Use of myostatin inhibitor for treating spinal muscular atrophy

Abstract

Administration of apitegromab leads to improvements in subjects with spinal muscular atrophy, including those with declining motor function while receiving a survival motor neuron targeted therapy.

Description

[0001] Attorney Docket No. 15094.0063-00304

[0002] USE OF MYOSTATIN INHIBITOR FOR TREATING SPINAL MUSCULAR ATROPHY

[0003] RELATED APPLICATIONS

[0004]

[0001] This Application claims the benefit of and priority to U.S. Provisional Application No. 63 / 704,000, filed October 6, 2024; U.S. Provisional Application No. 63 / 736,469, filed December 19, 2024; U.S. Provisional Application No. 63 / 768,004, filed March 6, 2025; and U.S. Provisional Application No. 63 / 785,462, filed April 8, 2025; each entitled “USE OF MYOSTATIN INHIBITOR FOR TREATING SPINAL MUSCULAR ATROPHY,” the contents of which are expressly incorporated herein by reference in their entirety.

[0005] SEQUENCE LISTING

[0006]

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on September 25, 2025, is named 15094.0063-00304_SL.xml and is 50,606 bytes in size.

[0007] FIELD

[0008]

[0003] The present disclosure relates to therapeutic methods, uses, and compositions comprising a myostatin inhibitor, preferably an anti-pro / latent myostatin antibody, to treat neuromuscular disorders, such as spinal muscular atrophy (SMA) in human patients.

[0009] BACKGROUND

[0010]

[0004] SMA is a progressive neuromuscular disorder in which a defect in the smn1 gene leads to deficiencies in the functional SMN protein, which is required for the normal development and maintenance of motor neurons. Patients with such loss-of-function mutations gradually lose motor function as their motor neurons degenerate, resulting in the atrophy of target muscle.

[0011]

[0005] Currently, three therapies are commercially available for the treatment of SMA, all of which aim to increase functional SMN protein levels in motor neurons. Among them, nusinersen and risdiplam represent a class of so-called “splice modifiers.” Nusinersen, which was the first such drug to be approved, has been studied most extensively. Observations from long-term clinical studies show that upon nusinersen treatment, patients experience improved motor function for approximately 1-2 years, as measured by Hammersmith Functional Motor Scale Expanded (HFMSE). Thereafter, the effect appears to reach a plateau during year 3-4, followed by progressive functional decline despite continued treatment (e.g., see FIG. 1 , left graph). As shown in FIG. 2, which illustrates the time course of disease progression, the decline phase that follows a stable phase or plateau is characterized by approximately 1 point decrease in HFMSE per year. Long-term clinical results of risdiplam show a similar pattern of initial improvement in motor function followed by plateau and decline (FIG. 1 , right graph). Attorney Docket No. 15094.0063-00304

[0012]

[0006] Previously, Applicant hypothesized that a selective inhibitor of myostatin, used in conjunction with a SMN-directed therapy, may further enhance motor function in SMA patients. Subsequently, Applicant conducted clinical studies (TOPAZ; ClinicalTrials.gov identifier: NCT03921528) and demonstrated that apitegromab, a monoclonal antibody that selectively binds pro / latent myostatin to inhibit its activation, can achieve significant improvement in motor function in SMA patients receiving an SMN-targeted therapy (e.g., nusinersen), during which the disease is predominantly in a stable phase (e.g., “plateau”). However, there remains a need to effectively treat progressive muscle weakness in SMA patients that are entering or in the progressive phase of decline even when on an SMN-targeted therapy (e.g., nusinersen or risdiplam). Subsequent work reported herein has identified use of a selective myostatin inhibitor as an effective treatment for SMA patients that are experiencing decline in muscle function despite having received an SMN-directed therapy (e.g., nusinersen and / or risdiplam).

[0013] SUMMARY

[0014]

[0007] Disclosed herein are data from a placebo-controlled clinical trial that evaluated the effect of a myostatin-selective inhibitor in SMA patients receiving a SMN-directed therapy during disease progression, e.g., the declining phase of the treatment effect. More specifically, data presented herein show that apitegromab achieved clinically meaningful improvement in motor function in patients whose disease is progressing (e.g., as measured by motor function), despite continued treatment with the background therapy.

[0015]

[0008] Accordingly, disclosed herein are methods of treating SMA using apitegromab, particularly in patients who, based on the timeline of disease progression, are in a declining phase of their SMN-targeted therapy (background therapy). In some embodiments, patients have been on a background therapy (e.g., standard of care therapy) for at least 3 years prior to starting myostatin inhibitor therapy. In some embodiments, patients have been on a background therapy (e.g., standard of care therapy (SOC)) for about 3-10 years prior to starting myostatin inhibitor therapy. In some embodiments, the patient has been on a nusinersen therapy for 40 months or longer. In some embodiments, the patient has been on a nusinersen therapy for 0.9 years or longer. In some embodiments, the patient has been on a nusinersen therapy for up to 10 years. In some embodiments, the patient has been on a risdiplam therapy for 36 months or longer. In some embodiments, the patient has been on a risdiplam therapy for 0.6 years or longer. In some embodiments, the patient has been on a risdiplam therapy for up to 6.1 years.

[0016]

[0009] Notably, data disclosed herein show that apitegromab treatment is able to shift the trajectory of SMA disease progression towards delaying decline, stabilizing disease state, or even improving motor function over the course of 12 months, including an approximately 2-point increase in HFMSE score. Apitegromab’s ability to change the course of disease progression in an advanced (e.g., declining) phase of SMA, that is, shifting from losing motor function to gaining motor function, is noteworthy. Nearly one in three patients in the study gained 3 points or more in HFMSE at 12 months, demonstrating that apitegromab was able to advance care on top of SOC. In comparison, the SUNFISH study, which enrolled patients of similar demographics as the current study, reported a 0.58-point increase in HFMSE after 12 months of treatment with an SMN-targeted therapy as monotherapy. Attorney Docket No. 15094.0063-00304

[0017]

[0010] The present disclosure includes, inter alia, therapeutic methods, uses, and compositions fortreating SMA patients with a muscle-enhancing agent (i.e., muscle-directed agent or muscle-targeted agent), such as apitegromab, also known as SRK-015. In various embodiments, apitegromab or a composition comprising apitegromab is used in the treatment of later-onset SMA in a human subject, either as monotherapy or as an adjunct to an SMN-targeted therapy. The data provided herein represent evidence of an enduring effect of a muscle-enhancing agent administered for a period of 48 months to patients with Type 2 and Type 3 SMA. Apitegromab therapy for treating subjects with SMA is provided herein.

[0018]

[0011] Surprisingly, in contrast to SMN-targeted therapies that work substantially better in younger patients, the clinical benefit observed with apitegromab were consistent across age groups, supporting the notion that, regardless of age or functional status, a broad population of SMA patients can benefit from a myostatin-selective inhibitor therapy including older patients, e.g., those aged 13-21 years. This is the first time a myostatin-selective inhibitor has demonstrated functional improvement in a pivotal placebo-controlled trial in any disease in clinical setting, raising the possibility that myostatin inhibitors, preferably myostatin- selective inhibitors, most preferably myostatin-selective activation inhibitors such as apitegromab, may be used in the treatment of a range of neuromuscular disorders, SMA and beyond, where patients experience a progressive decline in motor function.

[0019]

[0012] Furthermore, selection of certain SMA patient subpopulations who are particularly likely to benefit from a muscle-enhancing agent, such as a myostatin inhibitor, is disclosed herein. In some embodiments, the myostatin inhibitor is a myostatin-selective inhibitor, wherein optionally the myostatin-selective inhibitor is an antibody that binds latent myostatin thereby inhibiting its activation, such as apitegromab.

[0020]

[0013] In some embodiments, the patient has SMA and 2 copies of the SMN2 gene. In some embodiments, the patient has SMA and 3 copies of the SMN2 gene. In some embodiments, the patient has SMA and 4 copies of the SMN2 gene. In some embodiments, the patient has SMA and 5 copies of the SMN2 gene. In some embodiments, the patient has later-onset SMA. In some embodiments, the patient has Type 2 or Type 3 SMA. In some embodiments, the patient has later-onset SMA, e.g., Type 2 and Type 3 SMA. In some embodiments, the patient has Type 2 or Type 2-like SMA, wherein, optionally, the patient is 2 years or older. In some embodiments, the patient has non-ambulatory Type 3 or Type 3-like SMA, wherein, optionally, the patient is 2 years or older. In some embodiments, the patient has non-ambulatory SMA at the start of apitegromab treatment. In some embodiments, the patient is 2 years or older and has non- ambulatory SMA at the start of apitegromab treatment. In some embodiments, the patient is 2-12 years old and has non-ambulatory SMA at the start of apitegromab treatment. In some embodiments, the patient is 13-21 years old and has non-ambulatory SMA at the start of apitegromab treatment. In some embodiments, the patient is 2 years or older (e.g., 2-12 years old or 13-21 years old) and has ambulatory SMA at the start of apitegromab treatment.

[0021]

[0014] According to the present disclosure and the data presented herein, in some embodiments, the therapeutic dose is from 10 mg / kg to 20 mg / kg of apitegromab, when dosed every 4 weeks (i.e., Q4W) or monthly. In some embodiments, therapeutic doses of 10 mg / kg, 15 mg / kg, or 20 mg / kg may be used. 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., Attorney Docket No. 15094.0063-00304

[0022] Q4W) or once monthly. In some embodiments, the therapeutic dose is 20 mg / kg administered once every four weeks (i.e., Q4W) or once monthly.

[0023]

[0015] Apitegromab or another selective myostatin inhibitor may be used to treat SMA either alone (e.g., monotherapy) or in conjunction with another therapy, such as an SMN therapy or S MN -targeted therapy, including SMN upregulator therapy or SMN-corrector therapy (e.g., add-on / adjunct therapy or combination therapy). In some embodiments, the subject is treated with an SMN upregulator therapy such as nusinersen (SPINRAZA®) or risdiplam (EVRYSDI®). In some embodiments, the subject is treated with an SMN corrector therapy such as an SMN gene therapy, e.g., onasemnogene abeparvovec-xioi (ZOLGENSMA®). In some embodiments, the subject initiated the SMN-targeted therapy before the age of five. In some embodiments, the subject initiated the SMN-targeted therapy at or after the age of five. In some embodiments, the neuronal directed therapy increases progranulin, maintaining neuronal viability.

[0024]

[0016] In some embodiments, an SMN-targeted therapy (e.g., an SMN upregulator / corrector therapy) and apitegromab therapy (e.g., muscle-targeted therapy or muscle-directed therapy) are used as a combination, or add-on, or adjunct therapy. Thus, an SMN-targeted therapy and apitegromab may be used in the treatment of SMA in a patient, wherein the treatment comprises administration of the SMN-targeted therapy and the apitegromab in amounts sufficient to treat SMA, wherein the apitegromab therapy is intravenously administered to the patient at a dose of 10 mg / kg to 20 mg / kg (e.g., 10 mg / kg or 20 mg / kg) every four weeks or monthly. In some embodiments, the SMN-targeted therapy is an SMN1 -directed gene therapy. In some embodiments, the SMN-targeted therapy is an SMN upregulator therapy such as an SMN2-directed therapy, wherein optionally the SMN2-directed therapy is a splice modifier (e.g., nusinersen or risdiplam). In some embodiments, an SMN corrector may be administered orally, intrathecally, or intravenously. In some embodiments, the patient has later-onset SMA. In some embodiments, the patient has progressive SMA. In some embodiments, the patient has received or is receiving at least one SMN-targeted therapy and the patient has progressive SMA, wherein, optionally, the progressive SMA is indicated by a decline of the patient’s motor function over a period of 12 months.

[0025]

[0017] In some embodiments, a therapy comprising apitegromab and an SMN-targeted therapy (e.g., an SMN upregulator therapy such as nusinersen or risdiplam or an SMN corrector therapy such as onasemnogene abeparvovec-xioi) is used in the treatment of SMA in a patient 2 years or older with later- onset SMA (e.g., later-onset Type 2 or Type 3 SMA), wherein the treatment comprises administration of the SMN-targeted therapy and the apitegromab in amounts sufficient to treat SMA, wherein the apitegromab therapy is intravenously administered to the patient at a dose of 10 mg / kg or 20 mg / kg every four weeks or monthly.

[0026]

[0018] In some embodiments, the present disclosure provides a therapy comprising apitegromab and an SMN-targeted therapy (e.g., an SMN upregulator therapy such as nusinersen or risdiplam or an SMN corrector therapy such as onasemnogene abeparvovec-xioi) is used in the treatment of SMA in a patient 2 years or older with later-onset, non-ambulatory SMA, wherein the treatment comprises administration of the SMN-targeted therapy and the apitegromab in amounts sufficient to treat SMA, and wherein the apitegromab therapy is intravenously administered to the patient at a dose of 10 mg / kg or 20 mg / kg every Attorney Docket No. 15094.0063-00304 four weeks or monthly. In some embodiments, the patient has 2-5 copies (e.g., 2-4 copies, e.g., 3 copies) of SMN2.

[0027]

[0019] In some embodiments, the present disclosure provides a therapy comprising apitegromab and an SMN-targeted therapy (e.g., an SMN upregulator therapy such as nusinersen or risdiplam or an SMN corrector therapy such as onasemnogene abeparvovec-xioi) is used in the treatment of SMA in a patient aged 13-21 years with non-ambulatory or ambulatory SMA, wherein the treatment comprises administration of the SMN-targeted therapy and the apitegromab in amounts sufficient to treat SMA, wherein the apitegromab therapy is intravenously administered to the patient at a dose of 10 mg / kg or 20 mg / kg every four weeks or monthly, wherein, optionally, the patient has 2-5 copies (e.g., 2-4 copies, e.g., 3 copies) of the SMN2 gene. In some embodiments, the patient has an unknown number of copies of SMN2.

[0028]

[0020] 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 has an unknown number of copies of the SMN2 gene.

[0029]

[0021] In some embodiments, the patient commences the combination therapy at age five or older. In some embodiments, the patient commences the combination therapy before the age of five.

[0030]

[0022] In some embodiments, apitegromab therapy is used as an add-on or adjunct therapy to treat SMA. Thus, a composition comprising apitegromab may be used in the treatment of later-onset SMA in a patient, wherein the treatment comprises intravenous administration of the composition comprising a therapeutic dose of apitegromab, wherein the therapeutic dose is about 10 mg / kg to about 20 mg / kg every four weeks or monthly, and wherein the patient is treated with an SMN-targeted therapy. In some embodiments, the SMN-targeted therapy is an SMN1 -directed therapy, wherein optionally the SMN1 -directed therapy is a gene therapy. In some embodiments, the SMN-targeted therapy is an SMN2-directed therapy, wherein optionally the SMN2-directed therapy is an SMN upregulator therapy, e.g., an smn2 splice modifier. In some embodiments, any of the SMN-targeted therapies may be administered orally, intrathecally, or intravenously.

[0031]

[0023] In some embodiments, the patient has Type 2 SMA at the start of apitegromab treatment. In some embodiments, the patient has non-ambulatory Type 3 SMA at the start of apitegromab treatment. In some embodiments, the patient has ambulatory Type 3 SMA at the start of apitegromab treatment. 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 five copies of the SMN2 gene. In some embodiments, the patient has an unknown copy number of the SMN2 gene.

[0032]

[0024] In some embodiments, the patient commenced the SMN corrector therapy before the age of five. In some embodiments, the patient commenced the SMN corrector therapy at or after the age of five. Attorney Docket No. 15094.0063-00304

[0033]

[0025] In some embodiments, the patient was treated with the SMN-targeted therapy prior to starting the apitegromab therapy.

[0034]

[0026] In some embodiments, the patient has a HFMSE score of about 8 to about 48 at baseline.

[0035]

[0027] In some embodiments, a patient treated with apitegromab as disclosed herein has received or is treated with an SMN-targeted therapy, such as nusinersen, risdiplam, or onasemnogene abeparvovec-xioi. In some embodiments, a patient initiated the SMN-targeted therapy before the age of five. In some embodiments, the patient has received nusinersen before the age of five. In some embodiments, the patient has received risdiplam before the age of five. In some embodiments, the patient initiated the SMN-targeted therapy at or after the age of five. In some embodiments, the SMN-targeted therapy is an SMN upregulator therapy (e.g., nusinersen or risdiplam). In some embodiments, the patient has received nusinersen at or after the age of five. In some embodiments, the patient has received risdiplam at or after the age of five. In some embodiments, the patient has received the SMN-targeted therapy for at least six months (e.g., at least six months, at least one year, at least two years, at least three years, at least four years, or at least five years). In some embodiments, the patient has received nusinersen for about one to about eleven years (e.g., about four to about seven years) before starting apitegromab treatment. In some embodiments, the patient has received risdiplam for about six months to about six years (e.g., about two years to about four years) before starting the apitegromab treatment.

[0036]

[0028] In some embodiments, a patient who receives apitegromab therapy may attain improvement in motor function. In some embodiments, the improvement in motor function comprises an increase in an HFMSE score of the subject by at least about 2 points, e.g., by at least 2 points or at least 3 points, e.g., by 1 .8 points, as determined at 52 weeks or 12 months of apitegromab treatment as compared to baseline. In some embodiments, the improvement in motor function comprises an increase in an HFMSE score of the subject by at least about 2 points as determined at 52 weeks or 12 months of apitegromab treatment as compared to baseline. In some embodiments, the improvement in motor function comprises an increase in an RULM score of the subject as determined at 52 weeks or 12 months of apitegromab treatment as compared to baseline. In some embodiments, the improvement in the subject’s HFMSE or RULM score is observed at 8 weeks or 2 months after starting the apitegromab treatment. In some embodiments, the improvement in the subject’s HFMSE or RULM score is maintained at 52 weeks or 12 months of apitegromab treatment. In some embodiments, the improvement in motor function comprises an increase in a number of World Health Organization (WHO) motor developmental milestones attained by the subject as determined at 52 weeks or 12 months of apitegromab treatment as compared to baseline.

[0037]

[0029] In various embodiments, a patient who receives apitegromab therapy may attain improvement in quality of life. In some embodiments, the improvement in quality of life comprises an increase in a Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) score as determined at 52 weeks or 12 months of apitegromab treatment as compared to baseline. In some embodiments, the improvement in quality of life comprises a reduced level of fatigue severity at 52 weeks or 12 months of apitegromab treatment as compared to baseline and / or compared to a subject who has not received apitegromab, e.g., as seen in patients treated in the TOPAZ clinical trial (NCT03921528), wherein, optionally, the level of Attorney Docket No. 15094.0063-00304 fatigue severity is determined by a Patient Reported Outcomes Measurement Information System (PROMIS) score of the subject.

[0038]

[0030] In some embodiments, a patient who receives apitegromab therapy may have disease stabilization. Disease stabilization may correspond to a net zero (e.g., no change) or near-zero change (e.g., an increase or decrease of less than 20%) in an HFMSE score or RHS score over a baseline, e.g., for at least 12, 24, 36, or 48 months. In some embodiments, this is a clinically meaningful outcome over an untreated patient population (e.g., natural history), or one treated with prior art methods (e.g., background therapy), in which a gradual decline in motor function is expected. In some embodiments, the treatment stabilizes the subject’s HFMSE score for at least 12 months or 52 weeks.

[0039]

[0031] In some embodiments, a patient who receives apitegromab therapy may have a delay in disease progression. Delay in disease progression may include, for example, a slower rate of decrease in an HFMSE score over time, e.g., after at least 12, 24, 36, or 48 months of treatment, as compared to a suitable control (e.g., an untreated patient exhibiting the natural history of the particular patient population). In some embodiments, the delay of disease progression comprises a delay in the subject’s loss of motor function as compared to a subject who has not received apitegromab. In some embodiments, the delay in disease progression comprises a reduced rate of decline in the subject’s HFMSE score as compared to a subject who has not received apitegromab. In some embodiments, the treatment reduces the rate of decline in the subject’s HFMSE score by at least about 1 point per year (e.g., at least about 1 point per year, at least about 2 points per year, or at least 3 points per year) as compared to a subject who has not received apitegromab. In some embodiments, the delay in disease progression comprises a delay in the subject’s need for respiratory aid or intervention as compared to a subject who has not received apitegromab. In some embodiments, the treatment results in a delay in progressing from ambulatory to non-ambulatory SMA as compared to a subject who has not received apitegromab, wherein the subject has ambulatory SMA.

[0040]

[0032] In some embodiments, the subject’s motor function is in a phase of decline. In some embodiments, the subject's motor function is determined by a HFMSE score, and the subject’s HFMSE score is in a phase of decline at a rate of at least 1 point per year (e.g., at least 1 point per year, at least 2 points per year, at least 3 points per year).

[0041]

[0033] In some embodiments, a therapeutically effective amount of the apitegromab of 10 mg / kg to 20 mg / kg achieves one or more of the following in the subject: retaining motor function as compared to a decline in a control, delaying disease progression, delaying or preventing an ambulatory Type 3 SMA patient from becoming non-ambulatory, delaying or preventing need for respiratory aid or intervention, reducing the rate of a decline in one or more motor function scores as compared to a control, and / or maintaining at least net zero change in one or more motor function scores as compared to a baseline.

[0042]

[0034] In one aspect, the present disclosure for provides a composition for use in the treatment of SMA in a subject having SMA, wherein the treatment comprises intravenously administering to the subject 10 mg / kg or 20 mg / kg of apitegromab at an interval of once every four weeks or once a month for at least 52 weeks or 12 months, and wherein the treatment is sufficient to stabilize or delay disease progression or improve motor function or quality of life at 52 weeks or 12 months compared to baseline and / or a subject who has not received apitegromab. In some embodiments, the apitegromab treatment comprises administering an Attorney Docket No. 15094.0063-00304 amount of apitegromab sufficientto achieve one or more (e.g., all) of the following in the subject at 52 weeks or 12 months after starting apitegromab administration: a) an increase in HFMSE score of at least about 1 point as compared to baseline; b) an increase in RULM score as compared to baseline; c) additional WHO motor milestones as compared to baseline; d) an increase in PEDI-CAT score as compared to baseline; e) an increase in PROMIS score as compared to baseline; and f) a reduction in a rate of decline in the subject’s HFMSE score as compared to a subject who has not received apitegromab.

[0043]

[0035] In one aspect, the present disclosure for provides a composition for use in the treatment of SMA in a subject in need thereof, wherein the treatment comprises intravenously administering to the subject 10 mg / kg or 20 mg / kg of apitegromab at an interval of once every four weeks for at least 52 weeks, optionally wherein the treatment: a) stabilizes or delays disease progression at 52 weeks as compared to a subject who has not received apitegromab; b) improves motor function at 52 weeks as compared to baseline; or c) improves quality of life at 52 weeks compared to baseline.

[0044]

[0036] In one aspect, the present disclosure for provides a composition for use in the treatment of SMA in a subject in need thereof, wherein the treatment comprises intravenously administering to the subject 10 mg / kg or 20 mg / kg of apitegromab at an interval of once a month for at least 12 months, optionally wherein the treatment: a) stabilizes or delays disease progression at 12 months as compared to a subject who has not received apitegromab; b) improves motor function at 12 months as compared to baseline; or c) improves quality of life at 12 months compared to baseline.

[0045]

[0037] In some embodiments, the apitegromab is administered for at least 52 weeks or at least 12 months. In some embodiments, the apitegromab is administered for at least 48 months or at least 4 years.

[0046]

[0038] In one aspect, the present disclosure provides a composition comprising apitegromab for use in the treatment of spinal muscular atrophy (SMA) in a human subject in need thereof, wherein the treatment comprises intravenously administering to the subject 10 mg / kg of apitegromab at an interval of once every 4 weeks or once a month, wherein the subject has received and / or is receiving nusinersen, wherein, optionally, the treatment is sufficient to stabilize or delay disease progression or improve in motor function or quality of life as compared to a subject who has not received the apitegromab. In some embodiments, the subject has received nusinersen, and the subject initiated nusinersen treatment before 5 years of age. In some embodiments, the subject has received nusinersen, and the subject initiated nusinersen treatment at or after 5 years of age. In some embodiments, the subject has received nusinersen for at least 4 years.

[0047]

[0039] In one aspect, the present disclosure provides a composition comprising apitegromab for use in the treatment of spinal muscular atrophy (SMA) in a human in need thereof, wherein the treatment comprises intravenously administering to the subject 10 mg / kg of apitegromab at an interval of once every 4 weeks or once a month, wherein the subject has received and / or is receiving risdiplam, wherein, optionally, the treatment is sufficient to stabilize or delay disease progression or improve motor function or quality of life as compared to a subject who has not received the apitegromab. In some embodiments, the subject has received risdiplam and the subject initiated risdiplam treatment before 5 years of age. In some embodiments, the subject has received risdiplam and wherein the subject initiated risdiplam treatment at or after 5 years of age. In some embodiments, the subject has received risdiplam and the subject initiated Attorney Docket No. 15094.0063-00304 risdiplam treatment at or after 5 years of age. In some embodiments, the subject has received risdiplam for at least 2 years.

[0048]

[0040] In one aspect, the present disclosure provides a composition comprising apitegromab for use in the treatment of spinal muscular atrophy (SMA) in a human subject in need thereof, wherein the treatment comprises intravenously administering to the subject 10 mg / kg of apitegromab at an interval of once every 4 weeks or once a month, wherein the subject has received and / or is receiving nusinersen and / or risdiplam, wherein, optionally, the treatment is sufficient to stabilize or delay disease progression or improve motor function or quality of life as compared to a subject who has not received the apitegromab. In some embodiments, the subject has received nusinersen, and the subject initiated nusinersen treatment before 5 years of age. In some embodiments, the subject has received nusinersen, and the subject initiated nusinersen treatment at or after 5 years of age. In some embodiments, the subject has received nusinersen for at least 4 years. In some embodiments, the subject has received risdiplam and the subject initiated risdiplam treatment before 5 years of age. In some embodiments, the subject has received risdiplam and wherein the subject initiated risdiplam treatment at or after 5 years of age. In some embodiments, the subject has received risdiplam and the subject initiated risdiplam treatment at or after 5 years of age. In some embodiments, the subject has received risdiplam for at least 2 years.

[0049]

[0041] The present disclosure also provides a pharmaceutical composition comprising apitegromab for use in the treatment of SMA in a human subject in an amount effective to treat SMA; wherein the subject is treated with an SMN-targeted therapy comprising an SMN2 splice modifying agent capable of increasing SMN2 expression; wherein the subject is at least 2 years of age; wherein, optionally, the subject is between the age of 2-12 or 13-21 ; wherein, optionally, the subject has 2-4 copies of the SMN2 gene; wherein the treatment comprises administration of apitegromab at a dose ranging from about 10 mg / kg to 20 mg / kg; and wherein the composition is administered intravenously once every four weeks.

