) in the patient population, wherein the clinical response rate is measured by a six-minute walk test and / or a 30-second stand-up test.

[0317] In some embodiments, the patient population is a late-onset SMA population. In some embodiments, the patient population is a walkable type 3 SMA population. In some embodiments, the patient population includes human subjects aged 5 to 21 years. In some embodiments, the patient population is treated with SMN upregulatory therapy. In some embodiments, the SMN upregulatory therapy is nusinersen, risdipram, and / or onasemnogene abeparvovec. In some embodiments, the SMN control therapy is nusinersen. In some embodiments, the patient population initiated SMN upregulatory therapy at an age of 5 years or older. In some embodiments, a sufficient dose is a dose of approximately 5, 10, 15, or 20 mg / kg, with the option being greater than 2 mg / kg and less than or equal to 20 mg / kg. In some embodiments, a sufficient dose is a dose of 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or monthly.

[0318] In some embodiments, apiteglomab is administered in a dose that achieves a serum concentration of at least 600 micrograms of apiteglomab 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 to 1000 micrograms per milliliter. In some embodiments, the serum concentration is the steady-state serum concentration. In some embodiments, apiteglomab is administered in a dose that achieves a steady-state serum concentration after about 112 days. In some embodiments, this dose is 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or monthly.

[0319] In some embodiments, apiteglomab is administered in an amount sufficient to achieve target aggregation as measured by a serum latent myostatin concentration of at least 500 nanograms per milliliter (e.g., at least 500, 550, 600, or 650 nanograms per milliliter). In some embodiments, the serum latent myostatin concentration is about 550–1100 or 600–1000 nanograms per milliliter. In some embodiments, the serum latent myostatin concentration is the steady-state concentration measured in the trough. In some embodiments, this amount is a dose of 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or monthly.

[0320] In some embodiments, apiteglomab is administered in a dose that enables the subject to achieve one or more of the following: preserving motor function compared to deterioration in a control; delaying disease progression; delaying or preventing ambulation in walkable 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 a control; and / or maintaining at least a net zero change in one or more motor function scores compared to baseline. In some embodiments, this dose is 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or monthly.

[0321] In some embodiments, the Disclosure provides a method for treating SMA, comprising administering to a patient population a composition comprising apieglomab, wherein the patient population is administered by intravenous infusion every four weeks or monthly for at least six or twelve months in an amount sufficient to increase the clinical response rate (ratio of responders) in the patient population, wherein the clinical response rate is measured according to the Revised Upper Limb Module (RULM) and / or World Health Organization (WHO) milestones. In some embodiments, the Disclosure provides a composition comprising apieglomab for use in the treatment of SMA, wherein the patient population is administered by intravenous infusion every four weeks or monthly for at least six or twelve months in an amount sufficient to increase the clinical response rate (ratio of responders) in the patient population, wherein the clinical response rate is measured according to the RULM and / or WHO milestones. In some embodiments, the Disclosure provides the use of a composition comprising apiteglomab in the treatment of SMA, wherein a patient population is administered a sufficient amount of apiteglomab by intravenous infusion every four weeks or monthly for at least six or twelve months, and the clinical response rate is measured by RULM and / or WHO milestones. In some embodiments, the Disclosure provides the use of apiteglomab in the manufacture of a therapeutic composition for SMA, wherein a patient population is administered a sufficient amount of apiteglomab by intravenous infusion every four weeks or monthly for at least six or twelve months, and the clinical response rate is measured by RULM and / or WHO milestones.

[0322] In some embodiments, the patient population is a late-onset SMA population. In some embodiments, the patient population is a type 2 SMA population. In some embodiments, the patient population is a non-walking type 3 SMA population. In some embodiments, the patient population includes human subjects aged 2 years or older. In some embodiments, the patient population includes human subjects aged 5 to 21 years. In some embodiments, the patient population is treated with SMN upregulatory therapy. In some embodiments, the SMN upregulatory therapy is nusinersen, risdipram, and / or onasemnogene abeparvovec. In some embodiments, the SMN control therapy is nusinersen. In some embodiments, a sufficient dose is a dose of approximately 5, 10, 15, or 20 mg / kg, optionally greater than 2 mg / kg and less than or equal to 20 mg / kg. In some embodiments, a sufficient dose is a dose of 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or monthly.

[0323] In some embodiments, apiteglomab is administered in a dose that achieves a serum concentration of at least 600 micrograms of apiteglomab 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 to 1000 micrograms per milliliter. In some embodiments, the serum concentration is the steady-state serum concentration. In some embodiments, apiteglomab is administered in a dose that achieves a steady-state serum concentration after about 112 days. In some embodiments, this dose is 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or monthly.

[0324] In some embodiments, apiteglomab is administered in an amount sufficient to achieve target aggregation as measured by a serum latent myostatin concentration of at least 500 nanograms per milliliter (e.g., at least 500, 550, 600, or 650 nanograms per milliliter). In some embodiments, the serum latent myostatin concentration is about 550–1100 or 600–1000 nanograms per milliliter. In some embodiments, the serum latent myostatin concentration is the steady-state concentration measured in the trough. In some embodiments, this amount is a dose of 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or monthly.

[0325] In some embodiments, apiteglomab is administered in a dose that enables the subject to achieve one or more of the following: preserving motor function compared to deterioration in a control; delaying disease progression; delaying or preventing ambulation in walkable 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 a control; and / or maintaining at least a net zero change in one or more motor function scores compared to baseline. In some embodiments, this dose is 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or monthly.