[0050]

[0042] In some embodiments, the pharmaceutical composition is formulated for a dose of about 10 mg / kg once every 4 weeks. In some embodiments, the pharmaceutical composition is formulated for a dose of about 15 mg / kg once every 4 weeks. In some embodiments, the pharmaceutical composition is formulated for a dose of about 20 mg / kg once every 4 weeks. In some embodiments, the SMN-targeted therapy comprises an antisense oligonucleotide capable of modulating alternative splicing of SMN2. In some embodiments, the SMN-targeted therapy comprises a small molecule capable of modulating alternative splicing of SMN2. In some embodiments, the subject has a baseline HFMSE score ranging between 8-48. In some embodiments, the subject has history of scoliosis. In some embodiments, the subject received the SMN-targeted therapy before 5 years of age. In some embodiments, the subject received the SMN-targeted therapy at or after 5 years of age. In some embodiments, the effectiveness of apitegromab is measured by HFMSE, RULM, and / or WHO motor function milestones. The pharmaceutical composition for use according to any one of the preceding embodiments, wherein the treatment: a) stabilizes or delays disease progression in the human subject as compared to a human subject who has not received apitegromab; b) improves motor function in the human subject as compared to baseline and / or a human subject who has not received apitegromab; and / or c) improves quality of life in the human subject as compared to baseline and / or a human subject who has not received apitegromab. Attorney Docket No. 15094.0063-00304

[0051]

[0043] In some embodiments, the subject has entered a declining phase of their SMN-targeted therapy, as described herein, e.g., the subject may have been receiving an SMN-targeted therapy for at least about 3 years (e.g. 3 to 7 years) and preferably at least 40 months. As explained herein, the treatment may improve motor function over the course of 12 months, e.g. as measured by an increase in HFMSE score relative to a baseline score prior to treatment.

[0052]

[0044] In some embodiments, the present disclosure provides use of apitegromab in the manufacture of a pharmaceutical composition (e.g., a medicament) for the treatment of later-onset SMA in a human subject. The medicament is intended for administration to the subject at a dose of 10 mg / kg to 20 mg / kg of apitegromab every four weeks or monthly, optionally wherein the treatment: a) stabilizes or delays disease progression in a subject at 52 weeks or 12 months as compared to a subject who has not received apitegromab; b) improves motor function in a subject at 52 weeks or 12 months as compared to baseline; or c) improves quality of life at 52 weeks or 12 months as compared to baseline.

[0053]

[0045] In some embodiments, the present disclosure provides a myostatin inhibitor for use in the treatment of SMA in a subject in need thereof, wherein the treatment comprises administration of a myostatin inhibitor to the subject who has progressive SMA as determined by a decline in motor function over time as measured by a suitable motor function measure, wherein the subject is on an SMN-directed therapy. In some embodiments, the suitable motor function measures are known, including those disclosed herein (e.g., HFMSE, MFM32, RULM, RHS, MyoGrip, MyoPinch, or WHO developmental motor milestones). In some embodiments, the subject has been on the SMN-directed therapy for at least 6 months (e.g., at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years). In some embodiments, the SMN-directed therapy comprises an SMN2 splice modifier agent. In some embodiments, the myostatin inhibitor is selected from apitegromab (SRK-015), GYM-329, and Taldefgrobep alfa (BHV-2000).

[0054]

[0046] The clinical benefits demonstrated by apitegromab disclosed herein further raise the possibility that other myostatin-selective inhibitors, including those of different modalities, may also prove beneficial in treating neuromuscular disorders, SMA and beyond (e.g., Hereditary inclusion body myopathies; muscular dystrophies such as DMD, Becker’s and Facioscapulohumeral muscular dystrophy; and Amyotrophic lateral sclerosis). In some embodiments, such myostatin-selective inhibitors include agents intended to reduce or eliminate the expression of myostatin (e.g., gene silencing agents), such as, without limitation, RNAi, siRNA, and CRISPR-based agents. In some embodiments, such agents are used in conjunction with an smn1 gene therapy, such as onasemnogene abeparvovec-xioi (sold as ZOLGENSMA®).

[0055] BRIEF DESCRIPTION OF THE FIGURES

[0056]

[0047] FIG. 1 shows the effects of the SMN therapies nusinersen and risdiplam on HFMSE over time.

[0057]

[0048] FIG. 2 shows the long-term effects of SMN therapies nusinersen on HFMSE.

[0058]

[0049] FIG. 3 shows the trial design of the SAPPHIRE apitegromab clinical study in subjects with spinal muscular atrophy. Attorney Docket No. 15094.0063-00304

[0059]

[0050] FIG. 4 shows proportion of SAPPHIRE participants by SMN2 copy number.

[0060]

[0051] FIGs. 5A-C show baseline means of HFMSE total score (4A), RULM total score (4B) and WHO milestones attained at baseline (4C) for subjects in the SAPPHIRE clinical trial.

[0061]

[0052] FIG. 6 shows Forest Plot of least-squares mean difference and 95% confidence interval in change from baseline in HFMSE total score at Month 12 for subjects in the SAPPHIRE clinical trial (MITT Set, EXP Set and Full Analysis Set).

[0062]

[0053] FIG. 7 shows Forest Plot of least-squares mean difference and 95% confidence interval in change from baseline in HFMSE total score at Month 12, subgroup analyses for the SAPPHIRE clinical trial. Data are shown as LS mean (95% Cl) difference in change at month 12 between apitegromab and placebo for each subgroup.

[0063]

[0054] FIGs. 8A-B shows HFMSE changes over time of subjects in the SAPPHIRE clinical trial. Shown is least-squares mean change from baseline and 95% confidence interval in HFMSE total score by visit (MITT Set). FIG.8A shows change from baseline in HFMSE total score at month 12 for apitegromab and placebo groups. Data are shown as LS mean (± SE) change from baseline at month 12 for apitegromab and placebo treatment groups. HFMSE, Hammersmith Functional Motor Scale-Expanded; LS, least squares; SE, standard error; 2-12, population aged 2 to 12 years. FIG. 8B shows curves for apitegromab (SRK-015) combined versus placebo.

[0064]

[0055] FIGs. 9A-C show Proportion of Patients in the SAPPHIRE clinical trial achieving change from baseline HFMSE total score at Month 12. FIG.9A shows proportions for 10 mg / kg, 20 mg / kg and combined apitegromab (SRK-015) versus placebo. The number of participants achieving various magnitudes of improvements in HFMSE total score, including >3-point improvements are shown below the plot. FIG. 9B shows proportions of patients achieving a change of at least 3 points from baseline HFMSE at Month 12 for apitegromab (SRK-015) combined versus placebo. Apitegromab 20mg / kg vs. placebo, odds ratio=2.4, P=0.11 ; apitegromab 10mg / kg vs. placebo, odds ratio=3.8, P=0.01. FIG. 9C shows proportions of participants achieving various magnitudes of improvements / declines in HFMSE total score, including >3- point improvements, based on the observed data for the placebo and apitegromab treatment groups at month 12.

[0065]

[0056] FIG. 10 shows RULM changes overtime of subjects in the SAPPHIRE clinical trial. Data are shown as LS mean (± SE) change from baseline to the time of each RULM assessment through the end of the 12- month treatment period for placebo and apitegromab groups. One participant from the apitegromab 10mg / kg dose group was too young at baseline to conduct the RULM and therefore was not included in RULM analyses.

[0066]

[0057] FIG. 11 shows WHO motor development milestones overtime of subjects in the SAPPHIRE clinical trial. Data are shown as LS mean (± SE) change from baseline to the time of each WHO motor development milestone assessment through the end of the 12-month treatment period for placebo and apitegromab groups. WHO motor development milestones consist of 6 distinct gross motor milestones: sitting without support, standing with assistance, hands-and-knees crawling, walking with assistance, standing alone, and walking alone. Attorney Docket No. 15094.0063-00304

[0067]

[0058] FIG. 12 shows change from baseline in HFMSE score at 6, 12, 24, 26 and 48 months in TOPAZ subjects excluding measurements after scoliosis surgery.

[0068]

[0059] FIG. 13 shows change from baseline in RULM score at 6, 12, 24, 26 and 48 months in TOPAZ subjects excluding measurements after scoliosis surgery.

[0069]

[0060] FIG. 14 shows activity change from baseline in PEDI-CAT score at 6, 12, 24, 26 and 48 months in TOPAZ subjects.

[0070]

[0061] FIG. 15 shows parent proxy change from baseline in PROMIS score at 6, 12, 24, 26 and 48 months in TOPAZ subjects.

[0071]

[0062] FIG. 16 shows total latent myostatin level over time in subjects treated with 10 mg / kg apitegromab as compared to subjects treated with 20 mg / kg apitegromab in the SAPPHIRE clinical trial (main efficacy population [MEP], ages 2-12).

[0072]

[0063] FIG. 17A shows pre- and post-infusion serum concentrations of apitegromab over time in subjects treated with 10 mg / kg apitegromab as compared to subjects treated with 20 mg / kg apitegromab (main efficacy population, ages 2-12) in the SAPPHIRE clinical trial. Peaks and troughs of apitegromab exposure over time are included, in a log profile of apitegromab PK.

[0073]

[0064] FIG. 17B shows apitegromab concentrations at pre-infusion on scheduled visits plotted over time for subjects in the SAPPHIRE clinical trial. Data are shown as geometric mean (± SD) in pg / mL. PK samples from patients receiving placebo were not tested and therefore not included in PK assessments. Troughs (Ctrough) of apitegromab over time are included, in a linear PK profile of apitegromab.

[0074]

[0065] FIG. 18 shows pre- and post-infusion serum concentration of apitegromab (SRK-015) over time in subjects treated with 10 mg / kg apitegromab as compared to subjects treated with 20 mg / kg apitegromab in the SAPPHIRE clinical trial, in both the main efficacy population, ages 2-12 (MEP), and the exploratory population, ages 13-21 (EXP). Peaks and troughs (Cmax and Ctrough) of apitegromab exposure over time are included, in a log profile of apitegromab PK.

[0075]

[0066] FIG. 19 shows total latent myostatin level over time in subjects treated with 10 mg / kg apitegromab (SRK-015) as compared to subjects treated with 20 mg / kg apitegromab in the SAPPHIRE clinical trial, in both the main efficacy population, ages 2-12 (MEP), and the exploratory population, ages 13-21 (EXP). Also shown is total latent myostatin level overtime in subjects treated with placebo in EXP. Data are shown as mean (± SD) ng / mL. SD, standard deviation.

[0076]

[0067] FIG. 20 shows the design of OPAL, a phase 2, randomized, double-blind, multiple dose-study for evaluating the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, safety, and tolerability of apitegromab in patients aged <2 years old with SMA. Attorney Docket No. 15094.0063-00304

[0077] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0078] Definitions

[0079]

[0068] In order that the disclosure may be more readily understood, certain terms are first defined. These definitions should be read in light of the remainder of the disclosure and as understood by a person of ordinary skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. Additional definitions are set forth throughout the detailed description.

[0080]

[0069] Administer. The terms “administer,” “administering,” and “administration” include any method of delivery of a therapeutic agent, (e.g., an anti-pro / latent myostatin antibody, e.g., apitegromab), into a subject’s system orto a particular region in or on a subject (systemic and local administration, respectively). In some embodiments, the therapeutic agent is apitegromab. In some embodiments, the apitegromab is formulated for administration as a composition, e.g., a pharmaceutical composition. In some embodiments, apitegromab is formulated for intravenous administration. For example, in some embodiments, the apitegromab is administered by intravenous injection / infusion, e.g., by intravenous infusion. In some embodiments, the apitegromab is administered by intravenous infusion, e.g., over approximately one to two hours. In some embodiments, the apitegromab is administered by intravenous infusion over approximately two hours. In some embodiments, the infusion duration is less than two hours but no shorter than one hour.

[0081]

[0070] Antibody: As used herein, the term “antibody” encompasses any naturally occurring, recombinant, modified or engineered immunoglobulin or immunoglobulin-like structure or antigen-binding fragment or portion thereof, or derivative thereof. Thus, the term refers to an immunoglobulin molecule that specifically binds to a target antigen, and includes, for example, chimeric, humanized, fully human, and multispecific antibodies (including bispecific antibodies). An intact antibody will generally comprise at least two full-length heavy chains and two full-length light chains, but in some instances can include fewer chains such as antibodies naturally occurring in camelids which can comprise only heavy chains. Antibodies can be derived solely from a single source, or can be “chimeric,” that is, different portions of the antibody can be derived from two different antibodies. Antibodies, or antigen binding portions thereof, can be produced in hybridomas, by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. The term antibodies, as used herein, includes monoclonal antibodies, multispecific antibodies such as bispecific antibodies, minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as “antibody mimetics”), chimeric antibodies, humanized antibodies, human antibodies, and antibody fusions (sometimes referred to herein as “antibody conjugates”). The term “antigen binding fragment” encompasses an adnectin. In various embodiments of the therapeutic methods, uses, and compositions disclosed herein, an antibody is a pro / latent myostatin antibody (e.g., apitegromab).

[0082]

[0071] Apitegromab'. Apitegromab (also referred to as “SRK-015”) is an investigational, fully human immunoglobulin G (IgG) 4 monoclonal antibody (mAb) that selectively binds with high affinity to promyostatin and latent myostatin in skeletal muscle, which are soluble inactive precursor forms (i.e., proforms) of myostatin. Apitegromab binds to latent myostatin in such a way as to inhibit activation and release of the mature myostatin growth factor that inhibits muscle growth and strength in the extracellular environment. See, e.g., Chemical Abstracts Service (CAS) Registry Number: 2278276-46-1 ; International Attorney Docket No. 15094.0063-00304

[0083] Nonproprietary Name: apitegromab; and United States Adopted Name (USAN): apitegromab. Apitegromab is of the human immunoglobulin G4 (lgG4) / lambda isotype. Apitegromab is a selective myostatin inhibitor (a myostatin-selective activation inhibitor). See, e.g., International Pub. No. WO 2017 / 049011. The term “selective myostatin inhibitor” (or “myostatin-selective inhibitor”) refers to an agent capable of blocking, inhibiting, or otherwise antagonizing the activation or activities of myostatin / GDF-8 without affecting structurally related growth factors, such as Activin A. Apitegromab comprises CDR regions of SEQ ID NO:1 (HCDR1), SEQ ID NO:2 (HCDR2), SEQ ID NO:3 (HCDR3), SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3), as defined by the Kabat numbering system; or SEQ ID NO:7 (HCDR1), SEQ ID NO:8 (HCDR2), SEQ ID NO:9 (HCDR3); SEQ ID NQ:10 (LCDR1), SEQ ID NO:11 (LCDR2), and SEQ ID NO:12 (LCDR3), as defined by the IMGT numbering system; a heavy chain variable region of SEQ ID NO:13 and a light chain variable region of SEQ ID NO:14; and a heavy chain amino acid sequence of SEQ ID NO:15 and a light chain amino acid sequence of SEQ ID NO:16. These sequences can be found in Tables 1-4. It is to be understood when referring to these sequences of the heavy and light chain variable regions of apitegromab that they may each comprise an N-terminal pyroglutamic acid. For instance, apitegromab may comprise a heavy chain variable region and light chain variable region, wherein the N- terminal glutamine (Q) is cyclized to pyroglutamic acid.

[0084]

[0072] Baseline: As used herein, the term “baseline” or “baseline score” in the context of an SMA-related parameter refers to the numerical value of the SMA-related parameter of a patient at the start of or prior to treatment (e.g., within 6 months prior to starting treating) with an SMA therapy of the present disclosure (e.g., at the time of initial administration of apitegromab, alone or as an adjunct to a background therapy comprising an SMN therapy). Examples of SMA-related parameters include a score on a motor functional scale, e.g., a Revised Upper Limb Module (RULM) score, a Hammersmith Functional Motor Scale Expanded (HFMSE) score, and / or a Revised Hammersmith Scale (RHS) score.

[0085]

[0073] In some embodiments, a baseline RULM, RHS, or HFMSE score is measured in a patient to be treated with apitegromab, e.g., apitegromab as an adjunct to a background therapy comprising an SMN therapy (e.g., in a patient with later-onset SMA, e.g., a patient who has a non-ambulatory form of SMA, such as Type 2 or non-ambulatory Type 3 SMA). As used herein, an adjunct therapy refers to a therapy that is administered in conjunction with (i.e., serially, sequentially, or in parallel with) another therapy. In some embodiments, the baseline score is measured at or priorto the start of treatment with the apitegromab (i.e., apitegromab therapy). Measurement priorto treatment may for example, be a month or less (e.g. two weeks, one week, or less) prior to the start of treatment. In some embodiments, the patient is on the SMN therapy at the time of baseline measurement. In some embodiments, the patient has been on the SMN therapy for at least 6 months prior to baseline measurement. In some embodiments, the patient has been on the SMN therapy for at least two years at the time of initiating apitegromab therapy, at which time the baseline measurement is made. In some embodiments, the baseline scores used to assess therapeutic effects of the apitegromab treatment may vary due to the therapeutic effects of the background therapy. In some embodiments, the patient had responded to the background therapy alone by an increase in the motor function scores of, for example, 1 -7 points measured against pre-treatment, demonstrating the therapeutic ability of apitegromab to improve upon the effects of SMN background therapy alone. Attorney Docket No. 15094.0063-00304

[0086]

[0074] Both the RHS (Ramsey et al. (2022) PLOS ONE https: / / doi.org / 10.1371 / journal.pone.0278996) and HFMSE (Main et al. (2003). Eur J Paediatr Neurol. 7(4):155-9) have been validated for assessing the physical abilities of patients with Type 2 and Type 3 SMA. RULM has also been used to investigate the upper limb function of ambulatory and non-ambulatory patients with SMA (Mazzone et al. (2017) Muscle Nerve. 55(6):869-874).

[0087]

[0075] In some embodiments, the HFMSE is used to assess the physical abilities of patients with Type 2 and Type 3 SMA (O'Hagen et al. (2007) Neuromuscul Disord. 17(9-10):693-697; Glanzman et al. (201 1) J Child Neurol. 26(12):1499-1507). In some embodiments, the HFMSE is used to evaluate non-ambulatory SMA patients. The HFMSE consists of 33 items to assess an individual’s ability to perform various activities. Quality and execution of each movement for the parameters listed above are graded on a scale of 0, 1 , 2, where 0 denotes unable, 1 denotes performed with modification or adaptation, and 2 denotes without modification or adaptation. The maximum achievable score is 66.

[0088]

[0076] In other embodiments, a baseline Hammersmith Infant Neurological Exam (HINE) score is measured in a patient to be treated with apitegromab, e.g., apitegromab as an adjunct to a background therapy of an SMN therapy. The HINE evaluates seven different areas of motor milestone development, e.g., kicking, head control, rolling, sitting, crawling, standing orwalking, with a maximum score of 2-4 points for each developmental motor milestone (Day et al. (2022) BMC Pediatrics 22:632). The HINE can be used in its entirety or the HINE-2, which is the development module, can be used independently to assess the motor milestones during development. In other embodiments, Hammersmith Neonatal Neurological Examination (HNNE) is measured in an infant patient to be treated with apitegromab, e.g., apitegromab as an adjunct to a background therapy of an SMN therapy. The HNNE evaluates 34 items grouped in the categories of posture and tone, tone patterns, reflexes, movements, abnormal signs / patterns, and orientation / behavior (Pane et al. (2022) Eur. J Pediatr 181 :2821-29).

[0089]

[0077] In other embodiments, the Bayley Scales of Infant and Toddler Development, 4thedition (BSID-IV) assessment of motor skills is measured in a patient to be treated with apitegromab, e.g., apitegromab as an adjunct to a background therapy of an SMN therapy. The BSID-IV measures the level of functioning of infants and toddlers from 1 -42 months of age with typical development and those who have risk factors that may impact their development. It consists of a cognitive scale, a language scale, and a motor scale, the latter of which measures fine and gross motor skills. The gross motor tasks assess body movement. Infants are assessed for head control and their performance of activities such as rolling over, sitting upright and crawling. Toddlers are assessed for their ability to make stepping movements, support their own weight, stand, and walk without assistance. Preschool-age children are assessed for their ability to jump, climb stairs, run, maintain balance, kick a ball, and other activities that require body control or coordination.

[0090]

[0078] The RULM is based on 19 scorable items that reflect different functional domains and are graded on a 3- point system with a score of 0 (unable), 1 (able, with modification), and a maximum of 2 (able, no difficulty), with one additional item that is scored as a can / cannot score (a score of 1 is the highest score). The maximum total RULM score is 37 (Mazzone et al. (2017) Muscle Nerve. 55(6):869-874).

[0091]

[0079] RHS is a clinician rated SMA specific outcome measure that contains 36 items assessing physical motor performance. The assessed motor functional activities relate to sitting, supine, rolling, prone, ability Attorney Docket No. 15094.0063-00304 to move and get up from the floor, balance, standing, run / walk, stairs, ascending and descending a step and the ability to jump. Thirty-three items are graded according to an ordinal 0, 1 , 2 scale where 0 represents the least physical ability or function achieved, and 2 the highest. Three items are graded 0 and 1 where 0 represents an inability to complete the item, and 1 represents achieving the item. Two timed tests are included within the scale, and WHO motor milestones can also be completed concurrently. Ramsey et al. (2022) PLOS ONE https: / / doi.org / 10.1371 / journal.pone.0278996.

[0092]

[0080] Cohort: As used herein, the term the “cohort” or “cohort population” refers to a group or population of human subjects with shared factors or influences, such as age, SMA disease severity (e.g., Type 2 and / or Type 3 SMA), concurrent treatments (e.g., an SMN therapy), etc. In some embodiments, as used herein, a “cohort” refers to a group of human subjects with shared age, SMA disease severity, and / or concurrent treatments.

[0093]

[0081] 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 deficiency that can cause or make the subject susceptible to a certain disease or condition, a subject with a disease or condition of interest, a sample from a subject treated with a placebo, a sample from a subject priorto treatment, a sham or buffertreated subject or sample, an untreated subject or sample, and the like.

[0094]

[0082] Inhibit or inhibition of: The term “inhibit” or “inhibition of,” as used herein, means to reduce by a measurable amount, and can include but does not require complete prevention or inhibition.

[0095]

[0083] Effective amount. The terms “effective amount” and “therapeutically effective amount” refer to the ability or an amount to fulfill its intended purpose(s), i.e., a desired biological or medicinal response in a subject, and / or to achieve a statistically significant clinical benefit (e.g., efficacy) in a patient population. An “effective amount” may refer to a therapeutically effective amount or therapeutic dose, which is a dosage or dosing regimen that is sufficient to produce a detectable change in a parameter of a disease, e.g., a slowing, pausing, reversing, diminution, or amelioration in a parameter, symptom, or downstream effect of the disease. The terms “dose” and “dose level” are used interchangeably herein. The term encompasses but does not require the use of an amount that completely cures a disease. References herein to a dose of an anti-pro / latent myostatin antibody (e.g., a dose of apitegromab) may be a therapeutically effective dose, as described herein. In some embodiments, efficacy may be measured by well-known motor function assessments and / or by one or more surrogate biomarkers, e.g., serum concentration of latent TGFp and / or serum concentration of creatinine. For example, in certain embodiments of the present disclosure, the intended purpose may be to inhibit activation of myostatin in vivo, to achieve clinically meaningful outcome associated with the myostatin inhibition.

[0096]

[0084] Measure of the relevant intended purpose may be objective (i.e., measurable by some assay or marker) or subjective (i.e., subject gives an indication of or feels an effect). In some embodiments, a therapeutically effective amount is an amount that, when administered to a patient population that meets certain clinical criteria for SMA (for example, as determined by symptoms manifested, disease progression / stage, genetic profile, etc.), a statistically significant therapeutic response is obtained among the population. Attorney Docket No. 15094.0063-00304

[0097]

[0085] An effective amount may also refer to an amount that, when administered according to a particular regimen, produces a positive clinical outcome with a reasonably acceptable level of adverse effects (e.g., toxicity), such that the adverse effects, if present, are tolerable enough for a patient to continue with the therapeutic regimen, and the benefit of the therapy overweighs risk of toxicity. Those of ordinary skill in the art will appreciate that in some embodiments of the disclosure, a dosage may be considered to contain an effective amount if it contains an amount appropriate for administration in the context of a dosage regimen correlated with a positive outcome.

[0098]

[0086] Latent myostatin: As used herein, the term “latent myostatin” refers to an inactive precursor of mature myostatin which comprises a disulfide-linked homodimer, each molecule of the homodimer comprising the amino terminal prodomain non-covalently bound to the carboxyl terminal mature myostatin domain. In some embodiments, latent myostatin is generated from a pro myostatin that has been cleaved by a proprotein convertase, but which has not been cleaved by a protease from the BMP / tolloid family. In some embodiments, latent myostatin can be generated by combining the prodomain and the carboxy terminal mature myostatin domain in vitro and allowing them to fold properly. See, for example, Sengle et al. (2011) J. Biol. Chem., 286(7):5087-5099.

[0099]

[0087] Later-onset SMA: As used herein, unless explicitly defined otherwise, the term “later-onset SMA” refers to a SMA in a patient who does not exhibit onset of SMA symptoms until after 6 months of age (e.g., symptoms are not detected at a 6-month medical screening) irrespective of the genotype, irrespective of whether and when an SMN therapy is administered. A later-onset SMA patient may also be a patient characterized as having Type 2, Type 3 or Type 4 SMA based on the traditional disease classifications known in the art. Patients with later-onset SMA typically have at least two copies of the SMN2 gene (e.g., 2 copies, 3 copies, 4 copies, or more, e.g., 2-4 copies). In some embodiments, a patient with later-onset SMA is treated with or has received a motor neuron-directed therapy (e.g., has received such therapy before the age of five), such as an SMN-targeted therapy, e.g., an SMN upregulator. As opposed to later-onset SMA, “early-onset SMA” or “infantile-onset SMA” refers to SMA that manifests symptoms at or prior to 6 months of age (including patients who can also be categorized as Type 1 SMA using the traditional classification known in the art). By comparison, an early- or infantile-onset SMA patient typically has 1 or 2 copies of the SMN2 gene. In some embodiments, a patient has later-onset SMA due to having received early intervention, e.g., one or more SMN therapies, wherein the patient would be considered early-onset if the patient had not received such early intervention.

[0100]

[0088] In some embodiments, a patient with later-onset SMA has 2-4 copies of the SMN2 gene. In some embodiments, a patient with later-onset SMA has 1 -2 copies of the SMN2 gene. In some embodiments, patients with later-onset SMA due to early treatment intervention (i.e., patients who otherwise would have had onset of symptoms before 6 months of age) may also be referred to as an “emerging” or “treatment- emergent” later-onset SMA patient or patient population. In some embodiments, treatment-emergent later- onset SMA patients may have a different genotype (e.g., 1-2 copies of the SMN2 gene), phenotype (e.g., gait), and / or course of disease and response to myostatin treatment than non-treatment-emergent SMA patients. In some embodiments, a patient having later-onset SMA would not have been able to walk and / or sit unassisted (e.g., would have had Type 1 and / or non-ambulatory Type 2 SMA) in the absence of Attorney Docket No. 15094.0063-00304 treatment, e.g., SMN-targeted treatment, but is able to do so because of treatment. In some embodiments, a treatment-emergent later-onset SMA patient who would have had non-ambulatory Type 3 SMA such that they would have lost the ability to walk by 18 months of age in the absence of treatment, e.g., SMN-targeted treatment, retains the ability to walk at 18 months because of treatment. When considering treatment of ambulatory Type 3 SMA patients, in some embodiments any ambulatory patient is treated. In some embodiments, a Type 3 patient is one that would retain the ability to walk by 18 months in the absence of intervention. In some embodiments, a Type 3 patient is one that would lose the ability to walk in the absence of intervention. In some embodiments, a patient is identified through newborn screening or in utero and is initiated in treatment, e.g., SMN-targeted therapy, prior to disease onset. In some embodiments, SMA symptom onset is not observed because of early treatment initiation following newborn screening. In some embodiments, the treated patient has Type 4 SMA (e.g., a patient with 4 or more copies of the SMN2 gene and much later onset of symptoms, e.g., at 18 years of age or later).

[0101]

[0089] Mature myostatiir. As used herein, the term “mature myostatin” refers to a mature, biologically active form of myostatin. In some embodiments, mature myostatin is capable of myostatin receptor binding and / or activation. Activation and release of mature myostatin in vivo from its pro myostatin form is accomplished by several discrete protease cleavage events. To begin with, “pro myostatin” is cleaved by a proprotein convertase, resulting in “latent myostatin,” in which the mature myostatin is shielded from binding to its receptors by a portion of the prodomain. Activation and release of mature myostatin is accomplished after cleavage of latent myostatin by an additional protease from the BMP / tolloid family, such as mTLL-2. As used herein, the term “mature myostatin” can refer to both full-length mature myostatin, as well as fragments of the full-length mature myostatin which retain biological activity. So-called neutralizing antibodies that bind mature myostatin thereby interfere with its ability to bind and activate its cellular receptors.

[0102]

[0090] Motor neuron therapy: “Motor neuron therapy” refers to any therapy that can partially or completely restore motor neuron function. Examples include, but are not limited to, agents that affect neurotransmitter signaling, agents that reduce oxidative stress to neurons, and neuroprotective stem cell therapy. Motor neuron therapy incudes SMN therapy.

[0103]

[0091] Motor skills'. As used herein, “motor skill,” “motor skills,” or “motor function” refer to the ability of a subject to perform one or more tasks designed to measure muscle function. Motor function includes the ability to execute purposeful and coordinated movements involving muscles, nerves, and the brain. This involves the activation of motor neurons in the spinal cord and brain, which communicate with the muscles to produce movement and control posture, balance, and coordination. Motor function may further include muscles involved in physical movement and / or essential physiological systems, e.g., the airway, bulbar functions, cervical extension (e.g., use of the musculature that allows one to look up and down), and digestion. Motor skills can be measured by a test designed to assess certain physical activities, which yields a score indicative of the level of the patient’s muscle function. For example, a subject’s motor skills can be assessed using the Hammersmith Functional Motor Scale-Expanded (HFMSE) test; the Revised Upper Limb Module (RULM) test; the Revised Hammersmith Scale (RHS) test; a Motor Function Measure (MFM) Attorney Docket No. 15094.0063-00304 test (e.g., MFM-D1 , MFM-D2, MFM-32); WHO motor development milestones; or any other known test of muscle function.

[0104]

[0092] Muscle-directed therapy. As used herein, the term “muscle-directed therapy” or “muscle-targeted therapy” refers to any therapy that acts on the muscle and / or directly restores muscle function. Examples of muscle-directed therapies include myostatin inhibitors.

[0105]

[0093] Natural history. Natural history of SMA refers to the progression of SMA in a person over time without treatment.

[0106]

[0094] Pro / latent myostatirr. As used herein, the term “pro / latent myostatin” refers to pro myostatin, latent myostatin, or both. In some embodiments, an anti-pro / latent myostatin antibody binds specifically to pro myostatin. In some embodiments, an anti-pro / latent myostatin antibody binds specifically to latent myostatin. In some embodiments, an anti-pro / latent myostatin antibody binds specifically to both latent myostatin and pro myostatin. In some embodiments, the anti-pro / latent myostatin is apitegromab and binds specifically to both latent myostatin and pro myostatin. The term “pro myostatin” (or “promyostatin”) refers to an inactive precursor of mature myostatin which comprises a disulfide-linked homodimer, each molecule of the homodimer comprising the amino terminal prodomain covalently bound to the carboxyl terminal mature myostatin domain. In some embodiments, “pro myostatin” has not been cleaved by either a proprotein convertase, or a protease from the BMP / tolloid family. Promyostatin and latent myostatin (see below) are proforms of myostatin / GDF-8. As used herein, the term “proforms of myostatin” refers to inactive (e.g., precursor or latent) forms of the myostatin growth factor that are associated with the N-terminal latency-associated peptide (LAP) domain. Proforms of myostatin are comprised of dimers. The term encompasses both “promyostatin” and “latent myostatin.” The term excludes mature growth factor (GDF8) that is not associated with the LAP domain.

[0107]

[0095] Progression-. Progression of disease (e.g., SMA) is the process of worsening of symptoms or a decline of condition over a period of time. Absent pharmacological intervention (e.g., therapy), the progression is reflected by or corresponds to the natural history of the disease observed in a particular patient population. Disease progression may be assessed by the rate at which the condition worsens, and / or, the degree to which the condition becomes worse. For instance, progression of SMA encompasses a subject with ambulatory SMA transitioning from ambulatory to non-ambulatory SMA. Accordingly, efficacy may include the ability of a drug or therapy to delay or slow the progression of disease. For example, a patient may show a decline in a motor function score over time, but administration of a treatment (e.g., apitegromab treatment) may lead to a slower rate than what would be expected based on the natural history or as compared to a subject who has not received the treatment (e.g., apitegromab treatment). Efficacy may include the ability of a drug ortherapy to reduce the degree of decline. Efficacy may include stabilization of the disease, i.e., at least a net zero change in functional parameter(s) overtime. As used herein, the term “progressive SMA” refers to SMA where at least one symptom (e.g., motor function) is worsening (i.e., in a phase of decline) over time.

[0108]

[0096] Quality of life (QoL)-. As used herein, QoL is defined by outcomes that are meaningful from the patient perspective and which measure the impact of therapies on dimensions of life other than assessing survival or significant changes in motor milestones, such as activities of daily living, work productivity and Attorney Docket No. 15094.0063-00304 fatigue. “Fatigue” is the inability to sustain repetitive physical activities. It may serve as a target for therapeutic interventions. People with SMA commonly face challenges with endurance, i.e., the ability to have and sustain energy and strength throughout the day and conduct desired activities to a desired conclusion. As used herein, fatigue encompasses muscle fatigue and fatigue caused by a metabolic disorder.

[0109]

[0097] SMN therapy / SMN-targeted therapy. In the context of the present disclosure, the term “SMN therapy” or “SMN-targeted therapy” or “SMN-directed therapy” (used interchangeably herein) refers to pharmacological agents (drugs, biologies) aimed to increase the amount or availability of the functional SMN protein in patients for purposes of treating SMA. For instance, the terms “SMN2-targeted therapy,” “SMN2 upregulator therapy,” and “SMN2-directed therapy” are used interchangeably herein.

[0110]

[0098] SMN therapy includes “SMN upregulator therapy,” which are agents that can be used to increase or improve SMN gene expression (e.g., SMN1 gene expression and / or SMN2 gene expression), and “SMN corrector agents,” which are agents that can be used to restore expression of functional SMN protein. The term “SMN upregulator therapy” encompasses an “smn2 splice modifying agent” or “smn splice modifier” which is an agent that targets certain exon(s) of the SMN2 gene to increase the availability of an at least partially functional SMN protein in the body. Examples of an SMN2 splice modifying agents include, without limitation, nusinersen and risdiplam. The term “SMN corrector therapy” encompasses “SMN gene therapy,” which overcomes SMN deficiency by delivering a fully functional SMN1 gene into the target motor neuron cells to restore SMN1 expression. An example of SMN gene therapy includes, without limitation, onasemnogene abeparvovec-xioi. In some embodiments, a “functional SMN protein” is capable of promoting motor neuron function and / or survival or partially or fully restore motor neuron function in a cell (e.g., a cell within a subject). In some embodiments, a functional SMN protein is capable of restoring at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more of the motor neuron function in a cell (e.g., a cell within a subject). In some embodiments, full-length SMN protein is the result of protein translation (e.g., in a cell) of a correctly spliced SMN mRNA. In some embodiments, a functional SMN protein is encoded from SMN2 mRNA that contains exon 7.

[0111]

[0099] Specific binding-. As used herein, the term “specific binding” or “specifically binds” means that an antibody or antigen binding portion thereof exhibits a particular affinity for a particular structure (e.g., an antigenic determinant or epitope) in an antigen (e.g., a KD measured by Biacore®). In some embodiments, an antibody or antigen binding portion thereof specifically binds to a target, e.g., pro / latent myostatin, if the antibody has a KD for the target of at least about 10-8M, 10-9M, I O-10M, 10-11M, 10-12M, or less. In the context of the present disclosure, “an antibody that specifically binds an antigen with high affinity” generally refers to a KD of 1 .0 x 10-8M or less. In some embodiments, an antibody or antigen binding portion thereof may also “selectively” (i.e., “preferentially”) bind a target antigen if it binds that target with a comparatively greater strength than the strength of binding shown to other antigens, e.g., a 10-fold, 100-fold, 1000-fold, or greater comparative affinity for a target antigen (e.g., pro / latent myostatin) than for a non-target antigen (e.g., mature myostatin (GDF-8), GDF-11 , and / or other members of the TGFp superfamily of growth factors). Attorney Docket No. 15094.0063-00304

[0112]

[0100] Steady-state’. As used herein, the term “steady-state” refers to the situation where the overall intake of a molecule (e.g., apitegromab) is fairly in dynamic equilibrium with its elimination. In some embodiments, a steady-state serum concentration of apitegromab is measured as a maximum serum concentration (i.e., Cmax) or a minimum (trough) serum concentration (i.e., Cmin or Ctrough) of the apitegromab after administration, e.g., to a human subject or to a cohort of human subjects. For example, a steady state of apitegromab may be determined using the maximum serum concentration of apitegromab or the minimum serum concentration of apitegromab in a pharmacokinetics (PK) analysis. In some embodiments, the pharmacodynamic (PD) target is latent myostatin. In some embodiments, the PD profile of apitegromab is evaluated by measuring latent myostatin concentrations in serum. In some embodiments, the PD profile of apitegromab is evaluated by measuring a serum concentration as described in Cote et al. (2020) SLAS Discovery 25:95. In some embodiments, the serum latent myostatin concentration is a steady-state concentration. In some embodiments, the serum latent myostatin concentration is measured as a pre-dose or trough concentration (i.e., Cmin or Ctrough), e.g., in a human subject or in a cohort of human subjects.

[0113]

[0101] Subject. The term “subject” in the context of therapeutic applications refers to an individual who receives or is in need of clinical care or intervention, such as treatment, diagnosis, etc. Suitable subjects include vertebrates, including but not limited to mammals (e.g., human and non-human mammals). Where the subject is a human subject, the term “patient” may be used interchangeably. In a clinical context, the term “a patient population” or “patient subpopulation” is used to referto a group of individuals that falls within a set of criteria, such as clinical criteria, medical history, health status, gender, age group, genetic criteria, and / or lifestyle factors. As used herein, a human subject, patient, or patient population refer to an SMA patient or patient population unless the context indicates otherwise.

[0114]

[0102] Target engagement. As used herein, the term “target engagement” refers to the ability of a molecule (e.g., apitegromab) to bind to its intended target in vivo (e.g., latent myostatin), e.g., in skeletal muscle. As used herein, saturation in target engagement indicates a dosage sufficient to achieve certain therapeutic effects (e.g., efficacy), although it may be possible to obtain efficacy without saturation.

[0115]

[0103] Therapeutic dose: The term “therapeutic dose” refers to an amount (e.g., of apitegromab) sufficient to achieve efficacy as determined by clinical endpoints that measure therapeutic effects (e.g., by one or more of the clinical endpoint measurements discussed herein) when administered to a patient in a particular way (e.g., using a particular dosing regimen). For example, a therapeutic dose of apitegromab, when administered intravenously every four weeks, may be greater than 2 mg / kg and up to 20 mg / kg. In certain embodiments, the therapeutic dose of apitegromab, when administered intravenously every four weeks, is 10 mg / kg or 20 mg / kg.

[0116]

[0104] Treatment. As used herein, the term “treating” or “treatment” of a disease or disorder (e.g., SMA) is meant slowing, delaying, or preventing the onset of such a disease or disorder, or reversing, alleviating, ameliorating, inhibiting, slowing down, stabilizing, or stopping the progression, aggravation or deterioration, the progression or severity of a condition associated with such a disease or disorder, e.g., as compared to a baseline in the absence of the treatment (e.g., where treatment stops disease progression observed in the absence of treatment). The term includes but does not necessarily require a complete treatment or prevention of the disease or disorder. As used herein, “treating” or “treatment” refers to the administration Attorney Docket No. 15094.0063-00304 of one or more active agents (simultaneously or sequentially), or of one or more compositions including one or more active agents, to a subject, e.g., who has SMA, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disorder, the symptom of the disease, or the predisposition toward the disease, e.g., SMA.

[0117]

[0105] Treatment emergent patient population-. The traditional classification of SMA patient populations or types (e.g., Type 0, Type 1 , Type 2, non-ambulatory Type 3, ambulatory Type 3, Type 4 etc.) is largely based on the natural history of the disease manifestation, which shows strong correlation with the number of SMN2 gene copies. Based on the traditional classification, Type 0 is the most severe form which has in utero onset with reduced or absent movements and requires mechanical ventilation at birth. With the availability of approved SMN-targeted therapies (e.g., SMN2 upregulators, SMN1 gene therapy, etc.) and newborn screening in recent years, additional classifications may be warranted to describe emerging patient populations, referred to herein as “emergent” or “treatment emergent” patient populations. In these populations, the manifestations of SMA expected based on natural history and / or genetic analysis may be altered where patients have initiated an SMN-targeted therapy at an early age before manifestation of symptoms. In other words, early intervention can impact the course of the disease progression expected from the natural history, irrespective of the disease genotype. For example, an infant with a confirmed SMN1 deletion and one copy of the SMN2 gene, who receives an early SMN therapy, may be able to sit independently at 12 months, who otherwise would have been expected to develop Type 1 SMA. An SMA patient with two copies of the SMN2 gene may be expected to develop a severe (e.g., Type 2) disease form without receiving SMN-targeted therapy, but with SMN-targeted therapy, especially with an early intervention, the clinical presentation of such a patient may resemble that of a milderdisease form. A patient with non-ambulatory Type 3 SMA (who lost the ability to walk) may regain the ability to walk, or a patient with Type 2 SMA may walk for the first time, as a result of such therapy. Likewise, a patient expected to develop non-ambulatory Type 3 SMA after 18 months of age may exhibit a retained ability to walk at a later age due to early SMN-targeted therapy yet exhibit a different phenotype (e.g., gait) and / or response to SMA treatments (Mercuri et al. (2020) Nature Reviews Neurology, 16:706-715). To accommodate changes associated with the medical advancement in SMA therapy, the field continues to evolve, including adjustments to certain nomenclature / terminology, aimed to better describe various diseases.

[0118]

[0106] Type 1 SMA'. Typically, children with Type 1 SMA rapidly decline in the natural history of the disease (Cances et al. (2022) Orphanet J Rare Dis 17:300). Early symptoms include hypotonia, small or weak muscles, difficulty in breathing, trouble swallowing, weak cough or weak cry, and inability to sit. Infants with Type 1 are very weak and unable to sit. At 5-6 months of age, patients typically require respiratory and / or nutritional support. Over 90% of patients die before their second birthday. Such patients typically have 1-2 copies of the SMN2 gene.

[0119]

[0107] Type 2 SMA: Children with Type 2 SMA are non-ambulant absent therapeutic intervention and often have three copies of the SMN2 gene and become symptomatic between 6-18 months of age. Muscle weakness is very common and affects the ability to stand or walk without assistance and typically require wheelchairs. Generally, they start losing abilities before the age of two, however, they can sit independently, maintain head control and roll over. Attorney Docket No. 15094.0063-00304

[0120]

[0108] Type 3 SMA: In Type3 SMA patients, symptoms can begin after 18 months of age, usually in early childhood, e.g., based on clinical classification and / or physical milestones such as sitting or walking. These patients often have three or four or more copies of the SMN2 gene, with the more severe form of nonambulatory Type3 SMA typically being associated with three copies of the SMN2 gene (Type 3a) and the less severe form of non-ambulatory Type3 SMA typically being associated with four copies (Type 3b). Typically, Type 3 SMA patients can at least initially walk and climb with assistance, eat with utensils and dress themselves, but they cannot generally run, jump or climb without help. They lose many motor functions as they grow older, including the ability to walk and climb. Among Type 3 patients, those who are able to walk are referred to as ambulatory Type 3 SMA, whilst those who have lost the ability to walk are referred to as non-ambulatory Type3 SMA. Type 3 patients often lose ambulation by ages 4-16, e.g., on average around age 10.

[0121]

[0109] Type 4 SMA: Type 4 SMA is a rare, adult-onset form of SMA. These patients usually have four or more copies of the SMN2 gene and usually experience only mild muscle weakness, which may start around 18 years of age, but more often later (e.g., in the 20’s or 30’s).

[0122]

[0110] As more patients gain access to treatments, e.g., SMA therapy, a patient diagnosed as having Typel , 2, 3, or 4 SMA may demonstrate clinical improvement such that their phenotype more closely resembles another SMA type. For example, a patient who, in the absence of treatment, would be categorized as a Typel SMA patient may show characteristics of a Type 2 patient and thus be “Type 2- like”; a Type 2 patient may show characteristics of a Type 3 patient and thus be “Type 3-like”; a Type 3 patient may show characteristics of a Type 4 patient and thus be “Type 4-like”. As used herein, the terms “Type 1-like”, “Type 2-like”, “Type 3-like”, and “Type 4-like” with respect to SMA categorization refer to a clinical observation, measurement, or behavior of the patient irrespective of genotype or natural course of disease in the absence of intervention.

[0123]

[0111] Untreated subject: As used herein, the term “untreated subject” refers to a subject who has not received a particular treatment but does not exclude subject show have received other treatments. The term “untreated subject” encompasses the term “a subject who has not received a treatment.” For instance, a subject who has not received apitegromab treatment refers to a subject who has not been administered a prior dose of apitegromab but does not exclude a subject who has received treatments other than apitegromab (e.g., a subject who has been administered one or more SMN-targeted therapies).

[0124]

[0112] Wearable medical device-. A wearable medical device is a device that is autonomous, noninvasive and that performs a specific medical function, e.g., monitoring or support, and is attached to the body or to clothing. Examples include, but are not limited to wearable sensor devices, electromyogram patches, etc., including Acti-Myo® and AUTOMA, a wearable device that measures upper limb muscular activity.

[0125]

[0113] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” The term “about” when used in connection with percentages can mean ±1 %. The term “about” when used in connection with numbers can mean ±0.1 or ±10% unless the context indicates otherwise. Attorney Docket No. 15094.0063-00304

[0126]

[0114] The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”

[0127]

[0115] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified unless clearly indicated to the contrary. Thus, as a non-limiting example, a reference to “A and / or B,” when used in conjunction with open-ended language such as “comprising” can refer, in some embodiments, to A without B (optionally including elements other than B); in other embodiments, to B without A (optionally including elements other than A); in yet other embodiments, to both A and B (optionally including other elements); etc.

[0128]

[0116] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in some embodiments, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in other embodiments, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet other embodiments, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0129]

[0117] Use of ordinal terms such as “first,” “second,” “third,” etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term) to distinguish the claim elements.

[0130]

[0118] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 10 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 2-8, 1-5, etc.

[0131]

[0119] All references cited herein are incorporated by reference for any purpose. Where a reference and the specification conflict, the specification will control. It is to be appreciated that certain features of the disclosed compositions and methods, which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination. Attorney Docket No. 15094.0063-00304

[0132] Spinal Muscular Atrophy (SMA)

[0133]

[0120] Spinal muscular atrophy (SMA) is a debilitating, frequently fatal neuromuscular disease and the most common genetic cause of infant mortality (Awano et al. (2014) Neurotherapeutics 11 :786-795). It is a neuromuscular disease characterized by motor neuron loss and muscle atrophy. SMA is an autosomal recessive genetic disorder involving a mutation or deletion in the survival motor neuron 1 (SMN1) gene. Specifically, SMA is caused by reductions in the level of SMN protein, sufficient amounts of which are necessary to promote survival of the anterior horn cells of the spinal cord. Loss of motor neurons results in profound muscle atrophy, often leading to death due to respiratory insufficiency (Monani (2005) Neuron 48:885-896). Muscle pathology in SMA is characterized by the presence of small atrophic fibers believed to represent denervated or partially denervated myofibers. The presence of atrophic fibers is a classic indication of motor neuron denervation caused by the loss or dysfunction of motor neurons. Unlike Duchenne muscular dystrophy (DMD) patients, SMA patients do not exhibit features of necrosis and inflammatory changes even in the most severe cases of the disease (Le Verche V. et al. Spinal Muscular Atrophy; Disease Mechanisms and Therapy 2017; Ch. 21 :341 -356).

[0134]

[0121] There have been significant advancements in the SMA treatment landscape. However, progressive muscle weakness continues to be a clinical hallmark of SMA. Regardless of disease onset and baseline functional level, progressive muscle weakness can result in motor function decline, reduced quality of life, and increased dependence of SMA patients. There are no approved treatments that directly address progressive muscle weakness in SMA.

[0135]

[0122] While SMA patients typically lack a functional SMN1 gene, the paralogous gene, SMN2, produces low levels of functional SMN protein due to alternative splicing that truncates the transcript. The development of molecular medicine techniques have advanced the diagnosis of SMA patients based on genotyping of both SMN1 and SMN2 copy numbers. SMA patients are also diagnosed based on clinical presentation and categorized phenotypically based on the maximal motor milestone achieved and the age at symptom onset. Disease-modifying drugs have altered some of the traditional diagnosis and classification. Classification may, in some embodiments, be made based on one or more of age of initiation of therapy, age of symptom onset, and / or number of SMN2 copies, e.g., separately orto refine the definition of SMA phenotypes in the clinic beyond the traditional classifications defined by age of onset and severity alone (J^drzejowska M. et al. Degener Neurol Neuromuscul Dis. 2020;10:39-47).

[0136]

[0123] In some embodiments, a patient with later-onset SMA is treated with or has received a motor neuron-directed therapy (e.g., has received such therapy before the age of 5), such as an SMN therapy. In some embodiments, a patient with later-onset SMA has at least two copies of the SMN2 gene (e.g., at least three copies or at least four copies of SMN2). In some embodiments, a patient with later-onset SMA develops diagnosable symptoms of SMA after 6 months of age. A subject with SMA may be treated before exhibiting symptoms of the disease or after onset of diagnosable symptoms.

[0137]

[0124] In some embodiments, a patient with infantile-onset SMA is treated with or has received a motor neuron-directed therapy, such as an SMN therapy. In some embodiments, a patient with infantile-onset SMA has one copy of SMN2. In some embodiments, a patient with infantile onset SMA develops diagnosable symptoms of SMA before 6 months of age. In some embodiments, a patient with infantile onset Attorney Docket No. 15094.0063-00304

[0138] SMA would have developed diagnosable symptoms before 6 months of age but does not because of treatment, e.g., with an SMN therapy. In some embodiments, these subjects are diagnosed with infantileonset SMA based on, e.g., SMN2 copy number, and are distinguished from later-onset SMA patients on the basis of other factors beyond age of disease onset, e.g., genotype (such as SMN2 copy number), phenotype (such as gait or other observed motor traits), and / or response to SMA therapy.

[0139] Attorney Docket No. 15094.0063-00304

[0140]

[0125] A summary of SMA categorization and disease characteristics is provided below.

[0141] Attorney Docket No. 15094.0063-00304

[0142] Genotype-based classifications of SMA

[0143]

[0126] The clinical heterogeneity of SMA is due in part to the complicated genetics of the disease. Mutations in the SMN1 gene result in SMA (Lefebvre et al. (1995) Cell 80:155-165); however, in humans, a nearly identical gene, SMN2, is located in close proximity to SMN1 (Monani et al. (1999) Hum Mol Genet 8:1177-1183). The primary difference between these genes is a C to T transition which creates an exonic splice silencer, resulting in removal of exon 7 from the final mRNA transcript. The truncated SMN protein is unstable and quickly degraded. Nevertheless, approximately 10% of the mRNA produced from SMN2 is correctly spliced and produces full length SMN protein, but this amount is insufficient to fully compensate for loss of SMN1.

[0144]

[0127] The copy number of SMN2 varies between individuals and strongly correlates with SMA disease severity. More copies (e.g., three or four copies) are generally associated with milder forms of SMA. SMA patients with a single SMN2 copy are rare but this copy number is highly predictive of a severe Type 1 phenotype with a poor prognosis. The majority of patients with the Type 1 form of SMA have one or two copies of SMN2; most patients with Type 2 have three SMN2 copies; and most patients with Type 3 have three or four SMN2 copies. To illustrate, according to Calucho et al. ((2018) Neuromuscular Disorders. 28:208-215 at Table 2), about 80% of Type 1 SMA patients carry one or two SMN2 copies, about 94% of Type 2 patients carry two or three copies, about 93% of Type 3 patients carry three or four copies, and nearly 100% of Type 4 patients carry four to six SMN2 copies.