[0326] In some embodiments, the Disclosure provides a method for treating late-onset SMA in human subjects aged 2 years or older, comprising administering apiteglomab by intravenous infusion at a dose of more than 2 mg / kg and less than or equal to 20 mg / kg per month. In some embodiments, the Disclosure provides apiteglomab for use in the treatment of late-onset SMA in human subjects aged 2 years or older, wherein a dose of more than 2 mg / kg and less than or equal to 20 mg / kg of apiteglomab is administered monthly by intravenous infusion. In some embodiments, the Disclosure provides the use of apiteglomab for the treatment of late-onset SMA in human subjects aged 2 years or older, wherein a dose of more than 2 mg / kg and less than or equal to 20 mg / kg of apiteglomab is administered monthly by intravenous infusion. In some embodiments, the Disclosure provides the use of apiteglomab in the manufacture of a therapeutic composition for late-onset SMA in human subjects aged 2 years or older, wherein a dose of more than 2 mg / kg and less than or equal to 20 mg / kg of apiteglomab is administered monthly by intravenous infusion.

[0327] In some embodiments, apiteglomab is administered monthly at a dose of 10 mg / kg or 20 mg / kg. In some embodiments, apiteglomab is administered as an adjunct to SMN upregulation therapy. In some embodiments, apiteglomab is administered as an adjunct to SMN upregulation therapy including nusinersen.

[0328] In some embodiments, apiteglomab is administered in a dose that achieves a serum concentration of at least 600 micrograms of apiteglomab per milliliter (e.g., at least 600, 700, 800, 900, 1000 micrograms per milliliter or more). In some embodiments, the serum concentration is approximately 600–1000 micrograms per milliliter. In some embodiments, the serum concentration is the steady-state serum concentration. In some embodiments, apiteglomab is administered in a dose that achieves a steady-state serum concentration after approximately 112 days. In some embodiments, this dose is 10 mg / kg or 20 mg / kg of apiteglomab per month.

[0329] In some embodiments, apiteglomab is administered in an amount sufficient to achieve target aggregation as measured by a serum latent myostatin concentration of at least 500 nanograms per milliliter (e.g., at least 500, 550, 600, or 650 nanograms per milliliter). In some embodiments, the serum latent myostatin concentration is approximately 550–1100 or 600–1000 nanograms per milliliter. In some embodiments, the serum latent myostatin concentration is the steady-state concentration measured in the trough. In some embodiments, this amount is a monthly dose of 10 mg / kg or 20 mg / kg of apiteglomab.

[0330] In some embodiments, apiteglomab is administered in a dose that enables the subject to achieve one or more of the following: preserving motor function compared to deterioration in a control; delaying disease progression; delaying or preventing ambulation in walkable 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 a control; and / or maintaining at least a net zero change in one or more motor function scores compared to baseline. In some embodiments, this dose is 10 mg / kg or 20 mg / kg of apiteglomab per month.

[0331] In some embodiments, the Disclosure provides a method for treating late-onset SMA in a human subject, comprising administering apiteglomab to the subject at a dose greater than 2 mg / kg and less than or equal to 20 mg / kg (10 mg / kg to 20 mg / kg, e.g., 10 mg / kg or 20 mg / kg) every four weeks or monthly, wherein the subject has initiated motor neuron-directed therapy for SMA at an age of less than 5 years, and the motor neuron-directed therapy increases SMN1 or SMN2 expression. In some embodiments, the Disclosure provides apiteglomab for use in the treatment of late-onset SMA in a human subject, wherein the treatment comprises administering apiteglomab to the subject at a dose greater than 2 mg / kg and less than or equal to 20 mg / kg every four weeks or monthly, wherein the subject has initiated motor neuron-directed therapy for SMA at an age of less than 5 years, and the motor neuron-directed therapy increases SMN1 or SMN2 expression. In some embodiments, the Disclosure provides the use of apiteglomab for the treatment of late-onset SMA in human subjects, wherein the treatment comprises administering apiteglomab to a subject at a dose greater than 2 mg / kg and less than or equal to 20 mg / kg every four weeks or monthly, wherein the subject has initiated motor neuron-directed therapy for SMA at an age of less than 5 years, and the motor neuron-directed therapy increases SMN1 or SMN2 expression. In some embodiments, the Disclosure provides the use of apiteglomab in the manufacture of a therapeutic composition for late-onset SMA in human subjects, wherein the treatment comprises administering apiteglomab to a subject at a dose greater than 2 mg / kg and less than or equal to 20 mg / kg every four weeks or monthly, wherein the subject has initiated motor neuron-directed therapy for SMA at an age of less than 5 years, and the motor neuron-directed therapy increases SMN1 or SMN2 expression.

[0332] In some embodiments, treatment results in a mean increase of at least 2 points in the HFMSE score compared to the baseline score before treatment, for example, a mean increase in a cohort of at least 8 or 9 subjects, after 6 or 12 months. In some embodiments, the motor neuron-directed therapy is nusinersen, risdipram, and / or onasemnogene abeparvovec. In some embodiments, the motor neuron-directed therapy is nusinersen. In some embodiments, apiteglomab is administered by intravenous infusion. In some embodiments, apiteglomab is administered every 4 weeks or monthly at a dose greater than 2 mg / kg and less than or equal to 20 mg / kg. In some embodiments, apiteglomab is administered every 4 weeks or monthly at a dose of 10 mg / kg or 20 mg / kg. In some embodiments, late-onset SMA patients are also classified as type 2 SMA, type 3 SMA, or type 4 SMA patients. In some embodiments, type 3 SMA is either walkable or walkless.