[0145]

[0128] Traditional SMA classifications include Type 1 , Type 2, Type 3 and sometimes Type 4 SMA, in the order of severity. Type 1 SMA is typically diagnosed between birth and 6 months, and, without early intervention, patients never gain sufficient strength to sit independently. Without intervention, most Typel patients do not survive past two years of age without respiratory support. People with Types 2 and 3 produce greater amounts of SMN protein and have less severe, but still life-altering forms of SMA. Type 2 patients are generally diagnosed between 6 and 18 months of age. While they are able to sit unassisted, they cannot walk without aid. With Type 3 SMA, patients are typically diagnosed past the age of 18 months and are able to sit and walk unassisted, although they may become wheelchair-dependent later in life. Thus, Type 3 SMA includes both ambulatory and non-ambulatory subpopulations. Many ambulatory Type 3 SMA patients at some point transition to non-ambulatory as the disease progresses. Type 4 SMA is adult onset, mild in phenotype, and very rare.

[0146]

[0129] Although SMA stratification by type is a useful clinical paradigm, the disease phenotype exists more as a continuum than as discreet classifications. For example, patients carrying an SMA genetic mutation may also be pre-symptomatic (not manifesting obvious disease phenotypes).

[0147]

[0130] In some cases, a patient who carries a genetic mutation in the SMN gene (such as SMN1) may be phenotypically pre-symptomatic and identified for treatment on the basis of genetic screening. In some embodiments, the delay in disease manifestation may be at least in part due to an early intervention such Attorney Docket No. 15094.0063-00304 as an SMN upregulator therapy (e.g., SMN2 upregulator therapy and SMN1 gene therapy). Early intervention generally means the treatment is initiated prior to age 5, e.g., prior to age 4, age 3, age 2, age 1 , or soon after birth. Newborn genetic screening has become more widely accessible in recent years, which allows the identification of individuals born with genetic disorders, such as SMA. In the United States, for example, many states have included SMA in a panel of routine newborn screening among other known genetic disorders, which is typically conducted during the first few days of life. Therefore, babies carrying mutations in the SMN gene (SMN1) who are likely to develop the disease can be identified early, often when asymptomatic (pre-symptomatic). Early detection and diagnosis can lead to early treatment intervention, e.g., even before the child starts to develop symptoms. This may help prevent certain clinical manifestations and / or may delay the onset or progress of SMA.

[0148]

[0131] Genetic screening may be carried out in newborn / infant subjects, as well as in utero (e.g., in a fetus). In some embodiments, a subject is or has been identified as a carrier of an SMN mutation, e.g., by genetic screening either in utero or as a newborn / infant. In some embodiments, the genetic screening is carried out as a newborn / infant (e.g., within 24 hours of birth). In other embodiments, the genetic screening is carried out in utero.

[0149] Onset-based classifications of SMA

[0150]

[0132] Severe forms of SMA typically manifest early symptoms, e.g., before 6 months of age. This may be referred to as infantile-onset, as opposed to later-onset SMA. When SMA symptoms are present at birth or by the age of 6 months, the disease is also SMA Type 1 (also called infantile-onset or Werdnig-Hoffmann disease). Babies typically have generalized muscle weakness, a weak cry, and breathing distress.

[0151]

[0133] More recently, with the availability of approved SMN upregulator therapies, such as nusinersen, risdiplam, or onasemnogene abeparvovec-xioi, early intervention has been shown to be particularly effective in delaying the onset of and / or reducing the severity of more severe phenotypes of SMA based on the genotype of the particular patient. For example, some patients who were diagnosed with (or, due to a low copy number of SMN2 genes, were at risk of developing) Type 1 SMA, early intervention with SMN upregulator therapy may alter the phenotype to one that is more consistent with later-onset SMA.

[0152]

[0134] In some embodiments, symptom onset-based definition is useful to categorize certain patient populations that receive early intervention which changes the normal course or timeline of disease progression.

[0153] Targeting Myostatin to Improve Muscle Function - Myostatin Inhibition

[0154]

[0135] In some embodiments, the present disclosure encompasses the use of an agent that inhibits myostatin activation irrespective of the mechanism of action. In some embodiments, the inhibitor is a small molecule. In some embodiments, the inhibitor is an antibody or antigen-binding fragment (e.g., an adnectin such as taldefgrobep alfa). In some embodiments, the antibody is a myostatin-selective antibody, e.g., a pro / latent-myostatin selective antibody. Attorney Docket No. 15094.0063-00304

[0155]

[0136] In some embodiments, disclosed herein are antibodies capable of binding to pro myostatin and / or latent myostatin, thereby inhibiting myostatin activity, and uses thereof for treating diseases and disorders associated with muscle atrophy such as SMA.

[0156]

[0137] In some embodiments, the disclosure provides methods comprising the use of apitegromab or an antibody having the CDRs, sequences, variable domains sequences, or full-length antibody sequences provided in Tables 1-10 below.

[0157] Table 1. Amino acid sequences of Kabat CDRs for an anti-pro / latent myostatin antibody

[0158] Table 2. Amino acid sequences of IMGT CDRs for an anti-pro / latent myostatin antibody

[0159] Table 3. Amino acid sequences of variable regions for an anti-pro / latent myostatin antibody Attorney Docket No. 15094.0063-00304

[0160] Table 4. Amino acid sequences of full-length Ig chains for an anti-pro / latent myostatin antibody

[0161]

[0138] The antibodies disclosed herein may be used in any of the methods disclosed herein. In some embodiments, apitegromab comprises a heavy variable region and a light chain variable region each with a N-terminal pyroglutamic acid residue. In some embodiments, the N-terminal glutamine (Q) of the heavy chain variable region and / or light chain variable region of apitegromab may each independently cyclize or be cyclized to form a pyroglutamate.

[0162]

[0139] In some embodiments, the antibody or antigen-binding fragment thereof used in any ofthe methods disclosed herein comprises a heavy chain variable region comprising an amino acid sequence that is at least 75% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 13 and / or or a light chain variable region comprising an amino acid sequence that is at least 75% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the homologous heavy chain variable region and / or light chain variable region amino acid sequence do not vary within any of the CDR sequences provided herein. For example, in some embodiments, the degree of sequence variation (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or99%) may occur within a heavy chain variable and / or a light chain variable sequence excluding any of the CDR sequences provided herein.

[0163]

[0140] Inhibition of myostatin activation by apitegromab may lead to buildup of promyostatin and latent myostatin. Since promyostatin is predominantly found within the skeletal muscle and latent myostatin is Attorney Docket No. 15094.0063-00304 predominantly found in the serum, in some embodiments, serum latent myostatin levels may serve as a target engagement marker for apitegromab, e.g., target engagement with apitegromab in skeletal muscle. In some embodiments, serum latent myostatin levels and / or serum creatinine levels may be relatively low at baseline (i.e., prior to treatment) and increase following treatment with apitegromab. In some embodiments, an increase in serum latent myostatin and / or serum creatinine levels indicates target engagement with apitegromab, e.g., in skeletal muscle. In some embodiments, low baseline serum levels of latent myostatin and / or serum creatinine as compared to high levels following treatment indicates that a major portion of the drug target resides within skeletal muscle, rather than circulating systemically. In a similar manner, in some embodiments, serum latent myostatin levels may serve as a target engagement marker for other pro / latent myostatin antibodies such as, for example, GYM329 or an antibody or antigenbinding fragment that competes with apitegromab or GYM329 for binding in an analogous manner. In some embodiments, serum latent myostatin levels may be relatively low at baseline (i.e., prior to treatment) and increase following treatment with apitegromab. In some embodiments, an increase in serum latent myostatin levels indicates target engagement with apitegromab, e.g., target engagement with apitegromab in skeletal muscle. In some embodiments, low baseline serum levels of latent myostatin as compared to high levels following treatment indicates that a major portion of the drug target resides within skeletal muscle, rather than circulating systemically.

[0164]

[0141] In some embodiments, serum creatinine levels may serve as a target engagement marker for apitegromab. In some embodiments, serum creatinine levels may be relatively low at baseline (i.e., prior to treatment) and increase following treatment with apitegromab.

[0165]

[0142] In some embodiments, an increase in serum creatinine levels indicates target engagement with apitegromab, e.g., target engagement with apitegromab in skeletal muscle. In some embodiments, serum creatinine levels may serve as a target engagement marker for another pro / latent myostatin antibody, such as, for example, GYM329 (also referred to as RO7204239 and emugrobart) or an antibody or antigenbinding fragment that competes with apitegromab or GYM329 for antigen binding. Circulating creatine, i.e., 2-[carbamimidoyl(methyl)amino]acetic acid, is transported from the circulation into muscle where it serves as an energy storage buffer. Serum creatinine is derived from these muscle stores of creatine; creatine is converted to creatinine at a constant rate of about 1 .7% per day and released into the circulation. It is known that levels of serum creatinine correlate with muscle mass and inversely correlate with disease severity in spinal muscular atrophy (Alves et al (2019) Neurology 94:e921).

[0166]

[0143] In some embodiments, saturation in target engagement indicates a dosage sufficient to achieve certain therapeutic effects (e.g., efficacy), although it may be possible to obtain efficacy without saturation.

[0167]

[0144] In certain embodiments, the disclosure encompasses the use of an alternate anti-myostatin antibody or antigen-binding fragment, e.g., an anti-pro / latent myostatin antibody or antigen-binding fragment, e.g., a selective anti-pro / latent myostatin antibody, such as any one of the antibodies or antigenbinding fragments disclosed in PCT / JP2015 / 006323 (International Publication No. WO2016098357), the Attorney Docket No. 15094.0063-00304 content of which is hereby incorporated by reference in its entirety. A myostatin-selective inhibitor as used herein may be an alternate anti-pro / latent myostatin antibody or antigen-binding fragment as described herein, such as GYM329. In certain embodiments, the disclosure encompasses an anti-pro / latent myostatin antibody or antigen-binding fragment that is a humanized variant of MST1032-G1 m as disclosed in PCT / JP2015 / 006323. In certain embodiments, the disclosure encompasses an anti-pro / latent myostatin antibody or antigen-binding fragment comprising a heavy chain variable domain comprising three CDR sequences of HCDR1 , HCDR2, and HCDR3, and a light chain variable domain comprising three CDR sequences of LCDR1 , LCDR2, and LCDR3, wherein the heavy chain CDRs comprise the amino acid sequences of: X1X2DIS (HCDR1); IISYAGSTYYASWAKG (HCDR2; SEQ ID NO:18); GVPAYSX3GGDL (HCDR3; SEQ ID NO:19), respectively; and the light chain CDRs comprise amino acid sequences of: X4X5SQSVYX6X7NWLS (LCDR1 ; SEQ ID NO:20); WASTLAXs (LCDR2; SEQ ID NO:21); and AGGYGGGX9YA (LCDR3; SEQ ID NO:22), respectively, wherein each of X1-X9 is any amino acid residue. In certain embodiments, Xi 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; Xe is D or H; X? is N or E; Xa is S or Y; X9 is L or R. In certain embodiments, the antibody or antigen-binding fragment comprises the six CDR sequences of SEQ ID NOs:23-28; 29-34; 35-40; or 41 -46. In certain embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs:47-50. In certain embodiments, the antibody or antigen-binding fragment comprises a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs:51-54. In some embodiments, the antibody or antigen-binding fragment comprises a set of six CDRs (e.g., from the same MST1032 variant antibody) or a paired VH / VL (e.g., from the same MST1032 variant antibody) from those listed in the tables below.

[0168] Table 5. Consensus amino acid sequences of VH CDRs for an anti-pro / latent myostatin antibody or antigen-binding fragment

[0169] Table 6. Consensus amino acid sequences of VL CDRs for an anti-pro / latent myostatin antibody or antigen-binding fragment Attorney Docket No. 15094.0063-00304

[0170] Table 7. Amino acid sequences of VH CDRs for MST1032-G1m and humanized variants

[0171] Table 8. Amino acid sequences of VL CDRs for MST1032-G1m and humanized variants

[0172] Table 9. Amino acid sequences of heavy chain variable domains for MST1032-G1m and humanized variants

[0173] Table 10. Amino acid sequences of light chain variable domains for MST1032-G1m and humanized variants Attorney Docket No. 15094.0063-00304

[0174]

[0145] In certain embodiments, the disclosure encompasses the use of GYM329 or an antibody comprising any of the sequences (e.g., a set of six CDRs or a pair of variable domains) from Tables 5-10 above as an alternate anti-pro / latent myostatin antibody to treat a subject with SMA. In certain embodiments, GYM329 or an antibody comprising any of the sequences from Tables 5-10 above is used in conjunction with an SMN therapy (e.g., risdiplam, nusinersen and / or onasemnogene abeparvovec-xioi) for the treatment of SMA. In certain embodiments, GYM329 oran antibody comprising any ofthe sequences from Tables 5-10 above is used to treat an SMA subject who is ambulatory or has the ability to walk independently. In certain embodiments, GYM329 comprises a heavy chain variable domain sequence comprising the amino acid sequence of SEQ ID NO: 50 and a light chain variable domain sequence comprising the amino acid sequence of SEQ ID NO: 54. In certain embodiments, the subject has later- onset SMA. In certain embodiments, the subject has early-onset SMA. In certain embodiments, the patient has Type 2 or Type 3 SMA. In certain embodiments, the patient has ambulatory SMA. In certain embodiments, the patient has non-ambulatory SMA, e.g., non-ambulatory Type 2 and 3 SMA. In certain embodiments, the patient has non-ambulatory SMA. In certain embodiments, the subject is aged 2-10 years. In certain embodiments, the subject is aged 13-21 years. In certain embodiments, the subject is under 2 years old. In certain embodiments, the subject has been previously treated with an SMN upregulator. In certain embodiments, the subject has been previously treated with an SMN therapy, e.g., risdiplam, nusinersen and / or onasemnogene abeparvovec-xioi. In certain embodiments, the subject has not been previously treated with an SMN upregulator. In certain embodiments, GYM329 is used for the treatment of SMA in a subject who is ambulatory or has the ability to walk independently, preferably a subject aged 2-10 years, wherein the use comprises administering to the subject GYM329 in conjunction with an SMN therapy, wherein the subject has previously received at least one dose of the SMN therapy, e.g., risdiplam, nusinersen or onasemnogene abeparvovec-xioi. In certain embodiments, GYM329 is used for the treatment of SMA in a subject who is ambulatory or non-ambulatory, wherein the subject is aged up to 25 years, wherein optionally the patient is receiving an SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi). In some embodiments, the subject is able to walk or run 10 meters in less than or equal to 30 seconds and / or has a confirmed genetic diagnosis of 5q-autosomal recessive SMA and symptomatic disease. In some embodiments, the use of GYM329 or an antibody comprising any ofthe sequences from Tables 5-10 above alone or in conjunction with an SMN upregulator may lead to an improvement over the absence of treatment. The improvement may be measured by RHS and / or Motor Attorney Docket No. 15094.0063-00304

[0175] Function Measure-32 (MFM32) scores. The improvement may be in muscle mass as measured by MRI and / or Dual-Energy X-ray Absorptiometry (DXA) scans. The improvement may be in muscle strength as measured by myometry. The improvement in muscle strength measured by myometry may be an improvement in upper limb strength as measured by MyoGrip or MyoPinch. The improvement may be as assessed by the SMA Independence Scale (SMAIS). The improvement may be seen in more than one of the aforementioned metrics.

[0176]

[0146] In some embodiments, a composition comprising an anti-myostatin antibody, e.g., a selective anti- pro / latent myostatin antibody such as GYM329 or apitegromab, is used in the treatment of SMA in a patient two months of age or older, wherein optionally the treatment further comprises risdiplam (EVRYSDI®) or nusinersen. In some embodiments, GYM329 or apitegromab and risdiplam are administered to the patient as an adjunct or combination therapy. In some embodiments, GYM329 or apitegromab is administered in conjunction with an SMN therapy, e.g., nusinersen or risdiplam, e.g., administered to the patient as a combination therapy, e.g., to delay decline, stabilize, or improve motor function in patients who, based on the timeline of disease progression, may have entered the declining phase of their SMN-targeted therapy, e.g., those who have been receiving an SMN-targeted therapy for at least 40 months. In some embodiments, the patient has been on a nusinersen therapy for 40 months or longer. In some embodiments, the patient has been on a risdiplam therapy for 36 months or longer. In some embodiments, GYM329 or apitegromab is administered in conjunction with onasemnogene abeparvovec-xioi, e.g., administered to the patient as a combination therapy. In some embodiments, GYM329 or apitegromab is administered as an add-on or adjunct therapy to the patient who has been treated with (i.e., who has received) an SMN therapy (e.g., risdiplam, nusinersen, or onasemnogene abeparvovec-xioi). In some embodiments, the SMN therapy is administered as an add-on or adjunct therapy to the patient who has been treated with (i.e., who has received) GYM329 or apitegromab. In some embodiments, the patients has been administered the SMN therapy for at least eight weeks prior to receiving GYM329. In some embodiments, the patient receiving the SMN therapy receives GYM329 for at least 18 weeks, at least 24 weeks, at least 54 weeks or at least 72 weeks. In some embodiments, GYM329 or apitegromab is administered intravenously. In some embodiments, GYM329 or apitegromab is administered subcutaneously. In some embodiments, the patient is two to seven months of age, wherein optionally the patient has or is suspected to have Type 1 SMA. In some embodiments, the patient is 2 to 25 years of age, wherein optionally the patient has Type 2 or Type 3 SMA. In some embodiments, the patient is 5-10 years of age. In some embodiments, the patient is 2-4 years of age. In some embodiments, the patient is under 2 years old. In some embodiments, the patient is any age (e.g., infant, child, or adult) and has Type 1 , Type 2 or Type 3 SMA. In some embodiments, the patient is any age and has ambulatory SMA. In some embodiments, the patient is any age and has non-ambulatory SMA. In some embodiments, the motor activity of the patient is monitored by a wearable device. In an embodiment the wearable device is one or more instrumented insole. In some embodiments, motor function is measured as a change from baseline in the RHS, the MFM D1 , the MFM D2, the MFM32 or the SMA Independence Score (SMAIS) score. In Attorney Docket No. 15094.0063-00304 some embodiments, muscle strength is measured by myometry. In some embodiments, muscle wasting is monitored by MRL In some embodiments circulating myostatin levels are measured. In some embodiments, immune responses are monitored.

[0177]

[0147] In certain embodiments, the disclosure encompasses the use of taldefgrobep alfa as an alternate to an anti-pro / latent myostatin antibody to treat a subject with SMA. Taldefgrobep alfa is also known as BHV2000 or BMS-986089, which has a sequence of CAS 1580565-26-5, INN 10661 , and is an IgG (human Fc fragment) fusion protein with peptide (synthetic 17-aa linker) protein with adnectin, anti-(human GDF-8) human clone BMS-986089 fibronectin tenth Type III domain derived) dimer). In certain embodiments, taldefgrobep alfa is used in conjunction with an SMN upregulatortherapy (e.g., risdiplam, nusinersen and / or onasemnogene abeparvovec-xioi) for the treatment of SMA. In certain embodiments, taldefgrobep alfa is used to treat an SMA subject who is ambulatory or has the ability to walk independently. In certain embodiments, the subject has later-onset SMA. In certain embodiments, the subject has early-onset SMA. In certain embodiments, the patient has Type 2 or Type 3 SMA. In certain embodiments, the patient has ambulatory SMA. In certain embodiments, the patient has non-ambulatory SMA, e.g., non-ambulatory Type 2 and 3 SMA. In certain embodiments, the subject is aged 2-10 years. In certain embodiments, the subject is aged 13-21 years. In certain embodiments, the subject is under 2 years old. In certain embodiments, the subject has been previously treated with an SMN upregulator. In certain embodiments, the subject has been previously treated with risdiplam, nusinersen and / or onasemnogene abeparvovec-xioi. In certain embodiments, the subject has not been previously treated with an SMN upregulator. In certain embodiments, taldefgrobep alfa is used for the treatment of SMA in a subject who is ambulatory or has the ability to walk independently, preferably a subject aged 2-10 years, wherein the use comprises administering to the subject taldefgrobep alfa in conjunction with risdiplam, wherein the subject has previously received at least one dose of risdiplam, nusinersen or onasemnogene abeparvovec-xioi. In some embodiments, the subject is able to walk or run 10 meters in less than or equal to 30 seconds and / or has a confirmed genetic diagnosis of 5q-autosomal recessive SMA and symptomatic disease. In some embodiments, the use of taldefgrobep alfa alone or in conjunction with an SMN upregulator may lead to an improvement over the absence of treatment. The improvement may be measured by RHS and / or Motor Function Measure-32 (MFM32) scores. The improvement may be in muscle mass as measured by MRI and / or Dual-Energy X-ray Absorptiometry (DXA) scans. The improvement may be in muscle strength as measured by myometry. The improvement in muscle strength measured by myometry may be an improvement in upper limb strength as measured by MyoGrip or MyoPinch. The improvement may be as assessed by the SMA Independence Scale (SMAIS). The improvement may be seen in more than one of the aforementioned metrics.

[0178]

[0148] In some embodiments, a composition comprising an anti-myostatin antibody or antigen-binding fragment thereof, e.g., apitegromab or taldefgrobep alfa, is used in the treatment of SMA in a patient two months of age or older, wherein optionally the treatment further comprises an SMN therapy, e.g., nusinersen, risdiplam, or onasemnogene abeparvovec-xioi. In some embodiments, taldefgrobep alfa or Attorney Docket No. 15094.0063-00304 apitegromab and the SMN therapy are administered to the patient as a combination therapy. In some embodiments, taldefgrobep alfa or apitegromab is administered as an add-on or adjunct therapy to the patient who has been treated with (i.e. , who has received) an SMN therapy. In some embodiments, an SMN therapy is administered as an add-on or adjunct therapy to the patient who has been treated with (i.e., who has received) taldefgrobep alfa or apitegromab. In some embodiments, the patients has been administered an SMN therapy for at least eight weeks prior to receiving taldefgrobep alfa. In some embodiments, the patient receiving risdiplam receives taldefgrobep alfa for at least 18 weeks, at least 24 weeks, at least 12 months, or at least 24 months. In some embodiments, taldefgrobep alfa or apitegromab is administered intravenously. In some embodiments, taldefgrobep alfa or apitegromab is administered subcutaneously. In some embodiments, the patient is two to seven months of age, wherein optionally the patient has or is suspected to have Type 1 SMA. In some embodiments, the patient is 2 to 25 years of age, wherein optionally the patient has Type 2 or Type 3 SMA. In some embodiments, the patient is 5-10 years of age. In some embodiments, the patient is 2-4 years of age. In some embodiments, the patient is under 2 years old. In some embodiments, the patient is any age (e.g., infant, child, or adult) and has Type 1 , Type 2 or Type 3 SMA. In some embodiments, the patient is any age and has ambulatory SMA. In some embodiments, the patient is any age and has non-ambulatory SMA. In some embodiments, the motor activity of the patient is monitored by a wearable device. In an embodiment the wearable device is one or more instrumented insole. In some embodiments, motor function is measured as a change from baseline in the RHS, the MFM D1 , the MFM D2, the MFM32 or the SMA Independence Score (SMAIS) score. In some embodiments, muscle strength is measured by myometry. In some embodiments, muscle wasting is monitored by MRL In some embodiments circulating myostatin levels are measured. In some embodiments, immune responses are monitored.

[0179] Motor Neuron-Directed Therapies

[0180]

[0149] In some embodiments, motor neuron-directed therapies may be considered for use in the combination therapies disclosed herein, e.g., in patients who, based on the timeline of disease progression, may have entered the declining phase of their SMN-targeted therapy, e.g., those who have been receiving an SMN-targeted therapy for at least 40 months.

[0181]

[0150] As used herein, the term “motor neuron-directed therapy” refers to an agent aimed to improve (e.g., enhance or restore) neuronal function. Such therapies are useful for treating conditions that involve impaired signaling between a motor neuron and its target muscle. Specifically, motor neuron-directed therapies may be particularly useful in the treatment of conditions involving partial but not complete loss of neurons that innervate muscle. In some embodiments, a motor neuron-directed therapy is a gene therapy, a small molecule, or an antisense oligonucleotide. In some embodiments, a motor neuron-directed therapy is a “SMN upregulator.” In some embodiments, a motor neuron-directed therapy is an agent that is capable of fully restoring motor neuron function in a cell (e.g., a cell within a subject). In some embodiments, a motor neuron-directed therapy is an agent that is capable of partially restoring motor neuron function in a cell Attorney Docket No. 15094.0063-00304

[0182] (e.g., a cell within a subject). In some embodiments, a motor neuron-directed therapy is an agent that is capable of restoring at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more of the motor neuron function in a cell (e.g., a cell within a subject). A skilled artisan will understand that motor neuron function typically includes membrane excitability, axonal transport, vesicle trafficking, neurotransmitter release, mitochondrial function, and / or mitochondrial availability, and such functions are measured using assays known to those of ordinary skill in the art.

[0183]

[0151] In some embodiments, motor neuron-targeted therapy comprises a therapy that slows or halts neuronal degeneration. Such therapies are known in the context of Parkinson’s disease and Huntington’s disease. Such therapies may improve neuronal mitochondrial function, prevent protein deregulation, or reduce apoptosis. In an embodiment, a therapy that slows or halts neuronal degeneration may comprise providing progranulin (Chitramuthu et al. (2010) Molec Neurodegen 5:41) in combination with a muscle directed therapy, e.g., by providing progranulin gene therapy, e.g., with ALPHA-0602.

[0184]

[0152] In some embodiments, motor neuron-targeted therapy comprises percutaneous spinal cord stimulation. In some embodiments, the percutaneous spinal cord stimulation is combined with another motor neuron-targeted therapy, e.g., as in NCT05430113. In some embodiments, motor neuron-targeted therapy comprises a therapy that affects neurotransmitter signaling. In some embodiments, motor neuron- targeted therapy comprises a therapy that reduces oxidative stress to neurons. In some embodiments, motor neuron-targeted therapy comprises neuroprotective stem cell therapy.

[0185]

[0153] Exemplary motor neuron-directed therapies suitable for use in conjunction with apitegromab according to the present disclosure include but are not limited to SMN upregulator therapies (also referred to as SMN corrector therapies). Exemplary motor neuron-directed therapies include “SMN upregulators” such as splice modifiers, SMN gene replacement or gene therapy, SMN transcription enhancers, SMN protein translation enhancers, and SMN protein stabilizers further discussed below. The terms “splice corrector,” “splice modulator,” and “splice modifier,” as used herein, are interchangeable and refer to an agent that corrects aberrant splicing of RNA transcripts, such as those encoded by the SMN2 gene and / or modulates expression of an SMN protein. In some embodiments, SMN2 splice correctors increase the inclusion of exon 7 in the SMN2 pre-mRNA. In some embodiments, increased inclusion of exon 7 in the SMN2 pre-mRNA leads to increased expression of a functional SMN protein (e.g., from an SMN2 gene) in a cell or subject, such as an SMN protein that is capable of promoting neuron function and / or survival.

[0186]

[0154] In some embodiments, an SMN upregulator is an agent, for example, a small molecule or an oligonucleotide (e.g., an antisense oligonucleotide), that increases expression of a functional SMN protein, for example, by promoting the inclusion of exon 7 in an SMN2 mRNA transcript. In some embodiments, the cell is a cell within a subject, for example, a subject that is administered an SMN upregulator. In some embodiments, an SMN upregulator increases the relative amount of SMN2 mRNA that includes exon 7 as compared to SMN2 mRNA that does not include exon 7 in a cell, for example, a cell in a subject. In some embodiments, an “effective amount” of an SMN upregulator increases the amount of correctly spliced SMN2 Attorney Docket No. 15094.0063-00304 mRNA in a cell (e.g., a cell within a 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 SMN2 mRNA within a cell contains exon 7. In some embodiments, an “effective amount” of an SMN upregulator increases a level of SMN2 mRNA containing exon 7 in a subject by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or more. In some embodiments, an “effective amount” of an SMN upregulator increases a level of functional SMN protein in a subject by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or more.

[0187]

[0155] Novartis and PTC Therapeutics / Roche have both developed small molecules which selectively enhance SMN2 exon 7 inclusion, resulting in increased full-length SMN protein levels and therapeutic efficacy in mouse models of SMA (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 1 1 :511 -517; Ratni et al. (2016) J Med Chem 59:6086-6100). For example, risdiplam (formerly known as R07034067, CAS# 1825352-65-5) marketed by Roche underthe brand name EVRYSDI®, was the first oral medication approved to treat SMA. Branaplam (formerly known as LMI070 and NVS-SM1) is being studied in a Phase 1 / 2 multi-part first-in- human open label clinical study for infants with Type 1 SMA (see U.S. clinical trial NCT02268552, Novartis).

[0188]

[0156] Oral dosing of SMN-C2 (an analog of risdiplam, CAS# 1446311 -56-3), and SMN-C3 (CAS# 1449597-34-5) in mild and severe preclinical models of SMA showed that the compounds increased SMN protein levels in both brain and muscle tissues in treated mice, as compared to vehicle. The molecules also efficiently crossed the blood brain barrier (BBB). In the severe SMA mouse model, both compounds showed initial promise, yet the clinical programs were paused.

[0189]

[0157] Additional small molecule based SMN2 splice correctors are described in, for example, U.S. Patent Publication No. US 2009 / 0031435 and U.S. Patent No. 8,399,437; the contents of each are incorporated by reference herein in their entirety. It should be appreciated, however, that other small molecule splice correctors including SMN2 splice correctors known in the art, e.g., risdiplam, and would be apparent to the skilled artisan, are within the scope of this disclosure.

[0190]

[0158] In some embodiments, an SMN upregulator is an oligonucleotide molecule. In some embodiments, an SMN upregulator is an antisense molecule. In some embodiments, an SMN upregulator is an antisense molecule that increases expression of an SMN2 gene. In some embodiments, an SMN upregulator is an antisense molecule that increases expression of an SMN2 mRNA that contains exon 7. In some embodiments, an SMN upregulator is an antisense molecule that increases expression of functional SMN protein, for example, SMN protein encoded by SMN2 mRNA that contains exon 7. For example, antisense oligonucleotides directed to inhibit an intronic splice silencer site (ISS) in intron 7 of the SMN2 gene can modulate pre-mRNA processing, leading to a greater probability of exon 7 inclusion within the mature mRNA transcript of SMN2, resulting in the increased production of functional SMN protein. Attorney Docket No. 15094.0063-00304

[0191]

[0159] In some embodiments, antisense oligonucleotides (ASO) block an SMN2 intronic splicing silencer thus increasing exon 7 inclusion, again rescuing disease in mouse models of SMA (Hua et al. (2010) Genes Dev 24:1634-1644; Hua et al. (2011) Nature 478:123-126; Passini et al. (201 1) Sci Transl Med 3:72ra18). Biogen / lonis have developed nusinersen, an ASO splice modifier which shows clinical efficacy and was approved by the FDA for the treatment of SMA in pediatric and adult patients 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, each administration of nusinersen requires intrathecal delivery under general anesthesia. Additionally, while the antisense corrector nusinersen has proven promising, clinical efficacy appears modest: 60% of patients among infantile-onset SMA (Type I) are reported to be non-responders, and 43% of nusinersen-treated patients did not attain > 3-point increase as measured by HFMSE, while mean increase was less than six points in the treated patient group, as compared to placebo. Thus, only a partial improvement is achieved by nusinersen treatment.

[0192]

[0160] While these ASO treatments have shown efficacy preclinically, and nusinersen or clinically, none offers a complete cure for the disease. In mouse models, while both the small molecule and ASO splice modifiers significantly reduce disease severity, treated animals nevertheless have deficits in longevity, body weight, muscle mass, and muscle function compared to healthy animals (Hua et al. (2011) Nature 478:123- 126; Feng et al. (2016) Hum Mol Genet 25:964-975). In a double-blinded clinical trial in infantile-onset SMA, nusinersen resulted in clinically meaningful benefits at the time of interim analysis (41 % of treated versus 0% placebo had improvements in motor milestones using the Hammersmith Infant Neurological Examination). The motor function milestones reached are impressive for Type I patients, with five of 81 treated patients able to sit unaided (a milestone almost never reached in these patients). Nevertheless, these patients have not achieved the full range of developmental milestones, and in a normal individual the achieved milestones would be considered disappointing. In a second placebo-controlled trial in Type 2 SMA, nusinersen again showed clinically meaningful improvements, with scores on the HFMSE increasing by 5.9 points relative to the placebo group. Note that the maximum score on the HFMSE is 66 points, with most Type 2 patients scoring below 20 (Glanzman et al. (201 1) J Child Neurol 26:1499-1507; Kaufmann et al. (2011 ) Arch Neurol 68:779-786). Nevertheless, 43% of patients failed to achieve at least a 3-point improvement in motor function in this trial. These results indicate that, while SMN2 splice modulators have potential for significant effects on SMA disease course, additional functional gains are needed to further improve reduce disease burden.

[0193]

[0161] In some embodiments, an SMN upregulator is a gene therapy. As used herein, the term “gene therapy” refers to any procedure that uses nucleic acids to heal, cure, or otherwise improve a condition in a subject. In gene therapy, nucleic acids are delivered into specific cells. Delivery methods include viral and non-viral means, which are known in the art. See, for example, Patil et al. (2005) AAPS J. 7(1): E61 -E77; Gascon et al., Non-Viral Delivery Systems in Gene Therapy (2013); Somiari et al. (2000) Molecular Therapy, 2(3):178-187; Herweijer and Wolff (2003) Gene Therapy 10(6):453-458; Nayerossadat et al. Attorney Docket No. 15094.0063-00304

[0194] (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 can carry a therapeutic genetic payload and have been reprogrammed to allow for infection and subsequent transmittal of said payload into specific tissues without the side effects typically associated with wild-type viral infection. A number of viruses can be used as viral vectors, including retroviruses, adenoviruses, herpes simplex virus, lentiviruses, Poxvirus, and Epstein-Barr virus. While safer than wild-type viruses, viral vectors may induce an immune response, occasionally necessitating the use of non-viral delivery methods. In some embodiments, the viral vector is an AAV viral vector. Non-viral 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.

[0195]

[0162] SMN1 gene replacement therapy using adeno-associated viral vectors (AAV) has shown benefit in treatment of SMA; ZOLGENSMA® (onasemnogene abeparvovec-xioi, formerly known as AVXS-101), an AAV9-SMN1 vector from Novartis Gene Therapies (formerly AveXis), has been approved in the U.S. by the FDA for treatment of the treatment of pediatric patients less than two years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene. ANB-004, an AAV9- SMN1 vector from Biocad (WO 2022 / 164351), is in a Phase 1 / 2 clinical trial directed to symptomatic infants with SMA who are under 6 months of age.

[0196]

[0163] In some embodiments, the gene therapy comprises introduction of one or more transgenes into the patient. In some embodiments, gene transfer is achieved by the use of a suitable vector, such as viral vectors and lipid-based carriers. For viral-vector-mediated gene delivery, the gene therapy may involve the use of a particular serotype for an initial treatment, followed by a different serotype for the subsequent treatment, in order to minimize adverse immune responses in the subject. In some embodiments, the gene therapy involves targeted genome editing, such as the CRISPR / Cas9 technology or variant thereof. Nonlimiting examples of SMN upregulators suitable for use in conjunction with apitegromab according to the present disclosure include but are not limited to: nusinersen; risdiplam; and onasemnogene abeparvovec- xioi. Nusinersen is an SMN2-directed antisense oligonucleotide (ASO) designed to treat SMA caused by mutations that lead to SMN protein deficiency. See, e.g., Darras et.al. (2019) Neurology. 92(21) e2492- e2506; Mercuri et.al. (2018) N Engl J Med. 378:625-635. Risdiplam works in a similar way and is a pyridazine derivative that modifies the splicing ofSMN2 messenger RNA. See, e.g., 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-xioi is a recombinant adeno-associated virus vector 9-based gene therapy designed to deliver a copy of the gene encoding the human SMN protein.

[0197] Clinical Benefits of SMN Therapies

[0198]

[0164] Based on the natural history (i.e., are untreated) of non-ambulatory later-onset SMA patients who are five years or older, mean HFMSE scores are expected to decline over a 12-month period, with fewer Attorney Docket No. 15094.0063-00304 than 5% showing a 3-point or greater increase (Mercuri et al. (2016) Neuromuscul Disord. 26(2): 126-131). Natural history data from a longitudinal study in patients with ambulatory Type 3 SMA offer additional insights. These patients commonly experience motor function declines, which in some cases are severe, e.g., loss of ambulation (Coratti et al. (2020) American Neurology Association, 88:1109-1117, e.g., at Fig. 1). In this study of 130 subjects with a mean age of 10.05 and a mean HFMSE score of 52.81 at baseline, at 12 months the mean change in HFMSE from baseline was -0.79 points and 11 patients had lost ambulation (mean age of ambulation loss was 10.21 years (SD±6.43)). Until seven years ofage the subjects were relatively stable, showing modest functional improvement prior to the steeper decline observed in subsequent years.

[0199]

[0165] Among non-ambulatory later-onset SMA patients who are five years or older, based on the natural history of this patient population, mean HFMSE scores are expected to decline over a 12-month period, with few patients (e.g., less than 5%) showing a 3-point or greater increase in HFMSE score (Mercuri et al. (2016) Neuromuscul Disord. 26(2):126-131 ). Among Type 2 and Type 3 SMA patients who were not receiving a disease-modifying therapy, the natural history over 24 months showed declines in both upper limb strength and 32-item Motor Function Measure (MFM32) scores (Annoussamy et al. (2020) Annals of Clinical and Translational Neurology 8:359-373).

[0200]

[0166] Against this background, nusinersen has been reported to provide limited clinical benefits in patients who started the therapy at age five or older, e.g., as shown in FIG. 1. More specifically, in the CHERISH study, in patients who started on nusinersen at age five or older, there was a mean HFMSE decline of >0.5 points after 15 months of nusinersen treatment, and <15% of the patients showed a 3-point or greater increase in HFMSE score over that period (Mercuri et.al. (2018) N Engl J Med. 378:625-635, e.g., at Figure 2A). These patients were further observed beyond the 15 months in the earlier study. In the CHERISH trial, the majority of patients in this age range do not experience HFMSE improvements and rarely achieve a 3+ point increase. In the SUNFISH study, MFM was the primary endpoint for assessing risdiplam. HFMSE was a secondary endpoint. This third-party information is provided for background only and is not intended to convey or imply a comparison to the TOPAZ clinical trial results.

[0201]

[0167] Nusinersen treatment was shown to improve motor function during the first year of treatment and then plateau. In the initial CHERISH and subsequent SHINE trials, subjects achieved a 3.9-point increase in HFMSE score from baseline after the first 450 days of nusinersen treatment (mean ± SE) and a 4.6-point increase from baseline after 1650 days of treatment (mean ± SE). Thus, after approximately the first year of treatment, nusinersen provided less than one point improvement in HFMSE over the long term (Mercuri et aL, presented at World Muscle Society Congress 2020, p. 257).

[0202]

[0168] Disease burden persists in SMA patients despite current SMN targeted therapies. Treatments with SMN-targeted therapies plateau and then decline over time. For instance, as shown in FIG. 1 , HFMSE scores improved during the first year of nusinersen treatment, then appeared to remain steady for at least Attorney Docket No. 15094.0063-00304

[0203] 42 months of treatment (Mercuri et al. (2020), presented at World Muscle Society Congress, p. 257). Likewise, as shown in FIG. 1 , HFMSE scores also improved during the first year of risdiplam treatment, then appeared to remain steady for at least 24 months of treatment before declining (Oskoui et al (2021) presented at Muscular Dystrophy Association Clinical and Scientific Conference, poster 80). The improvements shown with nusinersen were dependent upon the age at which the subjects first began receiving nusinersen; the youngest subjects showed improvement in HFMSE scores that was sustained after the first year of treatment, however; the older subjects who began nusinersen treatment between the ages of 5.0 and 9.5 years lost the initial improvements between 12 and 36 months of treatment (Mueller- Felber et al (2020) presented at Eur. Acad. Neurol 6thCongress).

[0204]

[0169] After the plateau in improvement of motor function, however, there is a decrease in the motor function of subjects being administered nusinersen for about 40 months. FIG. 2 shows representative data of the decrease in motor function of subjects treated with nusinersen (adapted from Finkel RS et al. (2024), Presented at Cure SMA Annual Conference; patient age based on those received active treatment (mean or median)). This demonstrates a role for adjunct therapies to be used with nusinersen and risdiplam given the latters’ limited long-term efficacy. The progressive decline in motor function of patients on these SMN- targeted therapies indicate the potential value for a muscle-directed therapy to be used as an adjunct to a background SMN-targeted therapy. Indeed, as shown in the SAPPHIRE trial, apitegromab not only delayed decline, but even stabilized or improved motor function during a period in the time course of the disease in which those treated with just SMN-targeted therapy did not see a similar benefit. It is known that limitations in mobility persist after SMN-targeted therapy (Darras et al. (2019) Neurology 92(21):e2492-e2506). Furthermore, limitations in mobility and daily activities continue and are associated with a gradual deterioration in motor function ((Yang et al. (2022) Adv Ther 39:1915; Wan et al. (2020) Orphanet J Rare Dis 15:70).

[0205]

[0170] A study reporting the efficacy and safety of risdiplam in Type 2 and non-ambulant Type 3 SMA patients after 24 months of treatment (SUNFISH) showed no improvement in the 32-item Motor Function Movement outcome (MFM32) between 12 and 24 months (Oskoui et al. (2023) J. Neurol. https: / / doi.org / 10.1007 / s00415-023-11560-1). The MFM32 mean change in baseline was 1.7 points at 12 months ((0.8-2.5; 95% Cl) and 1.8 points at 24 months (0.7-2.9; 95% Cl). Nusinersen and risdiplam data consistently show that unless initiated early in life, treatment with SMN therapy results in an initial period of improvement followed by disease stabilization, with limited or no continuous improvement (Mercuri et al. (2018) N Engl J Med 378(7):625-635; Mercuri et al. (2020) 2ndInt’l Sci Clin Cong SMA). Thus, long-term treatment with an SMN-targeted therapy appears to initially improve, then stabilize the disease, e.g., it may prevent further loss of motor function. There continues to be a need for additional therapies that improve motor function in patients treated with SMN-targeted therapies (Mercuri et al. SUNFISH Part 2, presented at Amer Acad Neurol 2020). Attorney Docket No. 15094.0063-00304

[0206]

[0171] In some embodiments, the present disclosure provides a composition comprising apitegromab for use in the treatment of spinal muscular atrophy (SMA) in a subject in need thereof, wherein the treatment comprises intravenously administering to the subject 10 mg / kg to 20 mg / kg of apitegromab at an interval of once every four weeks for at least 52 weeks, optionally wherein the treatment: a) stabilize or delay disease progression in a subject at 52 weeks as compared to a subject who has not received apitegromab; b) improve motor function in a subject at 52 weeks as compared to baseline; or c) improve quality of life at 52 weeks as compared to baseline. In some embodiments, the delay of disease progression comprises a delay in the subject’s loss of motor function as compared to a subject who has not received apitegromab. In some embodiments, the delay in disease progression comprises a reduced rate of decline in the subject’s HFMSE score as compared to a subject who has not received apitegromab. In some embodiments, the treatment reduces the rate of decline in the subject’s HFMSE score by at least about 1 point per year (e.g., at least about 1 point per year, at least about 2 points per year, or at least 3 points per year) as compared to a subject who has not received apitegromab. In some embodiments, the treatment stabilizes the subject’s HFMSE score for at least 12 months or 52 weeks. In some embodiments, the delay of disease progression comprises a delay in the subject’s need for respiratory aid or intervention as compared to a subject who has not received apitegromab. In some embodiments, the subject has ambulatory SMA, and wherein the treatment results in a delay in progressing from ambulatory SMA to non-ambulatory SMA as compared to a subject who has not received apitegromab.

[0207]

[0172] In some embodiments, the improvement in motor function comprises an increase in an HFMSE score of the subject by at least about 2 points, e.g., by at least 2 points or at least 3 points, e.g., by 1.8 points, as determined at 52 weeks or 12 months of apitegromab treatment as compared to baseline. In some embodiments, the improvement in the subject’s HFMSE score or RULM score is observed at 8 weeks or 2 months after starting the apitegromab treatment. In some embodiments, the improvement in the subject’s HFMSE score or RULM score is maintained at 52 weeks or 12 months of apitegromab treatment. In some embodiments, the improvement in motor function comprises an increase in a number of World Health Organization (WHO) motor developmental milestones attained by the subject as determined at 52 weeks or 12 months of apitegromab treatment as compared to baseline.

[0208]

[0173] In some embodiments, the improvement in motor function is measured using Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), Hammersmith Infant Neurological Examination 2 (HINE-2), and / or Bayley Scales of Infant and Toddler Development (Fourth Edition) (BSID-4) Gross Motor Subscale (GMS). In some embodiments, the improvement in motor function is evaluated by the change from baseline in raw score of BSID-4 GMS after 12 weeks (e.g., after 12 weeks, after 24 weeks, after 36 weeks, after 48 weeks, after 52 weeks, after 96 weeks, after 104 weeks) of apitegromab administration. In some embodiments, the improvement in motor function is evaluated by the change from baseline in raw score of BSID-4 GMS after 48 weeks of apitegromab administration. Attorney Docket No. 15094.0063-00304

[0209]

[0174] In some embodiments, the improvement in quality of life comprises an increase in a Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) score as determined at 52 weeks or 12 months of apitegromab treatment as compared to baseline, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528). In some embodiments, the improvement in quality of life comprises a reduced level of fatigue severity at 52 weeks or 12 months of apitegromab treatment as compared to baseline and / or compared to a subject who has not received apitegromab, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528), wherein, optionally, the level of fatigue severity is determined by a Patient Reported Outcomes Measurement Information System (PROMIS) score of the subject.

[0210]

[0175] In some embodiments, the apitegromab treatment comprises administering an amount of apitegromab sufficient to achieve one or more (e.g., all) of the following in the subject at 52 weeks or 12 months after starting apitegromab administration: a) an increase in HFMSE score of at least about 1 point as compared to baseline; b) an increase in RULM score as compared to baseline; c) additional WHO motor milestones as compared to baseline; d) an increase in PEDI-CAT score as compared to baseline; e) an increase in PROMIS score as compared to baseline; and f) a reduction in a rate of decline in the subject’s HFMSE score as compared to a subject who has not received apitegromab, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528).

[0211] Add-On / Adjunct Therapy, Combination Therapy

[0212]

[0176] The present disclosure includes add-on therapy (also referred to as adjunct therapy) and combination therapy that comprise a first agent which is a motor neuron-directed therapy (e.g., SMN therapy) and a second agent which is a muscle-directed therapy (e.g., myostatin inhibitor, e.g., apitegromab) aimed to treat SMA in patients. The two agents are used in conjunction with each other to enhance therapeutic effects. Add-on or adjunct therapy means that therapy is administered to a patient who is on a background therapy. For example, the muscle-directed therapy such as apitegromab may be administered to SMA patients who are already receiving an SMN therapy. In comparison, a combination therapy refers to the administration of both therapies to a patient as part of a coordinated or predetermined therapeutic regimen by a physician or a team of physicians. Combinations and add-on therapy may be administered separately or in the same setting, e.g., during the same clinical visit.

[0213]

[0177] In various embodiments, the present disclosure provides use of an anti-pro / latent myostatin antibody (e.g., apitegromab) for the treatment of SMA in patients who also receive a therapy to address the motor neuron defect, such as a motor neuron-directed therapy, e.g., an SMN therapy, e.g., an SMN upregulator. The present disclosure encompasses methods for treating SMA in a subject who is treated with an SMN upregulator, comprising administration of an anti-pro / latent myostatin antibody. In various embodiments, the anti-pro / latent myostatin antibody is apitegromab.

[0214]

[0178] In various embodiments, the present disclosure provides use of an anti-latent myostatin antibody (e.g., GYM329) for the treatment of SMA in patients who also receive a therapy to address the motor neuron defect, such as a motor neuron-directed therapy, e.g., an SMN upregulator. The present disclosure Attorney Docket No. 15094.0063-00304 encompasses methods for treating SMA in a subject who is treated with an SMN upregulator, comprising administration of an anti-latent myostatin antibody. In various embodiments, the anti-pro / latent myostatin antibody is GYM329.

[0215]

[0179] In some embodiments, apitegromab used in conjunction with an SMN therapy provides additive clinical benefits. As observed overthe first 12 months of the TOPAZ study (NCT03921528), motor function improvements occurred earlier in the subjects receiving high dose apitegromab than in those receiving the low dose, indicating that the observed motor function increases were above and beyond the standard of care, in this case, nusinersen treatment, and are attributable to apitegromab. Furthermore, a scatter plot analysis comparing the duration of previous nusinersen treatment to gains in motor function measured by HFMSE in non-ambulatory Type 2 and 3 subjects after 12 months of apitegromab treatment demonstrated that there was no correlation between gains in motor function and duration of nusinersen treatment. In some embodiments, apitegromab used in conjunction with an SMN therapy provides synergistic clinical benefits. “Synergistic” means that when the two agents are used in conjunction with each other, either as add-on therapy or combination therapy, they together achieve efficacy that is greater than the sum of effects obtained by monotherapy of each.

[0216]

[0180] Apitegromab may be administered to SMA patients who are either responders, poor responders, or non-responders of an SMN upregulator therapy. For poor responders or non-responders, concurrent inhibition of myostatin signaling may improve neuromuscular signaling due in part to enhanced muscle function, thereby rendering the innervating motor neurons of non-responders more responsive to the SMN upregulator. Without wishing to be bound by particular theory, it is contemplated that enhancement of the muscle component may affect the neuronal component by positive feedback, and vice versa, due to the bidirectional nature of neuromuscular signaling.

[0217]

[0181] Although SMN upregulator poor responders and / or non-responders may nevertheless benefit from myostatin inhibition, an exemplary patient population includes those who are responders of an SMN upregulator. It is contemplated that motor function in these individuals may be further improved by a myostatin inhibition therapy such as apitegromab used in conjunction with a motor neuron-directed therapy, such as an SMN upregulator therapy.

[0218]

[0182] The phrase “in conjunction with,” in the context of treatment regimens for SMA that comprise two or more therapeutic agents (e.g., apitegromab used in conjunction with an SMN upregulator therapy), means that therapeutic effects of a first therapy overlaps temporally and / or spatially with therapeutic effects of a second and / or additional therapy in the subject receiving the two or more therapies. The two or more therapies need not be administered as a single formulation, nor do they have to be administered concurrently, nor via the same route. The first, second, and / or additional compositions may be administered concurrently (e.g., simultaneously), separately, or sequentially. Thus, the two or more therapies may be formulated as a single formulation for concurrent administration, or as separate formulations, for sequential, concurrent, or simultaneous administration of the therapies. When a subject who has been treated with a Attorney Docket No. 15094.0063-00304 first therapy to treat SMA (e.g., apitegromab) is administered with a second and additional therapies to treat the SMA (e.g., an SMN upregulator therapy), the second and additional therapies may be referred to as an “add-on" therapy (i.e., “adjunct” or “adjunctive" therapy).

[0219]

[0183] In some embodiments, the treatment regimens described herein that comprise two or more therapeutic agents (e.g., apitegromab used in conjunction with an SMN-targeted therapy such as an upregulator therapy) achieve improved clinical benefits in patients as compared to a monotherapy using each agent alone. Specifically, targeting affected muscles with a myostatin inhibition therapy such as apitegromab, in conjunction with a motor neuron-directed therapy such as an SMN upregulator therapy, may produce a beneficial clinical outcome relative to the myostatin inhibition therapy or motor neuron- directed therapy alone. Such effects may be additive or synergistic as compared to the respective monotherapies. In some embodiments, the effects of combining the two or more therapies are additive, i.e., the effects of the therapies used together are equal or about equal to the sum of the effects of the therapies when used independently. In some embodiments, the effects of combining the two or more therapies are synergistic, i.e., super-additive, i.e., the effects of the therapies used together are greater than the sum of the effects of the therapies when used independently.

[0220]

[0184] In some embodiments, one or more beneficial therapeutic effects of using apitegromab in conjunction with an SMN upregulator therapy (e.g., an effect on at least one symptom or the risk / rate of disease progression) is / are additive. In some embodiments, one or more beneficial therapeutic effects of using apitegromab in conjunction with an SMN upregulator therapy (e.g., an effect on at least one symptom or the risk / rate of disease progression) is / are synergistic. In some embodiments, apitegromab used in conjunction with an SMN upregulator therapy has a combined effect that is additive, synergistic, and / or provides one or more additional combination benefits. In some embodiments, apitegromab used in conjunction with an SMN upregulator therapy provides additive or synergistic effects on at least one efficacy parameter for SMA (e.g., an HFMSE score or an RULM score). In some embodiments, apitegromab used in conjunction with an SMN upregulator therapy provides additive or synergistic effects on an HFMSE score in a SMA patient and / or an SMA patient population. In some embodiments, apitegromab used in conjunction with an SMN upregulator therapy provides further increases in the HFMSE score, as compared to treatment with an SMN upregulator therapy alone (see, e.g., Example 1 and Darras et.al. (2019) Neurology. 92(21) e2492-e2506). In some embodiments, the further improvements in HFMSE score are additive. In some embodiments, the further improvements in HFMSE score are synergistic. In some embodiments, apitegromab used in conjunction with an SMN therapy provides additive or synergistic effects on an RULM score in a SMA patient and / or an SMA patient population. In some embodiments, apitegromab used in conjunction with an SMN therapy provides further increases in an RULM score, as compared to treatment with an SMN therapy alone. In some embodiments, the further improvements in RULM score are additive. In some embodiments, the further improvements in RULM score are synergistic. In some embodiments, apitegromab used in conjunction with an SMN therapy provides additive or synergistic effects on an RULM score in an SMA patient over at least 36 months, wherein, optionally, the combination therapy improves the Attorney Docket No. 15094.0063-00304

[0221] RULM score over 36 months or the combination therapy maintains an increase in RULM score over 36 months. In some embodiments, apitegromab used in conjunction with an SMN therapy provides additive or synergistic effects on an RULM score in an SMA patient over at least 48 months, wherein, optionally, the combination therapy improves the RULM score over 48 months or the combination therapy maintains an increase in RULM score over 48 months.