[0333] In some embodiments, apiteglomab is administered in a dose that achieves a serum concentration of at least 600 micrograms of apiteglomab 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 the steady-state serum concentration. In some embodiments, apiteglomab is administered in a dose that achieves a steady-state serum concentration after about 112 days. In some embodiments, apiteglomab is administered in a dose sufficient to achieve target aggregation as measured by a serum latent myostatin concentration of at least 500 nanograms per milliliter (e.g., at least 500, 550, 600, or 650 nanograms per milliliter). In some embodiments, the serum latent myostatin concentration is about 550–1100 or 600–1000 nanograms per milliliter. In some embodiments, serum latent myostatin concentration is trough concentration. In some embodiments, apiteglomab is administered in a dose that enables the subject to achieve one or more of the following: preserving motor function compared to deterioration in a control; delaying disease progression; delaying or preventing ambulation in walkable 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 a control; and / or maintaining at least a net zero change in one or more motor function scores compared to baseline. In some embodiments, this dose is 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or monthly.

[0334] In some embodiments, the Disclosure provides a method for treating SMA in human subjects under the age of 5 years who have not received SMN upregulatory therapy, comprising administering apiteglomab to the subject at a dose greater than 2 mg / kg and less than or equal to 20 mg / kg (e.g., 10 mg / kg or 20 mg / kg) every four weeks or monthly, wherein the disease progression is stabilized by apiteglomab so that the HFMSE score or RHS score measured at 6 or 12 months after the start of treatment does not fall below baseline, or worsen by more than 0.1, 0.2, 0.3, 0.4, or 0.5 points, wherein baseline is obtained at or before the start of treatment. In some embodiments, the Disclosure provides apiteglomab for use in the treatment of SMA in human subjects under the age of 5 years who have not received SMN upregulatory therapy, wherein the treatment comprises administering to the subject a dose of apiteglomab every four weeks or monthly at a dose greater than 2 mg / kg and less than or equal to 20 mg / kg (e.g., 10 mg / kg or 20 mg / kg), wherein the disease progression is stabilized by apiteglomab so that the HFMSE score or RHS score measured at 6 months after the start of treatment does not fall below baseline, and wherein baseline is obtained at or before the start of treatment. In some embodiments, the Disclosure provides the use of apiteglomab to treat SMA in human subjects under the age of 5 years who have not received SMN upregulatory therapy, wherein the treatment comprises administering to the subject a dose of apiteglomab every four weeks or monthly at a dose greater than 2 mg / kg and less than or equal to 20 mg / kg (e.g., 10 mg / kg or 20 mg / kg), wherein the disease progression is stabilized by apiteglomab so that the HFMSE score or RHS score measured at 6 months after the initiation of treatment does not fall below baseline, and wherein baseline is obtained at or before the initiation of treatment.In some embodiments, the Disclosure provides the use of apiteglomab in the manufacture of a therapeutic composition for SMA in human subjects under the age of 5 years who have not received SMN upregulatory therapy, wherein the treatment comprises administering to the subject a dose of apiteglomab every four weeks or monthly at a dose greater than 2 mg / kg and less than or equal to 20 mg / kg (e.g., 10 mg / kg or 20 mg / kg), wherein the disease progression is stabilized by the apiteglomab so that the HFMSE score or RHS score measured at 6 months after the start of treatment does not fall below baseline, and wherein baseline is obtained at or before the start of treatment.

[0335] In some embodiments, apiteglomab is administered by intravenous infusion. In some embodiments, apiteglomab is administered at a dose of 10 mg / kg every four weeks or monthly. In some embodiments, apiteglomab is administered at a dose of 20 mg / kg every four weeks or monthly.

[0336] In some embodiments, apiteglomab is administered in a dose that achieves a serum concentration of at least 600 micrograms of apiteglomab 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 the steady-state serum concentration. In some embodiments, apiteglomab is administered in a dose that achieves a steady-state serum concentration after about 112 days. In some embodiments, apiteglomab is administered in a dose sufficient to achieve target aggregation as measured by a serum latent myostatin concentration of at least 500 nanograms per milliliter (e.g., at least 500, 550, 600, or 650 nanograms per milliliter). In some embodiments, the serum latent myostatin concentration is about 550–1100 or 600–1000 nanograms per milliliter. In some embodiments, serum latent myostatin concentration is trough concentration. In some embodiments, apiteglomab is administered in a dose that enables the subject to achieve one or more of the following: preserving motor function compared to deterioration in a control; delaying disease progression; delaying or preventing ambulation in walkable 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 a control; and / or maintaining at least a net zero change in one or more motor function scores compared to baseline. In some embodiments, this dose is 10 mg / kg or 20 mg / kg of apiteglomab every four weeks or monthly.

[0337] In some embodiments, the Disclosure provides apiteglomab for use in the treatment of late-onset SMA in human subjects, wherein the treatment comprises administering apiteglomab in an amount that achieves a maximum serum concentration of at least 600 micrograms of apiteglomab per milliliter (e.g., at least 600, 700, 800, 900, 1000 micrograms per milliliter or more).