[0222]

[0185] In some embodiments, the apitegromab treatment is administered in conjunction with nusinersen, risdiplam, or onasemnogene abeparvovec-xioi. In some embodiments, the apitegromab is administered in conjunction with nusinersen. In some embodiments, the apitegromab is administered in conjunction with risdiplam. In some embodiments, the apitegromab is administered after an earlier administration of onasemnogene abeparvovec-xioi.

[0223] Patient Selection

[0224]

[0186] The disclosure includes identification or selection of suitable human subjects to be treated with a selective myostatin inhibitor, such as apitegromab. Suitable human subjects are patients who are likely to benefit from apitegromab therapy, either as monotherapy or in conjunction with (or in combination with) another therapy.

[0225]

[0187] In some embodiments, a patient or patient population is an early- or infantile-onset SMA patient or patient population. In some embodiments, a patient or patient population is a later-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-ambulatory Type 3 SMA patient or patient population. In some embodiments, a patient or patient population is an ambulatory patient or patient population. In some embodiments, a patient or patient population is an ambulatory Type 2 SMA patient or patient population. In some embodiments, a patient or patient population is an ambulatory Type 3 SMA patient or patient population. In some embodiments, a patient or patient population is an ambulatory later-onset SMA patient or patient population. In some embodiments, a patient or patient population is a non-ambulatory patient or patient population. In some embodiments, a patient or patient population is patient or patient population who has declining motor function prior to treatment with a selective myostatin inhibitor such as apitegromab. In some embodiments, a patient or patient population is a patient or patient population who has progressive SMA. In some embodiments, a patient or patient population is a presymptomatic or asymptomatic patient or patient population. In some embodiments, a patient or patient population is a symptomatic patient or patient population. In some embodiments, a patient or patient population has been diagnosed with 5q SMA.

[0226]

[0188] In some embodiments, the patient is at least 2 years of age. In some embodiments, the patient is 1-5 years of age. In some embodiments, the patient is older than 5 years of age. In some embodiments, the subject is 2-12 years of age. In some embodiments, the subject is 2-12 years of age and has Type 2 SMA. In some embodiments, the subject is 13-21 years of age. In some embodiments, the subject is 13- Attorney Docket No. 15094.0063-00304

[0227] 21 years of age and has Type 2 SMA. In some embodiments, the subject is 12-21 years of age and has Type 3 SMA.

[0228]

[0189] It is known that SMN2 copy number correlates with SMN onset and severity. In some embodiments, the subject has an undetermined number SMN2 gene copy number. Patients with three copies of SMN2 may develop SMA types 1 , 2 or 3, but the presence of three copies is 54% predictive of intermediate-severity SMA type 2 with onset between 7 months and 18 months of age, 15% predictive of type 1 and 31 % predictive of the milder type 3 phenotype (Strauss et al. (2022) Nat Med 28:1390-1397). In some embodiments, the subject has at least 2 copies of SMN2. In some embodiments, the subject has 2- 5 copies of SMN2. In some embodiments, the subject has 5 copies of SMN2. In some embodiments, the subject has 2-4 copies of SMN2. In some embodiments, the subject has 2 copies of SMN2. In some embodiments, the subject has 3 copies of SMN2. In some embodiments, the subject has 4 copies of SMN2. In some embodiments, the subject has 5 copies of SMN2.

[0229]

[0190] SMA patients who are likely to benefit from such therapy include those who meet one or more of the following criteria: has a documented diagnosis of 5q SMA and later-onset (e.g., Type 2 or 3) SMA prior to receiving a therapy for SMA; a non-ambulatory subject who is able to sit independently per WHO motor milestones definition; an ambulatory subject who is able to independently ambulate without aids over 10 meters in 30 seconds or less; a subject having an RHS score of less than or equal to 63 and / or an HFMSE score of 10 or greater (e.g., having an HFMSE score >10 and <45 at screening); a subject who does not use tracheostomy with positive pressure or chronic daytime non-invasive ventilatory support for greater than 16 hours daily within two weeks prior to treatment; a subject who does not have any acute or comorbid condition interfering with the well-being of the subject within two weeks prior to treatment; a subject who does not have severe scoliosis or contractures; a subject who has progressive SMA; and / or a subject who does not use systemic corticosteroids, valproic acid, or therapies with potential muscular or neuromuscular effects within 60 days except approved SMN up-regulator (also known as SMN corrector) therapy. Therapies with potential muscular or neuromuscular effects include androgens, insulin-like growth factor, growth hormone, systemic beta-agonist, botulinum toxin, muscle relaxants, muscle enhancing supplements or acetylcholinesterase inhibitors. In some embodiments, the patient has a documented diagnosis of 5q SMA and later-onset (e.g., Type 2 or 3) SMA prior to receiving a therapy for SMA and meets one or more of the additional criteria listed above. In some embodiments, there is a positive correlation between age- normalized change in motor function and age-normalized fold change in latent myostatin levels, e.g., in patients with Type 2 SMA. In various embodiments, the methods disclosed herein include the selection of such a patient or patient population(s) for treatment with a myostatin inhibitor, such as apitegromab, e.g., according to a dosage or regimen disclosed herein.

[0230]

[0191] In some embodiments, the patient has a documented diagnosis of 5q SMA and later-onset (and / or Type 2, Type 2-like, Type 3, or Type 3-like) SMA prior to receiving a therapy for SMA and meets one or more of the additional criteria listed above. In various embodiments, the methods disclosed herein include Attorney Docket No. 15094.0063-00304 the selection of such a patient or patient population(s) for treatment with apitegromab, e.g., according to a dosage or regimen disclosed herein. Patients and caregivers consider a 1 -point increase in HFMSE meaningful (McGraw et al. (2017) BMC Neurol 17:68. doi: 10.1186 / s12883-017-0853-y).

[0231]

[0192] In some embodiments, the subject has a baseline HFMSE score of about 8 to about 48. In some embodiments, the subject has a baseline HFMSE score of about 26.2. In some embodiments, the subject has a baseline HFMSE score of about 21 .3. In some embodiments, the subject has a baseline HFMSE score of about 25.4 In some embodiments, the subject has a baseline RULM score of about 26.2. In some embodiments, the subject has a baseline RULM score of about 26.3. In some embodiments, the subject attains less than 2 WHO motor milestones at baseline. In some embodiments, the subject attains a single WHO motor milestone at baseline.

[0232]

[0193] SMA patients who may be responsive to apitegromab therapy, either as monotherapy or in conjunction with (or in combination with) another therapy, include those having any type of SMA up to the age of two years, as well as those who show a phenotype of SMA Type 1 or have up to three SMN2 copies. In some embodiments, apitegromab may have enhanced therapeutic efficacy in younger patients, e.g., a population who is less than 21 years of age, because the patients have greater background anabolic activity. In some embodiments, younger patients, e.g., patients less than 21 years of age, or patients who are anabolically active, receive the apitegromab therapy. In some embodiments, the patient is aged two years or younger, e.g., newborn to 24 months old. In some embodiments, the patient is six weeks or younger, e.g., newborn to six weeks old. In some embodiments, the patient is up to 25 years old. In some embodiments, the patient is 2-21 years old. In some embodiments, the patient is 13-21 years old. In some embodiments, the patient is aged 12 years 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, apitegromab may be particularly efficacious in patients before the start of puberty (e.g., before age 12). In some embodiments, apitegromab treatment may be efficacious in preventing drastic decline in motor function associated with the start of puberty in younger patients (e.g., patients younger than 12 years old). In some embodiments, the patient is about two years old. In some embodiments, the patient is youngerthan two years old. In some embodiments, the patient shows a phenotype of SMA Type 1 . In some embodiments, the patient has up to three SMN2 copies. In various embodiments, the methods disclosed herein include the selection of such a patient or patient population(s) fortreatmentwith a myostatin inhibitor, such as apitegromab, e.g., according to a dosage or regimen disclosed herein.

[0233]

[0194] Patients who may be responsive to apitegromab therapy, either as monotherapy or in conjunction with (or in combination with) another therapy, include patients having Type 2 SMA with baseline (i.e., prior to the start of apitegromab therapy) serum latent myostatin (LM) concentrations of at least 1 ng / mL (e.g., greater than 1.5 ng / ml, greater than 2 ng / ml, greater than 2.5 ng / ml, greater than 3 ng / ml, or greater). In some embodiments, an apitegromab therapy, either as monotherapy or in conjunction with (or in combination with) another therapy, may be more effective in patients with higher baseline serum LM Attorney Docket No. 15094.0063-00304 concentrations as compared to patients with lower baseline serum LM concentrations. In some embodiments, such therapy may be particularly effective in patients who are younger than 12 years of age. In some embodiments, such therapy may be particularly effective in patients who are 2-5 years of age. In some embodiments, such therapy may be particularly effective in patients with Type 2 SMA who are 12-21 years of age. In some embodiments, such therapy may be particularly effective in patients with Type 3 SMA who are 12-21 years of age. In some embodiments, such therapy may be particularly effective in nonambulatory patients who are 2-21 years of age. In some embodiments, such therapy may be particularly effective in non-ambulatory patients who are 2-12 years of age. In some embodiments, such therapy may be particularly effective in Type 2 and Type 3 non-ambulatory patients who are 2-21 years of age. In some embodiments, such therapy may be effective in patients who are younger than two years of age. In some embodiments, Type 2 SMA patients who are younger than 12 years of age and have baseline serum LM concentrations of at least 1 ng / mL (e.g., greater than 1 .5 ng / ml, greaterthan 2 ng / ml, greaterthan 2.5 ng / ml, greater than 3 ng / ml, or greater) may be responsive to apitegromab therapy. In some embodiments, Type 2 SMA patients who are younger than two years of age and have baseline serum LM concentrations of at least 1 ng / mL (e.g., greater than 1.5 ng / ml, greater than 2 ng / ml, greater than 2.5 ng / ml, greater than 3 ng / ml, or greater) may be responsive to apitegromab therapy. In some embodiments, the apitegromab therapy comprises administering more than 2 mg / kg apitegromab, e.g., 10 mg / kg or 20 mg / kg.

[0234]

[0195] In some embodiments, a patient with SMA is administered apitegromab during a disease progression phase. In some embodiments, the disease progression phase comprises a decline in motor function. In some embodiments, the patient starts apitegromab during a disease progression phase. In some embodiments, the subject’s decline in motor function is determined by a HFMSE score, a 32-item Motor Function Measure (MFM32) score, a Revised Upper Limb Module (RULM), Revised Hammersmith Scale (RHS) score, a MyoGrip score, a MyoPinch score, or a WHO developmental motor milestone. In some embodiments, the subject’s motor function is determined by a HFMSE score, and wherein the subject’s HFMSE score is in a phase of decline at a rate of at least 1 point per year (e.g., at least 1 point per year, at least 2 points per year, at least 3 points per year). In some embodiments, the patient is showing disease progression including that the subject’s motor function is declining prior to treatment with a selective myostatin inhibitor, such as apitegromab, as indicated by a one point or greater decrease in a motor function assessment test score (e.g., HFMSE, RHS, and / or RULM score) over a period of 12 months or 24 months.

[0235]

[0196] In some embodiments, a method of treating SMA comprises administering an apitegromab therapy, either as a monotherapy or in conjunction with (or in combination with) another therapy, to a patient having baseline serum LM concentrations of at least 1 ng / mL (e.g., greater than 1.5 ng / ml, greater than 2 ng / ml, greater than 2.5 ng / ml, greater than 3 ng / ml, or greater). In some embodiments, a method of treating SMA comprises administering an apitegromab therapy, either as a monotherapy or in conjunction with (or in combination with) another therapy, to a patient who is younger than 12 years of age and who has baseline serum LM concentrations of at least 1 ng / mL (e.g., greater than 1.5 ng / ml, greater than 2 ng / ml, greater than 2.5 ng / ml, greater than 3 ng / ml, or greater). In some embodiments, a method of treating SMA Attorney Docket No. 15094.0063-00304 comprises administering an apitegromab therapy, either as a monotherapy or in conjunction with (or in combination with) another therapy, to a patient who is younger than 2 years of age and who has baseline serum LM concentrations of at least 1 ng / mL (e.g., greater than 1 .5 ng / ml, greater than 2 ng / ml, greater than 2.5 ng / ml, greater than 3 ng / ml, or greater). In some embodiments, the apitegromab therapy comprises administering more than 2 mg / kg apitegromab, e.g., 10 mg / kg or 20 mg / kg.

[0236]

[0197] In some embodiments, apitegromab is used for treating SMA, either as a monotherapy or in conjunction with (or in combination with) another therapy, in a patient having baseline serum LM concentrations of at least 1 ng / mL (e.g., greater than 1 .5 ng / ml, greaterthan 2 ng / ml, greaterthan 2.5 ng / ml, greater than 3 ng / ml, or greater). In some embodiments, apitegromab is used for treating SMA, either as a monotherapy or in conjunction with (or in combination with) another therapy, in a patient younger than 12 years of age having baseline serum LM concentrations of at least 1 ng / mL (e.g., greater than 1.5 ng / ml, greater than 2 ng / ml, greater than 2.5 ng / ml, greater than 3 ng / ml, or greater). In some embodiments, apitegromab is used for treating SMA, either as a monotherapy or in conjunction with (or in combination with) another therapy, in a patient younger than two years of age having baseline serum LM concentrations of at least 1 ng / mL (e.g., greater than 1.5 ng / ml, greater than 2 ng / ml, greater than 2.5 ng / ml, greater than 3 ng / ml, or greater). In some embodiments, the apitegromab is suitable for administering at more than 2 mg / kg apitegromab, e.g., 10 mg / kg or 20 mg / kg.

[0237]

[0198] In various embodiments, an SMA patient (e.g., any of the exemplary SMA patients described above) is on (is receiving) or has been treated with an SMN-targeted therapy. In some embodiments, the SMN-targeted therapy comprises nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi. In some embodiments, the patient is on (is receiving) or has been treated with nusinersen. In some embodiments, the patient has been previously treated with nusinersen. In some embodiments, the patient is on (is receiving) or has been treated with risdiplam. In some embodiments, the patient has been previously treated with risdiplam. In some embodiments, the patient is on (is receiving) or has previously received onasemnogene abeparvovec-xioi.

[0238]

[0199] In some embodiments, the subject has received at least one SMN-targeted therapy prior to starting apitegromab treatment. In some embodiments the subject has received at least one SMN-targeted therapy before 5 years of age. In some embodiments, the subject has received at least one SMN-targeted therapy at or after 5 years of age. In some embodiments, the subject has received the at least one SMN-targeted therapy for at least 6 months (e.g., at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years). In some embodiments, the subject has received the at least one SMN- targeted therapy for at least 4 years or at least 5 years. In some embodiments, the subject has received at least one SMN-targeted therapy priorto starting apitegromab treatment and has received the SMN-targeted therapy for at least 6 months. In some embodiments, the patient has received at least one SMN-targeted therapy before 5 years of age and has received the SMN-targeted therapy for at least 6 months. In some Attorney Docket No. 15094.0063-00304 embodiments, the patient has received at least one SMN-targeted therapy at or after 5 years of age and has received the SMN-targeted therapy for at least 6 months.

[0239]

[0200] In some embodiments, the patient has received nusinersen. In some embodiments, the patient received nusinersen before 5 years of age. In some embodiments, the patient received nusinersen at or after 5 years of age. In some embodiments, the patient has received nusinersen for at least 10 months (e.g., about 1 year to about 10 years or about 4 years to about 7 years) before starting the apitegromab treatment. In some embodiments, the patient has received nusinersen for at least 1 year (e.g., about 1 to about 10 years or about 4 to about 7 years) before staring the apitegromab treatment. In some embodiments, the patient has received nusinersen for about 1 to about 1 1 years (e.g., about 4 to about 7 years) before starting the apitegromab. In some embodiments, the patient received nusinersen before 5 years of age and has received nusinersen for about 1 to about 11 years (e.g., about 4 to about 7 years) before starting apitegromab. In some embodiments, the patient received nusinersen at or after 5 years of age and has received nusinersen for about 1 to about 11 years (e.g., about 4 to about 7 years) before starting apitegromab.

[0240]

[0201] In some embodiments, the patient has received risdiplam. In some embodiments, the patient received risdiplam before 5 years of age. In some embodiments, the patient received risdiplam at or after

[0241] 5 years of age. In some embodiments, the patient has received risdiplam for at least 6 months (e.g., about

[0242] 6 months to about 6 years or about 2 years to about 4 years) before starting the apitegromab treatment. In some embodiments, the patient has received risdiplam for 6 months to about 6 years (e.g., about 2 years to about 4 years) before starting the apitegromab treatment. In some embodiments, the patient received risdiplam before 5 years of age and has received risdiplam for 6 months to about 6 years (e.g., about 2 years to about 4 years) before starting the apitegromab treatment. In some embodiments, the patient received risdiplam at or after 5 years of age and has received risdiplam for 6 months to about 6 years (e.g., about 2 years to about 4 years) before starting the apitegromab treatment.

[0243]

[0202] In various embodiments, the present disclosure provides methods of treating a patient or patient population(s) with a myostatin inhibitor, such as apitegromab, alone or in conjunction with (or in combination with) a SMN-targeted therapy, wherein the patient or patient population(s) meets one or more of the following criteria: has any type of SMA before or up to the age of two years, shows a phenotype of SMA Type 1 , and / or has up to three SMN2 copies. In some embodiments, treatment comprises apitegromab therapy as monotherapy, e.g., according to a dosage or regimen disclosed herein. In some embodiments, treatment comprises apitegromab therapy in conjunction with (or in combination with) a SMN-targeted therapy, such nusinersen, risdiplam, or onasemnogene abeparvovec-xioi, e.g., according to a dosage or regimen disclosed herein. In some embodiments, the patient is on (is receiving) or has been treated with nusinersen. In some embodiments, the patient has been previously treated with nusinersen. In some embodiments, the patient is on (is receiving) or has been treated with risdiplam. In some embodiments, the Attorney Docket No. 15094.0063-00304 patient has been previously treated with risdiplam. In some embodiments, the patient has previously received onasemnogene abeparvovec-xioi.

[0244]

[0203] In some embodiments, the patient is symptomatic or pre-symptomatic. Pre-symptomatic patients include those who have been genetically identified as carriers of one or more mutations in the SMN1 gene, alone or in combination with identification of one or more additional genetic modifications (e.g., a determination of SMN2 copy number). Genetic identification of SMA patients may be carried out as part of newborn or in utero screening. At the time of the identification (e.g., diagnosis), the patient (e.g., newborn) may not show obvious / apparent symptoms (asymptomatic) but based on the genetic characteristics and possibly other factors, the patient may be expected to develop the disease.

[0245]

[0204] In severe cases, newborn babies may already show sign of the disease (i.e., symptomatic). Typically, such a patient is likely to have Type 1 SMA based on the natural history of SMA and is not generally expected to gain the ability to sit independently without intervention.

[0246]

[0205] In some embodiments, the patient is a newborn patient (age of zero to 6 months). In some embodiments, the patient is a fetus. In some embodiments, the patient is a pediatric patient, between the age of 6 months and 17 years. In some embodiments, the patient is younger than 2 years old. In some embodiments, the patient is younger than five years old. In some, the patient is five years old or younger, e.g., 2-5 years of age. In some embodiments, the patient is aged two years or younger, e.g., newborn to 24 months old. In some embodiments, the patient is aged six weeks or younger, e.g., newborn to six weeks old. In some embodiments, the patient is two years old or older. In some embodiments, the patient is 2-10 years of age. In some embodiments, the patient is 2-12 years of age. In some embodiments, the patient is 13-21 years of age. In some embodiments, the patient is five years old or older, e.g., 5-17 years of age. In some embodiments, the patient is between the ages of 5-21 years. In some embodiments, the patient is an adult.

[0247]

[0206] In some embodiments, the patient has not received or is not treated with an SMN corrector therapy, such as an SMN2 upregulator and / or an SMN1 gene therapy. In some embodiments, the patient has received or is treated with an SMN corrector therapy, such as an SMN2 upregulator therapy and / or an SMN1 gene therapy. In some embodiments, the patient initiates or initiated with the SMN corrector therapy before the age of five. In some embodiments, the patient initiates or initiated the SMN corrector therapy at or after the age of five. In some embodiments, the patient has received the SMN corrector therapy for at least about 40 months. In some embodiments, the patient has received the SMN corrector therapy for at least about 48 months. In some embodiments, the patient has received the SMN corrector therapy for at least about 4 years. In some embodiments, the patient has received the SMN corrector therapy for at least about 5 years. In some embodiments, the patient has received the SMN corrector therapy for up to 10 years.

[0248]

[0207] In some embodiments, a patient treated herein is in a period of stable disease decline such that the rate of decline in motor function (e.g., as measured by HFMSE and RHS scores) has not significantly Attorney Docket No. 15094.0063-00304 changed over a period of at least 6 months prior to starting treatment with a selective myostatin inhibitor (e.g., apitegromab). In some embodiments, the patient has stable disease such that the patient’s motor function (e.g., as measured by HFMSE and RHS scores) has not significantly changed over a period of at least 6 months prior to starting treatment with a selective myostatin inhibitor (e.g., apitegromab). In some embodiments, the patient has non-ambulatory SMA. In some embodiments, the patient has Type 2 or Type 3 non-ambulatory SMA. In some embodiments, the patient has ambulatory SMA. In some embodiments, the patient has Type 3 ambulatory SMA. In some embodiments, the patient initiated SMN upregulator / corrector therapy before the age of five. In some embodiments, the patient initiated SMN upregulator / corrector therapy after the age of five. In some embodiments, the patient is aged two years or younger, e.g., newborn to 24 months old. In some embodiments, the patient is 2-12 years old. In some embodiments, the patient is aged six weeks or younger, e.g., newborn to six weeks old. In some embodiments, the patient is 2-12 years old and initiated SMN upregulator / corrector therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi) before the age of 5. In some embodiments, the patient is 2-12 years old and initiated SMN upregulator / corrector therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi) after the age of five. In some embodiments, the patient is 5-12 years old and initiated SMN upregulator / corrector therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi) after the age of five.

[0249]

[0208] In some embodiments, the patient is a patient with 5q spinal muscular atrophy (SMA) with a bi- allelic mutation in the SMN1 gene and a clinical diagnosis of SMA Type 1 , or the patient is a patient with 5q SMA with a bi-allelic mutation in the SMN1 gene and up to three copies of the SMN2 gene. Such a patient may be treated with a selective myostatin inhibitor in conjunction with a 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 the gene therapy. In some embodiments, the patient’s motor milestones may be monitored, such as head control, rolling from back to sides, sitting without support for 30 seconds, sitting without support for at least 10 seconds, etc.

[0250]

[0209] In some embodiments, the patient is a Type 2 SMA patient who is able to sit but has never walked, wherein the patient is between 2 and 18 years of age. In some embodiments, an SMN1 gene therapy is used in the treatment of Type 2 SMA in a patient who is between 2-18 years of age and who is able to sit but has never gained the ability to walk, and wherein the patient is treated with a myostatin inhibitor, wherein optionally the myostatin inhibitor is a myostatin-selective inhibitor, such as apitegromab, GYM329, trevogrumab, or a variant of any one of the foregoing. In some embodiments, a myostatin inhibitor is used in the treatment of Type 2 SMA in a patient who is between 2-18 years of age and who is able to sit but has never gained the ability to walk, and wherein the patient is treated with a SMN1 gene therapy, wherein optionally the SMN1 gene therapy comprises onasemnogene abeparvovec-xioi. In preferred embodiments, the myostatin inhibitor is a myostatin-selective inhibitor, such as apitegromab, GYM329, trevogrumab, or a variant of any one of the foregoing. In some embodiments, an SMN1 gene therapy and a myostatin inhibitor are used as a combination therapy in the treatment of SMA in a patient who is between 2-18 years of age Attorney Docket No. 15094.0063-00304 and who is able to sit but has never gained the ability to walk, and wherein the patient is treated with a myostatin inhibitor, wherein optionally the myostatin inhibitor is a myostatin-selective inhibitor, such as apitegromab, GYM329, trevogrumab, or a variant of any one of the foregoing, and wherein further optionally, the SMN1 gene therapy comprises onasemnogene abeparvovec-xioi. In some embodiments, an antibody variant may have nucleic acid and / or amino acid sequences of significant homology (e.g., >90% sequence identity) and retains one or more physical and / or functional properties as compared to a known antibody.

[0251]

[0210] In some embodiments, the patient has a stable disease as assessed by motor function, such that the motor function assessment test score (e.g., HFMSE and RHS scores) has not significantly changed over a period of at least 6 months prior to treatment with a selective myostatin inhibitor, such as apitegromab. In some embodiments, the patient has received or is treated with an SMN corrector therapy.

[0252]

[0211] In some embodiments, the patient has undergone spinal fusion, e.g., primary posterior spinal fusion. “Spinal fusion surgery” and “scoliosis surgery” are used interchangeably herein.