[0338] In some embodiments, the maximum serum concentration is at least 600 micrograms per milliliter. In some embodiments, the maximum serum concentration is about 600 to 1000 micrograms per milliliter. In some embodiments, the serum concentration is the steady-state serum concentration. In some embodiments, this amount is a dose of apiteglomab greater than 2 mg / kg. In some embodiments, this amount is a dose of apiteglomab greater than 2 mg / kg but less than or equal to 20 mg / kg, optionally about 5, 10, 15, or 20 mg / kg, administered intravenously every four weeks or monthly. In some embodiments, this amount is a dose of 10 mg / kg or 20 mg / kg of apiteglomab administered intravenously every four weeks or monthly. In some embodiments, apiteglomab is administered in an amount sufficient to produce a mean increase of at least 1 point in the HFMSE score compared to the baseline score before treatment, for example, a mean increase in a cohort of at least 8 or 9 subjects. In some embodiments, apiteglomab is administered in a dose sufficient to produce a mean increase of at least 2 points in the HFMSE score compared to the baseline score before treatment, e.g., a mean increase in a cohort of at least 9 subjects. In some embodiments, late-onset SMA patients are type 2 or type 3 SMA patients, and optionally, subjects here are continuing SMN upregulatory therapy, and optionally, subjects here initiated SMN upregulatory therapy at an age of less than 5 years.

[0339] In some embodiments, the Disclosure provides apiteglomab for use in the treatment of late-onset SMA in human subjects, wherein the treatment comprises administering a sufficient amount of apiteglomab to achieve targeted association as measured by serum latent myostatin concentrations of at least 500 nanograms per milliliter (e.g., at least 500, 550, 600, or 650 nanograms per milliliter).

[0340] In some embodiments, the serum latent myostatin concentration is approximately 550–1100 or 600–1000 nanograms per milliliter. In some embodiments, the serum latent myostatin concentration is the steady-state concentration. In some embodiments, this amount is a dose of apiteglomab greater than 2 mg / kg. In some embodiments, this amount is a dose of apiteglomab greater than 2 mg / kg but less than or equal to 20 mg / kg, optionally about 5, 10, 15, or 20 mg / kg, administered intravenously every four weeks or monthly. In some embodiments, this amount is a dose of 10 mg / kg or 20 mg / kg of apiteglomab administered intravenously every four weeks or monthly. In some embodiments, apiteglomab is administered in an amount sufficient to produce a mean increase of at least 1 point in the HFMSE score compared to the baseline score before treatment, for example, a mean increase in a cohort of at least 8 or 9 subjects. In some embodiments, apiteglomab is administered in a dose sufficient to produce a mean increase of at least 2 points in the HFMSE score compared to the baseline score before treatment, e.g., a mean increase in a cohort of at least 9 subjects. In some embodiments, late-onset SMA is in patients classified as having type 2 or type 3 SMA, and subjects hereby optionally are continuing SMN upregulatory therapy, and subjects hereby optionally initiated SMN upregulatory therapy at an age of less than 5 years.

[0341] In some embodiments, the Disclosure provides compositions comprising apiteglomab for use in the treatment of SMA in human subjects, wherein the treatment comprises the administration of apiteglomab at a dose sufficient to achieve a serum exposure of at least 600 micrograms per milliliter to produce a clinical benefit characterized by improved motor function, disease stabilization, or delayed disease progression. In some embodiments, the treatment comprises intravenous administration of the composition at about 10 mg / kg or about 20 mg / kg of apiteglomab.

[0342] In some embodiments, the dose is approximately 10 mg / kg or approximately 20 mg / kg administered intravenously every four weeks or monthly. In some embodiments, the SMA is late-onset SMA, where optionally, the late-onset SMA is type 2, type 3, or type 4, where optionally, type 3 SMA is ambly or ambly. In some embodiments, the SMA is late-onset SMA, where optionally, the late-onset SMA is phenotypically characterized by symptom onset at an age of 6 months or older. In some embodiments, the SMA is late-onset SMA, where optionally, the late-onset SMA is genotypically characterized by having two or more copies of the SMN2 gene, where optionally, the subject carries 2, 3, 4, 5, or 6 copies of the SMN2 gene.

[0343] In some embodiments, human subjects initiated SMN upregulatory therapy at an age of less than 5 years, where optionally, subjects had a baseline HFMSE score of 12–44 or 14–42 prior to or at the initiation of apiteglomab treatment. In some embodiments, human subjects initiated SMN upregulatory therapy at an age of 5 years or older, where optionally, prior to or at the initiation of apiteglomab treatment, subjects had a baseline HFMSE score of 13–39 and / or b) subjects had a baseline RHS score of 44–62. In some embodiments, human subjects were not treated with SMN upregulatory therapy, where optionally, subjects had a baseline RHS score of 26–63.

[0344] In some embodiments, improved motor function includes an increase of at least 1 point from baseline in the motor function score after 6 months of treatment with apiteglomab. In some embodiments, improved motor function includes an increase of at least 2 points from baseline in the motor function score after 6 months of treatment with apiteglomab. In some embodiments, improved motor function includes an increase of at least 3 points from baseline in the motor function score after 6 months of treatment with apiteglomab. In some embodiments, improved motor function includes an increase of at least 4 points from baseline in the motor function score after 6 months of treatment with apiteglomab. In some embodiments, improved motor function includes an increase of at least 5 points from baseline in the motor function score after 6 months of treatment with apiteglomab. In some embodiments, disease stabilization includes no net loss of motor function score after 6 months of treatment with apiteglomab, where optionally, subjects are classified into a patient population in which disease progression, characterized by deterioration of motor function score, is statistically apparent over 12 months. In some embodiments, the motor function assessment score is the HFMSE score or the RHS score.

[0345] In some embodiments, the Disclosure provides a method for achieving a target saturation in a patient with SMA using apiteglomab, comprising administering to the patient with SMA approximately 10 mg / kg or approximately 20 mg / kg of apiteglomab by intravenous infusion every four weeks or monthly.

[0346] In some embodiments, the Disclosure provides a method for achieving a target saturation in a patient with SMA using apiteglomab, comprising administering a dose of apiteglomab to the patient with SMA in a dose sufficient to achieve a serum exposure of at least 600 micrograms per milliliter, wherein the apiteglomab is optionally administered by intravenous infusion every four weeks or monthly.

[0347] In some embodiments, the disclosure provides a method for treating a walkable SMA in a human subject, comprising administering to the subject by intravenous infusion of a composition comprising apiteglomab every four weeks or monthly for at least six months, wherein the subject has a baseline RHS score of at least 26 prior to or at the initiation of apiteglomab treatment, and wherein apiteglomab treatment achieving a serum exposure of at least 600 micrograms per milliliter of apiteglomab is sufficient to improve or stabilize the disease. In some embodiments, the subject initiated SMN upregulatory therapy at an age of 5 years or older. In some embodiments, the baseline RHS score is 63 or less.

[0348] In some embodiments, the Disclosure provides a method for treating a human subject with type 2 or non-walking type 3 SMA, comprising administering to the subject by intravenous infusion of a composition comprising apiteglomab every four weeks or monthly for at least six months, wherein the subject has initiated SMN upregulatory therapy at an age of five years or older, and wherein the subject has a baseline HFMSE score of 13 or greater, 39 or less, or both (13-39) prior to or at the initiation of apiteglomab treatment that achieves a serum exposure of at least 600 micrograms per milliliter. In some embodiments, the composition is sufficient to achieve an increase of at least one point in the HFMSE score relative to baseline after six months.

[0349] In some embodiments, the Disclosure provides a method for treating type 2 or non-walking SMA in a human subject, comprising administering to the subject by intravenous infusion of a composition comprising apiteglomab every four weeks or monthly for at least six months, wherein the subject has initiated SMN upregulatory therapy at an age of less than five years, and the subject has a baseline HFMSE score of 12 or greater, 44 or less, or both (12–44) prior to or at the initiation of apiteglomab treatment, achieving a serum exposure of at least 600 micrograms per milliliter. In some embodiments, the composition is sufficient to achieve an increase of at least one or three points in the HFMSE score relative to baseline after six months. In some embodiments, apiteglomab is dose-set at approximately 20 mg / kg.

[0350] In some embodiments, the Disclosure provides a selective myostatin inhibitor for use in the treatment of late-onset SMA in a human patient, wherein the human patient has immobile SMA, wherein the patient has a baseline HFMSE score in the range of 12 to 44 points, and wherein the patient is being treated with SMN upregulatory therapy, wherein the selective myostatin inhibitor is an antibody that prevents the release of mature myostatin by specifically binding to the latent myostatin complex. In some embodiments, the selective myostatin inhibitor is a neutralizing antibody or ligand trap that binds to mature myostatin.

[0351] In some embodiments, the Disclosure provides selective myostatin inhibitors and SMN upregulators for use in the treatment of late-onset SMA in human patients, where the patient has a baseline HFMSE score of 44 or less, and herein optionally, the selective myostatin inhibitor is an antibody that prevents the release of mature myostatin by specifically binding to latent myostatin complexes, and here further optionally, the SMN upregulator is an SMN2 upregulator and / or SMN1 gene therapy. In some embodiments, the selective myostatin inhibitor is a neutralizing antibody or ligand trap that binds to mature myostatin.

[0352] In some embodiments, the Disclosure provides a composition comprising apiteglomab for use in the treatment of SMA in human subjects, wherein the treatment comprises intravenous administration of the composition to a subject at doses of more than 2 mg / kg and less than or equal to 20 mg / kg of apiteglomab every four weeks or monthly, wherein the subject has initiated or is currently initiating SMN upregulatory therapy at an age of less than 5 years. In some embodiments, the SMA is late-onset SMA. In some embodiments, the subject has two or more copies of the SMN2 gene. In some embodiments, the SMA is type 2 SMA, wherein optionally, the subject has 2 to 4 copies of the SMN2 gene. In some embodiments, the subject is unable to walk. In some embodiments, the subject is 2 years of age or older. In some embodiments, the subject is genetically identified as a carrier of a mutation in the SMN1 gene, wherein optionally, the subject does not have symptoms of SMA or has symptoms of SMA. In some embodiments, the subject has a baseline HFMSE score of at least 12 points prior to or at the time of receiving the first dose of apiteglomab. In some embodiments, the composition is administered to the subject in an amount sufficient to achieve sustained (steady-state) target association of serum latent myostatin at least about 250 ng / mL. In some embodiments, the amount or dose of apiteglomab is 10 mg / kg or 20 mg / kg. In some embodiments, the subject has received at least four doses of SMN upregulatory therapy at the time of receiving the first dose of apiteglomab. In some embodiments, the subject has type 2 SMA. In some embodiments, apiteglomab is administered in a dose sufficient to produce an increase of at least 5 points in the HFMSE score compared to the baseline score after at least 12 months of treatment. In some embodiments, apiteglomab is administered in a dose sufficient to produce an increase of 6 to 20 points or more, and preferably at least 7 points, in the HFMSE score compared to the baseline score after at least 12 months of treatment. In some embodiments, the composition containing apiteglomab is administered intravenously at a dose of 20 mg / kg every four weeks or monthly. In some embodiments, the composition containing apiteglomab is administered intravenously at a dose of 10 mg / kg every four weeks or monthly.In some embodiments, the composition is formulated at a concentration of approximately 50 mg / mL.