[0253]

[0212] According to the present disclosure, patient selection or categorization may be based on the highest motor milestone achieved, relative to the number of SMN2 gene copies. Thus, the present disclosure includes therapeutic use of a myostatin-selective inhibitor (such as apitegromab, GYM329, or trevogrumab) in the treatment of SMA in a patient, wherein the treatment comprises administration of a composition comprising the myostatin-selective inhibitor. In some embodiments, the myostatin-selective inhibitor is apitegromab, which may be intravenously administered at a therapeutic dose, wherein the therapeutic dose is greaterthan 2 mg / kg and up to 20 mg / kg (such as 10 mg / kg). In preferred embodiments, the myostatin-selective inhibitor is apitegromab, which may be intravenously administered at a therapeutic dose of 10 mg / kg to 20 mg / kg (e.g., 10 mg / kg, 15 mg / kg, or 20 mg / kg). In some embodiments, the patient has 1 , 2, 3 or 4 copies of the SMN2 gene and achieves one or more of the gross motor milestones of: 1) raises / supports head (i.e., neck holding, e.g., while laying on their stomach able to raise or hold head); 2) rolls over; 3) sits in tripod position (e.g., uses hands to support self while sitting) or sit with support; 4) sits without support; 5) stands with support / assistance; 6) creeps / crawls; 7) pulls to standing position; 8) walks with assistance (e.g., cruises along furniture); 9) stands without support; 10) takes several independent steps but falls; 11) walks alone (e.g., walks independently, walks without support); 12) squats to pick up an object (e.g., a toy); 13) walks / creeps up and down the stairs; 14) runs; 15) jumps; 16) alternates feet going upstairs; 17) hops on one foot; 18) alternates feet going downstairs.

[0254]

[0213] In some embodiments, the patient has one copy of the SMN2 gene, and the highest motor milestone achieved is to raise or hold head while lying on stomach. In some embodiments, the patient has one copy of the SMN2 gene, and the highest motor milestone achieved is to roll over. In some embodiments, the patient has one copy of the SMN2 gene, and the highest motor milestone achieved is to sit with support. In some embodiments, the patient has one copy of the SMN2 gene, and the highest motor milestone achieved is to sit without support. In some embodiments, the patient has one copy of the SMN2 Attorney Docket No. 15094.0063-00304 gene, and the highest motor milestone achieved is to stand with support. In some embodiments, the patient has one copy of the SMN2 gene, and the highest motor milestone achieved is to crawl. In some embodiments, the patient has one copy of the SMN2 gene, and the highest motor milestone achieved is to pull to standing position. In some embodiments, the patient has one copy of the SMN2 gene, and the highest motor milestone achieved is to walk with assistance. In some embodiments, the patient has one copy of the SMN2 gene, and the highest motor milestone achieved is to stand without support. In some embodiments, the patient has one copy of the SMN2 gene, and the highest motor milestone achieved is to walk independently (without support). In some embodiments, the patient has one copy of the SMN2 gene, and the highest motor milestone achieved is to run. In some embodiments, the patient has one copy of the SMN2 gene, and the highest motor milestone achieved is to jump. In some embodiments, the patient has one copy of the SMN2 gene, and the highest motor milestone achieved is to alternate feet going upstairs. In some embodiments, the patient has one copy of the SMN2 gene, and the highest motor milestone achieved is to hop on one foot. In some embodiments, the patient has one copy of the SMN2 gene, and the highest motor milestone achieved is to alternate feet going downstairs.

[0255]

[0214] In some embodiments, the patient has two copies of the SMN2 gene, and the highest motor milestone achieved is to raise or hold head while lying on stomach. In some embodiments, the patient has two copies of the SMN2 gene, and the highest motor milestone achieved is to roll over. In some embodiments, the patient has two copies of the SMN2 gene, and the highest motor milestone achieved is to sit with support. In some embodiments, the patient has two copies of the SMN2 gene, and the highest motor milestone achieved is to sit without support. In some embodiments, the patient has two copies of the SMN2 gene, and the highest motor milestone achieved is to stand with support. In some embodiments, the patient has two copies of the SMN2 gene, and the highest motor milestone achieved is to crawl. In some embodiments, the patient has two copies of the SMN2 gene, and the highest motor milestone achieved is to pull to standing position. In some embodiments, the patient has two copies of the SMN2 gene, and the highest motor milestone achieved is to walk with assistance. In some embodiments, the patient has two copies of the SMN2 gene, and the highest motor milestone achieved is to stand without support. In some embodiments, the patient has two copies of the SMN2 gene, and the highest motor milestone achieved is to walk independently (without support). In some embodiments, the patient has two copies of the SMN2 gene, and the highest motor milestone achieved is to run. In some embodiments, the patient has two copies of the SMN2 gene, and the highest motor milestone achieved is to jump. In some embodiments, the patient has two copies of the SMN2 gene, and the highest motor milestone achieved is to alternate feet going upstairs. In some embodiments, the patient has two copies of the SMN2 gene, and the highest motor milestone achieved is to hop on one foot. In some embodiments, the patient has two copies of the SMN2 gene, and the highest motor milestone achieved is to alternate feet going downstairs.

[0256]

[0215] In some embodiments, the patient has three copies of the SMN2 gene, and the highest motor milestone achieved is to raise or hold head while lying on stomach. In some embodiments, the patient has three copies of the SMN2 gene, and the highest motor milestone achieved is to roll over. In some Attorney Docket No. 15094.0063-00304 embodiments, the patient has three copies of the SMN2 gene, and the highest motor milestone achieved is to sit with support. In some embodiments, the patient has three copies of the SMN2 gene, and the highest motor milestone achieved is to sit without support. In some embodiments, the patient has three copies of the SMN2 gene, and the highest motor milestone achieved is to stand with support. In some embodiments, the patient has three copies of the SMN2 gene, and the highest motor milestone achieved is to crawl. In some embodiments, the patient has three copies of the SMN2 gene, and the highest motor milestone achieved is to pull to standing position. In some embodiments, the patient has three copies of the SMN2 gene, and the highest motor milestone achieved is to walk with assistance. In some embodiments, the patient has three copies of the SMN2 gene, and the highest motor milestone achieved is to stand without support. In some embodiments, the patient has three copies of the SMN2 gene, and the highest motor milestone achieved is to walk independently (without support). In some embodiments, the patient has three copies of the SMN2 gene, and the highest motor milestone achieved is to run. In some embodiments, the patient has three copies of the SMN2 gene, and the highest motor milestone achieved is to jump. In some embodiments, the patient has three copies of the SMN2 gene, and the highest motor milestone achieved is to alternate feet going upstairs. In some embodiments, the patient has three copies of the SMN2 gene, and the highest motor milestone achieved is to hop on one foot. In some embodiments, the patient has three copies of the SMN2 gene, and the highest motor milestone achieved is to alternate feet going downstairs.

[0257]

[0216] In some embodiments, the patient has four copies of the SMN2 gene, and the highest motor milestone achieved is to sit with support. In some embodiments, the patient has four copies of the SMN2 gene, and the highest motor milestone achieved is to sit without support. In some embodiments, the patient has four copies of the SMN2 gene, and the highest motor milestone achieved is to stand with support. In some embodiments, the patient has four copies of the SMN2 gene, and the highest motor milestone achieved is to crawl. In some embodiments, the patient has four copies of the SMN2 gene, and the highest motor milestone achieved is to pull to standing position. In some embodiments, the patient has four copies of the SMN2 gene, and the highest motor milestone achieved is to walk with assistance. In some embodiments, the patient has four copies of the SMN2 gene, and the highest motor milestone achieved is to stand without support. In some embodiments, the patient has four copies of the SMN2 gene, and the highest motor milestone achieved is to walk independently (without support). In some embodiments, the patient has four copies of the SMN2 gene, and the highest motor milestone achieved is to run. In some embodiments, the patient has four copies of the SMN2 gene, and the highest motor milestone achieved is to jump. In some embodiments, the patient has four copies of the SMN2 gene, and the highest motor milestone achieved is to alternate feet going upstairs. In some embodiments, the patient has four copies of the SMN2 gene, and the highest motor milestone achieved is to hop on one foot. In some embodiments, the patient has four copies of the SMN2 gene, and the highest motor milestone achieved is to alternate feet going downstairs. Attorney Docket No. 15094.0063-00304

[0258]

[0217] In some embodiments, the patient has more than four copies of the SMN2 gene, and the highest motor milestone achieved is to sit with support. In some embodiments, the patient has more than four copies of the SMN2 gene, and the highest motor milestone achieved is to sit without support. In some embodiments, the patient has more than four copies of the SMN2 gene, and the highest motor milestone achieved is to stand with support. In some embodiments, the patient has more than four copies of the SMN2 gene, and the highest motor milestone achieved is to crawl. In some embodiments, the patient has more than four copies of the SMN2 gene, and the highest motor milestone achieved is to pull to standing position. In some embodiments, the patient has more than four copies of the SMN2 gene, and the highest motor milestone achieved is to walk with assistance. In some embodiments, the patient has more than four copies of the SMN2 gene, and the highest motor milestone achieved is to stand without support. In some embodiments, the patient has more than four copies of the SMN2 gene, and the highest motor milestone achieved is to walk independently (without support). In some embodiments, the patient has more than four copies of the SMN2 gene, and the highest motor milestone achieved is to run. In some embodiments, the patient has more than four copies of the SMN2 gene, and the highest motor milestone achieved is to jump. In some embodiments, the patient has more than four copies of the SMN2 gene, and the highest motor milestone achieved is to alternate feet going upstairs. In some embodiments, the patient has more than four copies of the SMN2 gene, and the highest motor milestone achieved is to hop on one foot. In some embodiments, the patient has more than four copies of the SMN2 gene, and the highest motor milestone achieved is to alternate feet going downstairs.

[0259]

[0218] In some embodiments, the patient has one copy of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of walking independently. In some embodiments, the patient has one copy of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of standing independently. In some embodiments, the patient has one copy of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of standing with assistance. In some embodiments, the patient has one copy of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of hands and knees crawling. In some embodiments, the patient has one copy of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of walking with assistance.

[0260]

[0219] In some embodiments, the patient has two copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of walking independently. In some embodiments, the patient has two copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of standing independently. In some embodiments, the patient has two copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of standing with assistance. In some embodiments, the patient has two copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of hands and knees crawling. In some embodiments, the patient has two copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of walking with assistance. Attorney Docket No. 15094.0063-00304

[0261]

[0220] In some embodiments, the patient has three copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of walking independently. In some embodiments, the patient has three copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of standing independently. In some embodiments, the patient has three copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of standing with assistance. In some embodiments, the patient has three copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of hands and knees crawling. In some embodiments, the patient has three copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of walking with assistance.

[0262]

[0221] In some embodiments, the patient has four copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of walking independently. In some embodiments, the patient has four copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of standing independently. In some embodiments, the patient has four copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of standing with assistance. In some embodiments, the patient has four copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of hands and knees crawling. In some embodiments, the patient has four copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of walking with assistance.

[0263]

[0222] In some embodiments, the patient has more than four copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of walking independently. In some embodiments, the patient has more than four copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of standing independently. In some embodiments, the patient has more than four copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of standing with assistance. In some embodiments, the patient has more than four copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of hands and knees crawling. In some embodiments, the patient has more than four copies of the SMN2 gene and has achieved the WHO Motor Developmental Milestone of walking with assistance.

[0264]

[0223] In some embodiments, the subject is able to raise or support their head before the age of three months, 6 months, nine months, or 12 months. In some embodiments, the subject is able to roll over before the age of 6 months, nine months or 12 months. In some embodiments, the subject is able to sit with support or sit in tripod position before the age of 6 months, nine months, or 12 months. In some embodiments, the subject is able to sit without support before the age of 6 months, nine months, or 12 months. In some embodiments, the subject is able to stand with support before the age of nine months or 12 months. In some embodiments, the subject is able to stand without support before the age of 12 months. In some embodiments, the subject is able to creep or crawl before the age of 6 months, nine months, or 12 months. In some embodiments, the subject is able to pull to standing position before the age of nine months or 12 months. Attorney Docket No. 15094.0063-00304

[0265]

[0224] In some embodiments, subject is able to walk with assistance before the age of 12 months or 15 months. In some embodiments, the subject is able to walk without assistance before the age of 12 months, or 15 months. In some embodiments, the subject is able to run before the age of 15 months, 18 months or 24 months. In some embodiments, the subject is able to jump before the age of 15 months, 18 months or 24 months. In some embodiments, the subject is able to squat to pick up an object before the age of 15 months, 18 months or 24 months. In some embodiments, the subject is able to walk or creep up and down the stairs before the age of 15 months, 18 months or 24 months. In some embodiments, the subject is able to alternate feet going upstairs before the age of 30 months or 36 months (3 years). In some embodiments, the subject is able to alternate feet going downstairs before the age of 36 months (3 years). In some embodiments, the subject is able to hop on one foot before the age of four years or five years.

[0266]

[0225] The present disclosure provides therapeutic use of apitegromab in the treatment of SMA in a patient, wherein the treatment comprises intravenous administration of a composition comprising apitegromab at a therapeutic dose, wherein the therapeutic dose is greater than 2 mg / kg and up to 20 mg / kg (such as 10 mg / kg or 20 mg / kg), and wherein optionally the patient may be selected from any of the following category or categories, or the patient is characterized in that:

[0267]

[0226] The patient is aged two years or younger, e.g., newborn to 24 months old, wherein optionally the patient has non-ambulatory Type 2 or Type 3 SMA, wherein further optionally the patient is receiving an SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi).

[0268]

[0227] The patient is aged two years or younger, e.g., newborn to 24 months old, wherein optionally the patient has ambulatory SMA, wherein further optionally the patient is receiving an SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi).

[0269]

[0228] The patient is aged six weeks or younger, e.g., newborn to six weeks old.

[0270]

[0229] The patient is aged two years or older, wherein optionally the patient has non-ambulatory Type 2 or Type 3 SMA, wherein further optionally the patient is receiving an SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi).

[0271]

[0230] The patient is aged two years or older, wherein optionally the patient has ambulatory SMA, wherein further optionally the patient is receiving an SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi).

[0272]

[0231] The patient is 2-21 years old, wherein optionally the patient has non-ambulatory Type 2 or Type 3 SMA, wherein further optionally the patient is receiving an SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi).

[0273]

[0232] The patient is 2-21 years old, wherein optionally the patient has ambulatory SMA, wherein further optionally the patient is receiving an SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi).

[0274]

[0233] The patient is 2-12 years old, 2-10 years old, 2-5 years old, or 5-12 years old. Attorney Docket No. 15094.0063-00304

[0275]

[0234] The patient is 5-21 years old, wherein optionally the patient has non-ambulatory Type 2 or Type 3 SMA, wherein further optionally the patient is receiving an SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi).

[0276]

[0235] The patient is 5-21 years old, wherein optionally the patient has ambulatory SMA, wherein further optionally the patient is receiving an SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi).

[0277]

[0236] The patient is 13-21 years old, wherein optionally the patient has non-ambulatory Type 2 or Type 3 SMA, wherein further optionally the patient is receiving an SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi).

[0278]

[0237] The patient is 13-21 years old, wherein optionally the patient has ambulatory SMA, wherein further optionally the patient is receiving an SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi).

[0279]

[0238] The patient is up to 25 years old, wherein optionally the patient has ambulatory or non-ambulatory SMA, wherein further optionally the patient is receiving an SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi).

[0280]

[0239] The patient has later-onset SMA, wherein optionally the patient is receiving an SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi).

[0281]

[0240] The patient has ambulatory SMA, wherein optionally the patient is receiving an SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi).

[0282]

[0241] The patient has non-ambulatory SMA, wherein optionally the patient is receiving an SMN therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi).

[0283]

[0242] The patient has Type 2 SMA.

[0284]

[0243] The patient has Type 3 SMA, wherein optionally the patient has non-ambulatory Type 3 SMA.

[0285]

[0244] The patient has Type 3 SMA, wherein optionally the patient has ambulatory Type 3 SMA.

[0286]

[0245] The patient has at least two copies of the SMN2 gene, e.g., two, three, four, five, or six copies of the SMN2 gene; or, wherein optionally the patient has 2-4 copies of the SMN2 gene.

[0287]

[0246] The patient has at least two copies of the SMN2 gene, e.g., two, three, or four, etc. copies of the SMN2 gene; or, wherein optionally the patient has 2-4 copies of the SMN2 gene, wherein optionally the patient has Type 2 SMA or non-ambulatory Type 3 SMA.

[0288]

[0247] The patient has at least three copies of the SMN2 gene, e.g., three, four, five, or six copies of the SMN2 gene; or, wherein optionally the patient has 3-5 copies of the SMN2 gene, wherein optionally the patient has ambulatory SMA, wherein further optionally the ambulatory SMA is Type 4 SMA. Attorney Docket No. 15094.0063-00304

[0289]

[0248] The patient has SMA (e.g., any type of SMA) and is up to two years of age, wherein optionally the patient has been treated with an SMN therapy, wherein further optionally the SMN therapy comprises an SMN2 upregulator (such as nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi) or an SMN1 gene therapy.

[0290]

[0249] The patient has Type 1 SMA with up to three copies of the SMN2 gene, wherein optionally the patient has been treated with an SMN therapy, wherein further optionally the SMN therapy comprises an SMN2 upregulator (such as nusinersen and / or risdiplam) or an SMN1 gene therapy (such as onasemnogene abeparvovec-xioi).

[0291]

[0250] The patient has symptomatic SMA.

[0292]

[0251] The patient has presymptomatic SMA.

[0293]

[0252] The patient is identified as a carrier of SMA mutation(s) but is asymptomatic (pre-symptomatic).

[0294]

[0253] The patient has not been treated with SMN-targeted therapy.

[0295]

[0254] The patient is on (is receiving) or has been treated with an SMN-targeted therapy, wherein optionally the SMN-targeted therapy is a gene therapy, splice modifier, or combination thereof, wherein further optionally the splice modifier is a nucleic acid-based agent or low molecular weight compound that modifies SMN2 splicing.

[0296]

[0255] The patient is on (is receiving) or has been treated with an SMN-targeted therapy, wherein optionally the SMN-targeted therapy is a gene therapy, splice modifier, or combination thereof, wherein further optionally the splice modifier is a nucleic acid-based agent or low molecular weight compound that modifies SMN2 splicing; and wherein the patient commenced the SMN-targeted therapy before the age of five.

[0297]

[0256] The patient is on (is receiving) or has been treated with an SMN-targeted therapy, wherein optionally the SMN-targeted therapy is a gene therapy, splice modifier, or combination thereof, wherein further optionally the splice modifier is a nucleic acid-based agent or low molecular weight compound that modifies SMN2 splicing, and wherein the patient commenced the SMN-targeted therapy at age five or older.

[0298]

[0257] The patient is on an SMN-targeted therapy for at least 12 months at the time of starting apitegromab therapy (e.g., prior to receiving a first dose of apitegromab).

[0299]

[0258] The patient is on an SMN-targeted therapy for at least 15 months at the time of starting apitegromab therapy (e.g., prior to receiving a first dose of apitegromab).

[0300]

[0259] The patient is on an SMN-targeted therapy for at least 24 months at the time of starting apitegromab therapy (e.g., prior to receiving a first dose of apitegromab). Attorney Docket No. 15094.0063-00304

[0301]

[0260] The patient is on nusinersen for at least 1 year (e.g., about 1 to about 10 years, e.g., about 4 to about 7 years) at the time of starting apitegromab therapy (e.g., prior to receiving a first dose of apitegromab).

[0302]

[0261] The patient is on risdiplam for at least 6 months (e.g., about 6 months to about 6 years or about 2 years to about 4 years) before starting apitegromab therapy (e.g., prior to receiving a first dose of apitegromab).

[0303]

[0262] The patient is five years old or younger at the time of starting apitegromab therapy.

[0304]

[0263] The patient is two years old or younger at the time of starting apitegromab therapy.

[0305]

[0264] The patient is six weeks old or younger at the time of starting apitegromab therapy.

[0306]

[0265] The patient is before the age of five at the time of receiving a first dose of apitegromab.

[0307]

[0266] The patient has a baseline HFMSE score of at least 10, e.g., at least 13, e.g., a score of 13-39, e.g., no greater than 39.

[0308]

[0267] In some embodiments, the present disclosure provides therapeutic use of apitegromab in the treatment of SMA in a patient who is 2-12 years old and has received at least 6 months of an SMN upregulator / corrector therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi) before starting apitegromab treatment, wherein the apitegromab treatment comprises intravenous administration of a composition comprising apitegromab at 10 mg / kg or 20 mg / kg, e.g., once every four weeks or once monthly. In some embodiments, the patient initiated the SMN upregulator / corrector therapy before the age of five. In some embodiments, the patient initiated the SMN upregulator / corrector therapy after the age of five. In some embodiments, present disclosure provides therapeutic use of apitegromab in the treatment of SMA in a patient who is 2-12 years old and has received at least 6 months of risdiplam before starting apitegromab treatment, wherein the apitegromab treatment comprises intravenous administration of a composition comprising apitegromab at 10 mg / kg or 20 mg / kg once every four weeks or once monthly. In some embodiments, present disclosure provides therapeutic use of apitegromab in the treatment of SMA in a patient who is 2-12 years old and has received at least 10 months of nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi before starting apitegromab treatment, wherein the apitegromab treatment comprises intravenous administration of a composition comprising apitegromab at 10 mg / kg or 20 mg / kg once every four weeks or once monthly.

[0309]

[0268] In some embodiments, the present disclosure provides therapeutic use of apitegromab in the treatment of SMA in a patient who is 5-12 years old and has received at least 6 months of an SMN upregulator / corrector therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi) before starting apitegromab treatment, wherein the apitegromab treatment comprises intravenous administration of a composition comprising apitegromab at 10 mg / kg or 20 mg / kg, e.g., once every four weeks or once monthly. In some embodiments, the patient initiated the SMN upregulator / corrector therapy before the age of five. In some embodiments, the patient initiated the SMN upregulator / corrector therapy after the age of Attorney Docket No. 15094.0063-00304 five. In some embodiments, present disclosure provides therapeutic use of apitegromab in the treatment of SMA in a patient who is 5-12 years old and has received at least 6 months of risdiplam before starting apitegromab treatment, wherein the apitegromab treatment comprises intravenous administration of a composition comprising apitegromab at 10 mg / kg or 20 mg / kg once every four weeks or once monthly. In some embodiments, present disclosure provides therapeutic use of apitegromab in the treatment of SMA in a patient who is 5-12 years old and has received at least 10 months of nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi before starting apitegromab treatment, wherein the apitegromab treatment comprises intravenous administration of a composition comprising apitegromab at 10 mg / kg or 20 mg / kg once every four weeks or once monthly (e.g., for at least 48 weeks).

[0310]

[0269] In some embodiments, the present disclosure provides therapeutic use of apitegromab in the treatment of a patient having later-onset (e.g., Type 2 or Type 3) SMA who has received at least 6 months of an SMN-targeted therapy (e.g., an SMN upregulator / correctortherapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi) before starting apitegromab treatment, wherein the apitegromab treatment comprises intravenous administration of a composition comprising 10 mg / kg or 20 mg / kg apitegromab once every four weeks or once monthly for at least 12 months, 24 months, 36 months, or 48 months. In some embodiments, the patient has received at least 6 months of risdiplam prior to starting the apitegromab treatment. In some embodiments, the patient has received at least 10 months of nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi prior to starting the apitegromab treatment. In some embodiments, the subject is aged 2-21 years. In some embodiments, the patient initiated the SMN-targeted therapy before the age of five. In some embodiments, the patient initiated the SMN-targeted therapy after the age of five. In some embodiments, the subject has not received onasemnogene abeparvovec-xioi or apitegromab previously.

[0311]

[0270] In some embodiments, the present disclosure provides therapeutic use of apitegromab in the treatment of SMA in a patient who is 13-21 years old and has received at least 6 months of risdiplam before starting apitegromab treatment, and who has not received onasemnogene abeparvovec-xioi or apitegromab previously, wherein the apitegromab treatment comprises intravenous administration of a composition comprising 10 mg / kg or 20 mg / kg apitegromab once every four weeks or once monthly, e.g., for at least 52 weeks. In some embodiments, the patient initiated risdiplam treatment before the age of five. In some embodiments, the patient initiated risdiplam treatment after the age of five.

[0312]

[0271] In some embodiments, the present disclosure provides therapeutic use of apitegromab in the treatment of SMA in a patient who is 13-21 years old and has received at least 10 months of nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi before starting apitegromab treatment, and who has not received onasemnogene abeparvovec-xioi or apitegromab previously, wherein the apitegromab treatment comprises intravenous administration of a composition comprising 10 mg / kg or 20 mg / kg apitegromab once every four weeks or once monthly, e.g., for at least 52 weeks. In some embodiments, the patient initiated nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi treatment before the age of five. In some Attorney Docket No. 15094.0063-00304 embodiments, the patient initiated nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi treatment after the age of five.

[0313]

[0272] In some embodiments, the present disclosure provides therapeutic use of apitegromab in the treatment of SMA in a patient who is aged five years or younger, wherein the patient has not received an SMN-targeted therapy (e.g., an SMN upregulator / corrector therapy, e.g., nusinersen, risdiplam, or onasemnogene abeparvovec-xioi) before starting apitegromab treatment, wherein the treatment comprises concurrent (e.g., simultaneous, separate, or sequential) administration of a composition comprising apitegromab and a composition comprising an SMN-targeted therapy (e.g., an SMN upregulator / corrector therapy, e.g., nusinersen, risdiplam, or onasemnogene abeparvovec-xioi). 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 four weeks or once monthly.

[0314]

[0273] In some embodiments, the present disclosure provides therapeutic use of apitegromab in the treatment of SMA in a patient who is aged 2 years or younger, e.g., newborn to 24 months old, wherein the patient has not received an SMN upregulator / corrector therapy before starting apitegromab treatment, wherein the treatment comprises concurrent (e.g., simultaneous, separate, or sequential) administration of a composition comprising apitegromab and a composition comprising an SMN-targeted therapy (e.g., an SMN upregulator / corrector therapy, e.g., nusinersen, risdiplam, or onasemnogene abeparvovec-xioi).

[0315]

[0274] In some embodiments, the present disclosure provides therapeutic use of apitegromab in the treatment of SMA in a patient who is aged six weeks or younger, e.g., newborn to six weeks old, wherein the patient has not received an SMN-targeted therapy (e.g., an SMN upregulator / corrector therapy) before starting apitegromab treatment, wherein the treatment comprises concurrent (e.g., simultaneous, separate, or sequential) administration of a composition comprising apitegromab and a composition comprising an SMN-targeted therapy (e.g., an SMN upregulator / corrector therapy, e.g., nusinersen, risdiplam, or onasemnogene abeparvovec-xioi). In some embodiments, the patient has presymptomatic SMA. In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, the composition comprising apitegromab is administered intravenously. In some embodiments, the composition comprising apitegromab is administered at a frequency of once every four weeks or once monthly.