[0353] In some embodiments, the Disclosure provides a method for achieving an increase of at least 7 points in an HFMSE score compared to a baseline score in a human subject, comprising administering to the subject an intravenous infusion of a composition comprising approximately 10 mg / kg or 20 mg / kg of apiteglomab every 4 weeks or monthly for at least 12 months, wherein the subject has late-onset SMA and initiated treatment with nusinersen at an age of less than 5 years.

[0354] In some embodiments, the Disclosure provides a method for monitoring the treatment of SMA in human subjects, comprising administering a composition comprising apiteglomab to a subject by intravenous infusion every four weeks or monthly in a dose greater than 2 mg / kg and less than or equal to 20 mg / kg; and detecting a serum latent myostatin concentration, where a serum latent myostatin concentration of at least about 250 ng / mL indicates therapeutic efficacy, where the subject has late-onset (optionally type 2) SMA and initiated treatment with nusinersen at an age of less than 5 years. In some embodiments, the subject is unable to walk. In some embodiments, the subject is 2 years of age or older. In some embodiments, apiteglomab is administered every four weeks or monthly at a dose of 10 mg / kg or 20 mg / kg. In some embodiments, the method further comprises administering an additional dose of apiteglomab to a subject having a serum latent myostatin concentration of at least about 250 ng / mL.

[0355] In some embodiments, the Disclosure provides a method for treating SMA in a human subject, comprising administering to the subject a composition comprising apiteglomab, wherein apiteglomab is administered every four weeks or monthly in an amount greater than 2 mg / kg but less than or equal to 20 mg / kg (e.g., 10 mg / kg or 20 mg / kg), wherein administration of apiteglomab is omitted for up to three consecutive times if the subject has a serum latent myostatin concentration of at least 250 ng / mL, wherein the subject has late-onset SMA and initiated SMN upregulatory therapy at an age of less than 5 years. In some embodiments, apiteglomab is administered by intravenous infusion. In some embodiments, the subject is unable to walk and / or has type 2 SMA. In some embodiments, the subject is 2 years of age or older.

[0356] In some embodiments, the Disclosure provides a method for treating SMA in a human subject, comprising administering to the subject a composition comprising a selective myostatin inhibitor, wherein the selective myostatin inhibitor is optionally an antibody that selectively binds to promyostatin / latent myostatin, and wherein the selective myostatin inhibitor is administered in an amount that achieves a steady-state serum latent myostatin concentration of at least about 100 ng / mL, preferably at least about 250 ng / mL, in the subject, wherein the subject has late-onset (optionally type 2) SMA and initiated SMN upregulatory therapy at an age of less than 5 years. In some embodiments, the serum concentration is the steady-state concentration. In some embodiments, the subject is unable to walk. In some embodiments, the subject is 2 years of age or older. In some embodiments, the selective myostatin inhibitor is apiteglomab. In some embodiments, apiteglomab is administered by intravenous infusion. In some embodiments, apiteglomab is administered at a dose of 20 mg / kg every four weeks or monthly.

[0357] In some embodiments, the Disclosure provides a composition comprising apiteglomab for use in the treatment of SMA in human subjects, wherein the treatment comprises intravenous administration to the subject every four weeks or monthly at a dose of apiteglomab greater than 2 mg / kg and less than or equal to 20 mg / kg of the composition, wherein the subject is treated with SMN upregulatory therapy, wherein the subject initiated or has initiated SMN upregulatory therapy at an age of 5 years or older. In some embodiments, the SMA is type 2 or type 3 SMA, wherein optionally, the subject has 2 to 4 copies of the SMN2 gene. In some embodiments, the subject has a walking-impaired type 3 SMA. In some embodiments, the subject is genetically identified as a carrier of a mutation in the SMN1 gene, wherein optionally, the subject does not have symptoms of SMA or has symptoms of SMA. In some embodiments, the subject has a baseline HFMSE score of at least 13 points prior to or at the time of receiving the first dose of apiteglomab. In some embodiments, the composition is administered to the subject in an amount sufficient to achieve sustained (steady-state) target association of serum latent myostatin at least about 100 ng / mL, or preferably at least about 250 ng / mL. In some embodiments, the dose of apiteglomab is 10 mg / kg or 20 mg / kg. In some embodiments, the subject is 5 to 21 years of age. In some embodiments, apiteglomab is administered in a dose sufficient to achieve no or minimal decrease in the HFMSE score compared to the baseline score after at least 12 months of treatment. In some embodiments, apiteglomab is administered in a dose sufficient to produce an increase of at least 1 point, and preferably at least 3 points, in the HFMSE score compared to the baseline score after 12 months of treatment. In some embodiments, the dose of apiteglomab is 20 mg / kg.

[0358] In some embodiments, the disclosure provides a method for stabilizing disease progression in a human subject having non-walking SMA, comprising administering to the subject by intravenous infusion of a composition comprising apiteglomab every four weeks or monthly for at least 12 months, wherein the subject initiated or has initiated SMN upregulatory therapy at an age of 5 years or older. In some embodiments, apiteglomab is administered in a dose sufficient to achieve no or minimal decrease in the HFMSE score compared to the baseline score after at least 12 months of treatment. In some embodiments, apiteglomab is administered in a dose of approximately 20 mg / kg.

[0359] In some embodiments, the Disclosure provides a composition comprising apiteglomab for use in the treatment of SMA in a human subject, wherein the treatment comprises intravenous administration every four weeks or monthly to a subject at a dose of apiteglomab greater than 2 mg / kg and less than or equal to 20 mg / kg of the composition, wherein the subject has a walkable SMA, and optionally, the subject has not received SMN upregulatory therapy. In some embodiments, the subject has a walkable type 3 SMA, and optionally, the subject has three or more copies of the SMN2 gene. In some embodiments, the subject is genetically identified as a carrier of a mutation in the SMN1 gene, and optionally, the subject does not have symptoms of SMA or has symptoms thereof. In some embodiments, the subject has a baseline RHS score of at least 26 points prior to or at the time of receiving the first dose of apiteglomab. In some embodiments, the composition is administered to the subject in an amount sufficient to achieve sustained (steady-state) target association of serum latent myostatin at least about 100 ng / mL, or preferably at least about 250 ng / mL. In some embodiments, the dose of apiteglomab is 10 mg / kg or 20 mg / kg. In some embodiments, apiteglomab is administered in a dose sufficient to stabilize the RHS score compared to the baseline score after at least 12 months of treatment. In some embodiments, stabilization of the RHS score includes a deterioration of less than 1, 2, or 3 points in the RHS score compared to the baseline score. In some embodiments, the dose of apiteglomab is 20 mg / kg. In some embodiments, the subject initiated SMN upregulatory therapy at an age of 5 years or older.

[0360] In some embodiments, the disclosure provides a method for preventing or delaying the loss of walking ability in a human subject having SMA, comprising administering a composition comprising apiteglomab to the subject at a dose of apiteglomab greater than 2 mg / kg and less than or equal to 20 mg / kg every four weeks or monthly for at least 12 months, wherein the subject has walkable SMA, and optionally, the subject has not received SMN upregulatory therapy. In some embodiments, the patient has walkable type 3 SMA. In some embodiments, progression is determined by a delay in the transition from walkable to walkable after 12 months of apiteglomab treatment compared to the natural history of the walkable SMA patient population. In some embodiments, progression is determined by a slower rate or lesser degree of deterioration in motor function scores relative to baseline after 12 months of apiteglomab treatment compared to the natural history of the walkable SMA patient population. In some embodiments, the composition is formulated at a concentration of apiteglomab of about 50 mg / mL. In some embodiments, SMN upregulatory therapy comprises nusinersen, onasemnogene abeparvovec, and / or risdipram. In some embodiments, SMN upregulatory therapy comprises nusinersen. In some embodiments, SMN upregulatory therapy comprises intrathecal administration.

[0361] In some embodiments, the Disclosure provides SMN upregulatory therapy and muscle-targeted therapy for use in the treatment of SMA in human subjects, wherein the therapy comprises initiation of SMN upregulatory therapy before the age of 5 years, and wherein the muscle-targeted therapy comprises intravenous administration every four weeks or monthly at a dose greater than 2 mg / kg and less than or equal to 20 mg / kg of a composition comprising apiteglomab, wherein optionally, the dose of apiteglomab is about 10 mg / kg. In some embodiments, the composition comprising apiteglomab is formulated at a concentration of about 50 mg / mL. In some embodiments, the SMN upregulatory therapy comprises nusinersen, onasemnogene abeparvovec, and / or risdiplam.

[0362] In some embodiments, the disclosure provides a method for treating late-onset SMA in a human subject, comprising intravenously administering to the subject a composition comprising apiteglomab at a therapeutic dose of more than 20 mg / kg or less every four weeks or monthly, wherein the composition is formulated at a concentration of about 50 mg / mL. In some embodiments, the therapeutic dose is sufficient to achieve a steady-state serum concentration of at least about 100 ng / mL or preferably at least about 250 ng / mL of latent myostatin. In some embodiments, the subject has 2 to 4 copies of the SMN2 gene. In some embodiments, the subject has type 2 SMA. In some embodiments, the subject has or had the ability to sit upright at 12 months of age and lacked or had lacked the ability to walk at 18 months of age. In some embodiments, the subject has ambulation-deficient type 3 SMA. In some embodiments, the subject has lost the ability to walk by 18 months of age. In some embodiments, the subject has 3 to 6 copies of the SMN2 gene. In some embodiments, the subject has walking-able type 3 SMA. In some embodiments, the subject retained the ability to walk at 18 months of age. In some embodiments, the subject undergoes a transition from walking-able to walking-unable at ages 18 months or older. In some embodiments, the subject is treated with SMN-targeted therapy. In some embodiments, the subject initiated or was initiated with SMN-targ...

Claims

1. A composition comprising apiteglomab for use in the treatment of spinal muscular atrophy (SMA) in humans, The treatment comprises administering apiteglomab intravenously at a dose of 10 mg / kg once every four weeks or once a month for at least 24 weeks or 6 months, and The treatment increases motor function as measured by the Hammersmith Functional Motor Scale (HFMSE) score in the subject 24 weeks or 6 months after the start of treatment, compared to the subject's baseline HFMSE score. Composition for use.

2. The treatment achieves an increase of at least one point, at least two points, or at least three points in the HFMSE score compared to baseline. A composition for use according to claim 1.

3. The composition for use according to claim 1 or claim 2, wherein the apiteglomab is administered over a period of at least 52 weeks or 12 months.

4. The composition for use according to any one of claims 1 to 3, wherein the subject is aged 2 years or older.

5. The composition for use according to any one of claims 1 to 4, wherein the human subject is 2 to 21 years of age.

6. The composition for use according to any one of claims 1 to 5, wherein the human subject is 2 to 12 years old.

7. The composition for use according to any one of claims 1 to 6, wherein the human subject is 2 to 5 years old.

8. The composition for use according to any one of claims 1 to 7, wherein the spinal muscular atrophy is late-onset SMA.

9. The composition for use according to claim 8, wherein the delayed-onset SMA is a non-walking SMA.

10. The composition for use according to claim 8, wherein the delayed-onset SMA is a walkable SMA.

11. The composition for use according to any one of claims 1 to 10, wherein the subject is a carrier of or has been identified as a carrier of a survival motor neuron 1 (SMN1) mutation.

12. The composition for use according to any one of claims 1 to 11, wherein the subject has at least two copies of the survival motor neuron 2 (SMN2) gene.

13. The composition for use according to any one of claims 1 to 12, wherein the subject is also administered survival motor neuron (SMN) upregulation therapy.

14. The composition for use according to claim 13, wherein the SMN upregulation therapy comprises a splicing modifier, an SMN gene substitution or gene therapy, an SMN transcription enhancer, an SMN protein translation enhancer, or an SMN protein stabilizer.

15. The composition for use according to claim 13, wherein the SMN upcontrol therapy comprises nusinersen and / or risdiplam.

16. The composition for use according to any one of claims 1 to 15, wherein the subject has a baseline serum latent myostatin concentration of at least 1 ng / mL.

17. The treatment is (a) Achieve a steady-state serum latent myostatin concentration of at least 250 ng / mL in the subjects after administration of apiteglomab; and / or (b) Achieve a steady-state serum apiteglomab concentration of at least 50 μg / mL in the subjects after administration of apiteglomab. A composition for use according to any one of claims 1 to 16.

18. The serum latent myostatin concentration in a steady state is 550 to 2400 ng / mL. The composition for use according to claim 17.

19. The composition for use according to claim 17 or claim 18, wherein the steady state is 14 days or more after administration of apiteglomab.

20. The use of apiteglomab in the manufacture of a therapeutic drug for spinal muscular atrophy (SMA) in humans, The treatment comprises administering the apiteglomab intravenously at a dose of 10 mg / kg once every four weeks or once a month for at least 24 weeks or 6 months, and The treatment increases motor function as measured by the Hammersmith Functional Motor Scale (HFMSE) score in the subject 24 weeks or 6 months after the start of treatment, compared to the subject's baseline HFMSE score. use.

21. The treatment results in an increase of at least 1, at least 2, or at least 3 points in the HFMSE score compared to baseline. The use described in claim 20.

22. The use according to claim 20 or 21, wherein the apiteglomab is administered over a period of at least 52 weeks or 12 months.

23. The use according to any one of claims 20 to 22, wherein the subject is aged 2 years or older.

24. The use according to any one of claims 20 to 23, wherein the human subject is 2 to 21 years of age.

25. The use according to any one of claims 20 to 24, wherein the human subject is 2 to 12 years of age.

26. The use according to any one of claims 20 to 25, wherein the human subject is 2 to 5 years old.

27. The use according to any one of claims 20 to 26, wherein the spinal muscular atrophy is late-onset SMA.

28. The use according to claim 27, wherein the delayed-onset SMA is a walking-impaired SMA.

29. The use according to claim 27, wherein the delayed-onset SMA is a walkable SMA.

30. The use according to any one of claims 20 to 29, wherein the subject is a carrier of or has been identified as a carrier of a survival motor neuron 1 (SMN1) mutation.

31. The use according to any one of claims 20 to 30, wherein the subject has at least two copies of the survival motor neuron 2 (SMN2) gene.

32. The use according to any one of claims 20 to 31, wherein the subject is also administered survival motor neuron (SMN) upregulation therapy.

33. The use according to claim 32, wherein the SMN upregulation therapy includes a splicing modifier, an SMN gene substitution or gene therapy, an SMN transcription enhancer, an SMN protein translation enhancer, or an SMN protein stabilizer.

34. The use according to claim 32, wherein the SMN upregulation therapy comprises nusinersen and / or risdiplam.

35. The use according to any one of claims 20 to 34, wherein the subject has a baseline serum latent myostatin concentration of at least 1 ng / mL.

36. The aforementioned treatment, (a) Achieve a steady-state serum latent myostatin concentration of at least 250 ng / mL in the subjects after administration of apiteglomab; and / or (b) Achieve a steady-state serum apiteglomab concentration of at least 50 μg / mL in the subjects after administration of apiteglomab. The use described in any one of claims 20 to 35.

37. The steady-state serum latent myostatin concentration is 550 to 2400 ng / mL. The use described in claim 36.

38. The use according to claim 36 or claim 37, wherein the steady state is 14 days or more after administration of apiteglomab.

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