[0316]

[0275] In some embodiments, the present disclosure provides therapeutic use of a myostatin-selective inhibitor, e.g., apitegromab, GYM329, ortrevogrumab, in the treatment of presymptomatic SMA in a human patient. In some embodiments, the patient has not previously received an SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) before starting the myostatin-selective inhibitor treatment. In some embodiments, the patient has previously received or is receiving an SMN upregulator / corrector therapy (e.g., an SMN1 gene therapy). In some embodiments, the treatment comprises concurrent (e.g., simultaneous, separate, or sequential) administration of a composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, and a composition comprising an SMN upregulator / corrector therapy, (e.g., an SMN1 gene therapy). In some embodiments, the patient has two Attorney Docket No. 15094.0063-00304 copies of the SMN2 gene. In some embodiments, the composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, is administered intravenously. In some embodiments, the composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, is administered at a frequency of once every four weeks or once monthly. In some embodiments, the myostatin-selective inhibitor binds selectively to pro-latent myostatin. In some embodiments, the myostatin-selective inhibitor is apitegromab.

[0317]

[0276] In some embodiments, the present disclosure provides therapeutic use of a myostatin-selective inhibitor, e.g., apitegromab, GYM329, ortrevogrumab, in the treatment of SMA in a patient who is aged five years or younger. In some embodiments, the patient has not previously received an SMN upregulator / corrector therapy (e.g., an SMN1 gene therapy) before starting the myostatin-selective inhibitor treatment. In some embodiments, the patient has previously received or is receiving an SMN upregulator / corrector therapy (e.g., an SMN1 gene therapy). In some embodiments, the patient is administered the SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) at age five years or younger. In some embodiments, the treatment of SMA comprises concurrent (e.g., simultaneous, separate, or sequential) administration of a composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, and a composition comprising an SMN upregulator / corrector therapy, e.g., an SMN1 gene therapy. In some embodiments, the composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, is administered intravenously. In some embodiments, the patient has presymptomatic SMA. In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, the composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, is administered at a frequency of once every four weeks or once monthly. In some embodiments, the myostatin-selective inhibitor binds selectively to pro / latent myostatin. In some embodiments, the myostatin-selective inhibitor is apitegromab.

[0318]

[0277] In some embodiments, the present disclosure provides therapeutic use of a myostatin-selective inhibitor, e.g., apitegromab, GYM329, ortrevogrumab, in the treatment of SMA in a patient who is aged two years or younger, e.g., newborn to 24 months old. In some embodiments, the patient has not previously received an SMN upregulator / correctortherapy (e.g., an SMN1 gene therapy) before starting the myostatin- selective inhibitor treatment. In some embodiments, the patient has previously received or is receiving an SMN upregulator / corrector therapy (e.g., an SMN1 gene therapy). In some embodiments, the patient is administered the SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) at age two years or younger (e.g., newborn to 24 months). In some embodiments, the treatment comprises concurrent (e.g., simultaneous, separate, or sequential) administration of a composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, and a composition comprising an SMN upregulator / corrector therapy (e.g., an SMN1 gene therapy). In some embodiments, the patient has presymptomatic SMA. In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, the composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, is administered intravenously. In some embodiments, the composition comprising a Attorney Docket No. 15094.0063-00304 myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, is administered at a frequency of once every four weeks or once monthly. In some embodiments, the myostatin-selective inhibitor binds selectively to pro / latent myostatin. In some embodiments, the myostatin-selective inhibitor is apitegromab.

[0319]

[0278] In some embodiments, the present disclosure provides therapeutic use of a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, in the treatment of SMA in a patient who is aged six weeks or younger, e.g., newborn to six weeks old, wherein the treatment comprises concurrent (e.g., simultaneous, separate, or sequential) administration of a composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, and a composition comprising an SMN upregulator / corrector therapy, (e.g., an SMN1 gene therapy). In some embodiments, the patient has not previously received an SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) before starting the myostatin-selective inhibitor treatment. In some embodiments, the patient has previously received or is receiving an SMN upregulator / corrector therapy (e.g., an SMN1 gene therapy). In some embodiments, the patient has presymptomatic SMA. In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, the composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, is administered intravenously. In some embodiments, the composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, is administered at a frequency of once every four weeks or once monthly. In some embodiments, the myostatin-selective inhibitor binds selectively to pro-latent myostatin. In some embodiments, the myostatin-selective inhibitor is apitegromab.

[0320]

[0279] In some embodiments, the present disclosure provides a myostatin-selective inhibitor and an SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) for use in the treatment of presymptomatic SMA in a patient, wherein the treatment comprises administration of the myostatin-selective inhibitor and the SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) to a presymptomatic patient in amounts effective to treat SMA. In some embodiments, the patient has two copies of the SMN2 gene, and / orwherein the patient is six weeks or younger at the time of administration of the SMN upregulator / corrector therapy (e.g., SMN1 gene therapy). In some embodiments, the myostatin-selective inhibitor is apitegromab, GYM329, or trevogrumab.

[0321]

[0280] In some embodiments, the present disclosure provides a myostatin-selective inhibitor and an SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) for use in the treatment of presymptomatic SMA in a patient, wherein the treatment comprises administration of the myostatin-selective inhibitor and the SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) to a presymptomatic patient in amounts effective to treat SMA, wherein the patient has two copies of the SMN2 gene, wherein the patient is six weeks or younger at the time of administration of the SMN upregulator / corrector therapy (e.g., SMN1 gene therapy), and wherein the myostatin-selective inhibitor is apitegromab, GYM329, or trevogrumab.

[0322]

[0281] In some embodiments, the present disclosure provides a myostatin-selective inhibitor for use in the treatment of presymptomatic SMA in a patient, wherein the treatment comprises administration of the Attorney Docket No. 15094.0063-00304 myostatin-selective inhibitor to a presymptomatic patient in amounts effective to treat SMA. In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, the patient is administered with an SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) at six weeks or younger. In some embodiments, the myostatin-selective inhibitor is apitegromab, GYM329, ortrevogrumab.

[0323]

[0282] In some embodiments, the present disclosure provides a myostatin-selective inhibitor for use in the treatment of presymptomatic SMA in a patient, wherein the treatment comprises administration of the myostatin-selective inhibitor to a presymptomatic patient in amounts effective to treat SMA, wherein the patient has two copies of the SMN2 gene, wherein the patient is administered with an SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) at six weeks or younger, and wherein the myostatin-selective inhibitor is apitegromab, GYM329, or trevogrumab.

[0324]

[0283] In some embodiments, the present disclosure provides therapeutic use of an SMN upregulator / corrector therapy (e.g., SMN1 gene therapy), in the treatment of presymptomatic SMA in a human patient, wherein the treatment comprises concurrent (e.g., simultaneous, separate, or sequential) administration of a composition comprising an SMN upregulator / corrector therapy, (e.g., an SMN1 gene therapy) and a composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab. In some embodiments, the patient has not previously received a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab before starting the SMN upregulator / corrector therapy. In some embodiments, the patient has previously received or is receiving a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab. In some embodiments, the patient is administered the SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) at age five years or younger. In some embodiments, the patient is administered the SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) at two years or younger (e.g., newborn to 24 months old). In some embodiments, the patient is administered the SMN upregulator / corrector therapy (e.g., SMN1 gene therapy) at age six weeks or younger (e.g., newborn to six weeks old). In some embodiments, the patient has two copies of the SMN2 gene. In some embodiments, the composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, is administered intravenously. In some embodiments, the composition comprising a myostatin-selective inhibitor, e.g., apitegromab, GYM329, or trevogrumab, is administered at a frequency of once every four weeks or once monthly. In some embodiments, the myostatin-selective inhibitor binds selectively to pro-latent myostatin. In some embodiments, the myostatin-selective inhibitor is apitegromab.

[0325]

[0284] In some embodiments, a myostatin-selective inhibitor is used in the treatment of SMA in a patient who is two months or older, who is treated with an SMN therapy, such as nusinersen, risdiplam, or onasemnogene abeparvovec-xioi. In some embodiments, the apitegromab is administered as an adjunct to an SMN upregulator therapy comprising nusinersen, risdiplam, or onasemnogene abeparvovec-xioi.

[0326]

[0285] In some embodiments, a myostatin-selective inhibitor is used in the treatment of presymptomatic SMA in a patient with up to three copies (e.g., two copies, three copies) ofthe SMN2 gene orwho has been Attorney Docket No. 15094.0063-00304 diagnosed with Type 1 SMA, wherein the patient receives or is receiving a gene therapy, such as onasemnogene abeparvovec-xioi. Optionally, the patient is six weeks or younger. Further optionally, the patient weighs between 2.6 kg and 21 .0 kg.

[0327]

[0286] In some embodiments, a myostatin-selective inhibitor is used in the treatment of SMA in a patient who is younger than 2 years old. In some embodiments, the patient had a gestational age of >35 weeks and gestational body weight >2.0 kg at birth. In some embodiments, the patient has a confirmed diagnosis of 5q autosomal recessive SMA. In some embodiments, the patient has been diagnosed with 5q autosomal recessive SMA before or at birth. In some embodiments, the patient has confirmed presence of at least one SMN2 gene copy. In some embodiments, the patient has been treated with an approved SMN1- targeted therapy (e.g, onasemnogene abeparvovec-xioi, an SMN1 gene therapy) or are continuing to be treated with an approved SMN2-targeted therapy (e.g., nusinersen or risdiplam, each an SMN2 upregulator therapy). In some embodiments, the patient has a body weight for age that is no less than 1stpercentile based on the World Health Organization (WHO) Child Growth Standards before myostatin-selective inhibitor treatment. In some embodiments, the patient has delayed motor milestones for age attributed to SMA or a CHOP-INTEND score <55. In some embodiments, the patient has a stable nutritional status throughout the treatment. In some embodiments, the patient does not require a gastric feeding tube. In some embodiments, the patient does not have major orthopedic issues (e.g., severe scoliosis, severe contractures, or interventional procedure (e.g., spine or hip surgery)) that have the potential to limit the ability of the subject to be evaluated on any motor function outcome measure within 6 months of beginning treatment or during treatment. In some embodiments, the patient does not have any other physical limitations (e.g., the subject requires cast for contractures) that would prevent the patient form undergoing motor function outcome measures throughout the treatment.

[0328]

[0287] In some embodiments, the present disclosure provides an SMN1 upregulator / corrector therapy (e.g., SMN1 gene therapy) for use in the treatment of presymptomatic SMA in a patient, wherein the treatment comprises administration of the SMN1 upregulator / corrector therapy (e.g., SMN1 gene therapy) to a presymptomatic patient in amounts effective to treat SMA, wherein the patient is administered the SMN1 upregulator / corrector therapy (e.g., SMN1 gene therapy) at six weeks or younger, wherein the patient is further treated with a myostatin-selective inhibitor, and wherein the myostatin-selective inhibitor is apitegromab, GYM329, or trevogrumab.

[0329]

[0288] The data disclosed herein further support the notion that myostatin inhibitor is helpful to improve SMA treatment in patients who receive SMN therapies. In particular, the data suggest that subpopulations of patients who experience or suffer from certain types of disease-related symptoms may particularly benefit from myostatin inhibitor therapy, pointing to patient selection considerations. Certain SMA patient subpopulations who are particularly likely to benefit from a myostatin inhibitor include but are not limited to the following cohorts of patients who manifest the indicated disease-related symptoms: patients who suffer from muscle weakness and / or tightness; patients who suffer from severe fatigue (for example, as assessed Attorney Docket No. 15094.0063-00304 by art-recognized measures, such as PROMIS); patients who suffer from difficulty with or impaired bulbar function (e.g., difficulty coughing, swallowing / feeding, difficulty chewing or smiling); patients who are prone to respiratory infections; and / or patients who suffer from difficulty with or impaired emptying (e.g., urgency and frequency of urination, and / or bowel movement). Accordingly, in some embodiments, a myostatin inhibitor is used in the treatment of SMA in a patient, wherein the treatment comprises administration of a myostatin inhibitor to treat SMA, wherein the patient has impaired bulbar function, wherein optionally, the patient has difficulty coughing, difficulty swallowing or feeding, and / or, difficulty chewing or smiling. In some embodiments, a myostatin inhibitor is used in the treatment of SMA in a patient, wherein the treatment comprises administration of a myostatin inhibitor to treat SMA, wherein the patient is prone to respiratory infections. In some embodiments, a myostatin inhibitor is used in the treatment of SMA in a patient, wherein the treatment comprises administration of a myostatin inhibitor to the patient who suffers from severe fatigue, wherein optionally the severity of fatigue is assessed by PROMIS. In some embodiments, a myostatin inhibitor is used in the treatment of SMA in a patient, wherein the treatment comprises administration of a myostatin inhibitor to the patient who has difficulty with or impaired emptying (e.g., urgency and frequency of urination, and / or bowel movement).

[0330]

[0289] Accordingly, the present disclosure provides patient selection considerations aimed to help identify SMA patients who are more likely to benefit from muscle-enhancing therapies, such as myostatin inhibitors. According to the present disclosure, a myostatin inhibitor is used in the treatment of SMA in a patient who receives an SMN therapy, wherein the patient suffers from muscle weakness / tightness, fatigue, impaired bulbar function (optionally, coughing, and / or difficulty swallowing or feeding), and / or, impaired emptying (optionally, urgency and frequency of urination, and / or bowel movement). In some embodiments, the myostatin inhibitors include agents that inhibit myostatin, GDF11 and Activin A. In some embodiments, the myostatin inhibitors include agents that inhibit myostatin and GDF11 but not Activin A. In preferred embodiments, the myostatin inhibitors are agents that selectively inhibit myostatin (i.e., myostatin-selective inhibitor) which do not bind or inhibit GDF11 or Activin A. Myostatin-selective inhibitors include neutralizing antibodies or antigen-binding fragments thereof that selectively bind myostatin but not GDF11 or Activin A, and antibodies or antigen-binding fragments thereof that bind pro / latent myostatin thereby inhibiting activation of mature myostatin. The latter includes, for example, apitegromab (SRK-015), GYM329 (RO7204239), variants thereof, or antibodies that cross-block or cross-compete for antigen binding with apitegromab or GYM329. In most preferred embodiments, the myostatin-selective inhibitor is apitegromab. Additional Indications

[0331]

[0290] Data presented herein indicate that the disclosed treatment regimens, e.g., including dose selections, for apitegromab may provide clinical benefit for human patients beyond those with 5q13.2 mutations and beyond those with any form of SMA. Non-5q13.2 mutations can result in early onset or late onset forms of SMA with a range of clinical phenotypes. Sequencing methods can detect a variety of genes associated with spinal muscular atrophy, which may present as conditions such as, but not limited to, early onset scapuloperoneal spinal muscular atrophy and Farber disease (Teoh et al. (2017) Neural Attorney Docket No. 15094.0063-00304

[0332] Plasticity 2017;2017:6509493. doi: 10.1 155 / 2017 / 6509493. Epub 2017 May 28; Axente et al. (2021) J. Medicine and Life 14(3):424-427).

[0333]

[0291] Apitegromab may provide clinical benefit for human patients diagnosed with other indications that share certain attributes of SMA. Such attributes include one or more of the criteria such as: disease with relatively young patient population, disease in which muscles are structurally intact or function is retained, disease that impacts fast-twitch fiber, and the availability of an established endpoint that relies on fast-twitch fibers.

[0334]

[0292] Beyond SMA, additional indications that may benefit from treatment with the antibodies disclosed herein (e.g., apitegromab) include but are not limited to dystrophies such as Becker’s muscular dystrophy, Becker’s muscular dystrophy with micro-dystrophin gene therapy, Duchenne’s muscular dystrophy, Duchenne’s muscular dystrophy with micro-dystrophin gene therapy, facioscapulohumeral muscular dystrophy (FSHD), and other muscular dystrophies, as well as Pompe Disease, Pompe disease with enzyme replacement therapy (including but not limited to Lumizyme and Nexviazyme), late-onset Pompe disease, post-cancer muscle recovery, and glucocorticoid-induced myopathy (e.g., in a subset of patients unable to discontinue steroid therapy). Becker’s muscular dystrophy may be particularly suitable for treatment with the antibodies disclosed herein (e.g., apitegromab). Becker’s muscular dystrophy patients typically have higher levels of circulating myostatin as compared to Duchenne’s muscular dystrophy patients (see, e.g., Burch et al. (2017) J Neurol. 264(3):541-553; Mariot et al. (2017) Nat Commun. 8: 1859). In other embodiments, the indication treated is amyotrophic lateral sclerosis (ALS). In other embodiments, the indication treated is post-cancer muscle recovery, e.g., post-cancer muscle recovery in pediatric patients (as some children may develop severe muscle wasting from chemotherapy). The antibodies disclosed herein (e.g., apitegromab) may be used as monotherapy or as add-on therapy to provide muscle- directed approaches to enhance other stabilizing treatments (e.g., treatments such as gene therapy in Duchenne’s muscular dystrophy or enzyme replacement therapy in lysosomal storage disorders).

[0335] Dosage Selection and Administration

[0336]

[0293] In various embodiments of the methods, uses, and compositions disclosed herein, an effective amount of an anti-pro / latent myostatin antibody (e.g., apitegromab) is administered to a human subject in need of the treatment via intravenous administration, e.g., by continuous infusion over a period of time.

[0337]

[0294] In some embodiments, apitegromab is administered to a patient as a weight-based dose, i.e., a dose dependent on the patient’s bodyweight. In some embodiments, suitable dosages of apitegromab include greater than 2 and up to 20 mg / kg, optionally about 5, 10, 15, or 20 mg / kg. In some embodiments, the therapeutic dose of apitegromab is 10 mg / kg. In some embodiments, the therapeutic dose of apitegromab is 20 mg / kg. In some embodiments, a dose greaterthan 20 mg / kg may be used while retaining a similar safety profile, although there may be diminished need for higher dosage given the surprisingly good therapeutic and PK profile of e.g., 20 mg / kg and 2 mg / kg, respectively. Attorney Docket No. 15094.0063-00304

[0338]

[0295] PK analyses of apitegromab show a correlation between drug clearance and age. These data indicate that younger patients (with lighter body weight) show slower clearance of apitegromab than older patients (with heavier body weight). This finding may point to dose selection for suitable intermediate doses to be, for example, 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12 mg / kg, 15 mg / kg, etc. Apitegromab demonstrated linear pharmacodynamics in both healthy volunteers and subjects treated with apitegromab with a mean terminal half-life of 23-40 days.

[0339]

[0296] Target engagement analyses from 6-month and 12-month studies indicated that apitegromab at 20 mg / kg achieved target saturation, whilst 2 mg / kg showed partial target engagement. In some embodiments, due to this target saturation at 20 mg / kg, a lower dose is used, e.g., a dose of 10 mg / kg. Target engagement analysis after 24-months was consistent with the earlier studies and further demonstrated that apitegromab target engagement correlated with motor function improvements. Both the amount of latent myostatin and the fold change in latent myostatin, when normalized to the age at which the subjects started treatment provide pharmacodynamic markers of improvements in motor function.

[0340]

[0297] In some embodiments, a suitable dosage of apitegromab is 20 mg / kg. In some embodiments, a suitable dose of apitegromab is 15 mg / kg. In some embodiments, a suitable dosage of apitegromab is 10 mg / kg. In some embodiments, the apitegromab is intravenously administered to a patient every four weeks or monthly at 5 mg / kg, 7.5 mg. kg, 10 mg / kg or 12 mg / kg.

[0341]

[0298] In some embodiments, apitegromab is administered to a patient at a dose of 20 mg / kg. In some embodiments, due to its favorable safety profile when administered at a dose of 20 mg / kg, apitegromab may be administered to a patient at a dose of more than 20 mg / kg, e.g., wherein the dose is upto 30 mg / kg, e.g., 25 mg / kg. In some embodiments, apitegromab is administered to a patient at a dose of more than 20 mg / kg (e.g., about 25 mg / kg, about 30 mg / kg). In some embodiments, apitegromab is intravenously administered to a patient at a dose of 10-20 mg / kg every four weeks or monthly.

[0342]

[0299] In some embodiments, apitegromab is initially administered to a patient at 2 mg / kg, and the dose is increased to a dose of at least 10 mg / kg (e.g., 10 mg / kg, 15 mg / kg, 20 mg / kg) at a later time if additional motor improvement is needed. In some embodiments, the dose is increased to at least 10 mg / kg after the patient has been treated with 2 mg / kg apitegromab for at least four months. In some embodiments, the dose is increased to at least 10 mg / kg after the patient has been treated with 2 mg / kg apitegromab for 6 months. In some embodiments, the dose is increased to at least 10 mg / kg afterthe patient has been treated with 2 mg / kg apitegromab for 12 months. In some embodiments, the dose is increased to at least 10 mg / kg after the patient has been treated with 2 mg / kg apitegromab for 24 months. In some embodiments, increasing the apitegromab dose from 2 mg / kg to at least 10 mg / kg (e.g., 10 mg / kg, 15 mg / kg, 20 mg / kg) produces a dose response, e.g., as determined by the subject’s latent myostatin concentrations. In some embodiments, motor improvement is measured by RULM. In some embodiments, motor improvement is measured by RHS. In some embodiments, motor improvement is measured by HFMSE. In some embodiments, motor improvement is measured by the achievement of WHO Development Milestones. Attorney Docket No. 15094.0063-00304

[0343]

[0300] In some embodiments, apitegromab is administered to a patient at a dose of less than 10 mg / kg. In some embodiments, apitegromab is administered to a patient at a dose of at least 0.5 mg / kg and less than 10 mg / kg. In some embodiments, apitegromab is administered to a patient at a dose of at least 0.75 mg / kg and less than 10 mg / kg. In some embodiments, apitegromab is administered to a patient at a dose of at least 0.75 mg / kg and no more than 7.5 mg / kg. In some embodiments, apitegromab is administered to a patient at a dose of 1 mg / kg, 1 .5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, or 7.5 mg / kg. In some embodiments, apitegromab is administered to a patient at a dose of 0.75 mg / kg. In some embodiments, apitegromab is administered to a patient at a dose of 7.5 mg / kg.

[0344]

[0301] In some embodiments, apitegromab is administered to a patient once every 2-6 weeks. In some embodiments, apitegromab is administered to a patient once every 2-5 weeks. In some embodiments, apitegromab is administered to a patient once every 2-4 weeks. In some embodiments, apitegromab is administered to a patient once every 3-6 weeks. In some embodiments, apitegromab is administered to a patient once every 3-5 weeks. In some embodiments, apitegromab is administered to a patient once every 3-4 weeks. In some embodiments, apitegromab is administered to a patient once every 4-6 weeks. In some embodiments, apitegromab is administered to a patient once every 4-5 weeks. In some embodiments, apitegromab is administered to a patient once every 5-6 weeks. In some embodiments, apitegromab is administered to a patient once every 2 weeks. In some embodiments, apitegromab is administered to a patient once every 3 weeks. In some embodiments, apitegromab is administered to a patient about once every fourweeks, once a month, etc. In some embodiments, apitegromab is administered to a patient once every 4 weeks. In some embodiments, apitegromab is administered to a patient once a month. In some embodiments, apitegromab is administered to a patient once every 5 weeks. In some embodiments, apitegromab is administered to a patient once every 6 weeks. Such antibody may be administered via intravenous injection / infusion, e.g., by intravenous infusion, or another suitable route of administration (e.g., subcutaneously (e.g., under the skin) or intrathecally (e.g., intra spinally). Similarly, an SMN upregulator, e.g., splice modifier, may be administered orally, e.g., by mouth, or another suitable route of administration.

[0345]

[0302] In some embodiments, the subject has received an SMN upregulator prior to the administration of the apitegromab. In some embodiments, the subject is concurrently receiving an SMN upregulator at the same time as the administration of the apitegromab. In some embodiments, the subject will receive an SMN upregulator after administration of the apitegromab.

[0346]

[0303] In some embodiments, the subject receiving an SMN upregulator is administered apitegromab at least 24 hours (e.g., at least 36 hours, at least 48 hours, or more) priorto a dose (e.g., a maintenance dose) of the SMN upregulator (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi). In some embodiments, the subject receiving an SMN upregulator is administered apitegromab at least 14 days (e.g., Attorney Docket No. 15094.0063-00304 least 21 days, or more) after a dose (e.g., a maintenance dose) of the SMN upregulator (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi).

[0347]

[0304] In some embodiments, the subject has received an SMN upregulator within 6 months of administration of the apitegromab. In some embodiments, the subject has received an SMN upregulator within three months of administration of the apitegromab. In some embodiments, the subject has received an SMN upregulator within 6 months, five months, four months, three months, two months, or one month of administration of the apitegromab. In some embodiments, the subject has received an SMN upregulator within four weeks, three weeks, two weeks, or one week of administration of the apitegromab. In some embodiments, the subject has received an SMN upregulator on the same day as administration of the apitegromab.

[0348]

[0305] In some embodiments, the subject is expected to receive an SMN upregulator within 6 months of administration of the apitegromab. In some embodiments, the subject is expected to receive an SMN upregulator within three months of administration of the apitegromab. In some embodiments, the subject is expected to receive an SMN upregulator within 6 months, five months, four months, three months, two months, or one month of administration of the apitegromab. In some embodiments, the subject is expected to receive an SMN upregulator within four weeks, three weeks, two weeks, or one week of administration of the apitegromab.

[0349]

[0306] In some embodiments, the SMN upregulator is an antisense nucleotide and is administered to the central nervous system of the subject via intrathecal injection. In some embodiments, the antisense nucleotide is administered to the subject every few months, e.g., monthly, every two months, every three months, every four months, every five months, every 6 months or every 12 months. In other embodiments, an initial treatment may involve more frequent dosing, followed by a less frequent maintenance dose thereafter.

[0350]

[0307] In some embodiments, the SMN upregulator is a small molecule and is orally administered to the subject. In some embodiments, the small molecule is administered to the subject daily. In other embodiments, the small molecule is administered to the subject weekly, biweekly, or monthly.

[0351]

[0308] In some embodiments, the SMN upregulator is a gene therapy and is administered via intravenous injection. In some embodiments, the SMN upregulator is a gene therapy and is administered via intrathecal injection. In some embodiments, an initial treatment may include more frequent dosing, followed by a less frequent maintenance dose thereafter. Less frequent maintenance doses may be preferable in order to avoid improper immune responses to the gene therapy.

[0352]

[0309] In some embodiments, the apitegromab is administered to the subject via intravenous administration, e.g., by intravenous infusion. In some embodiments, the apitegromab is administered once every four weeks or monthly, to the subject. In some embodiments, an initial treatment may involve more frequent dosing, followed by a less frequent maintenance dose thereafter. In some embodiments, Attorney Docket No. 15094.0063-00304 apitegromab may be initially dosed 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, an initial dose or doses of apitegromab may be administered at 20 mg / kg, followed by one or more lower dose (e.g., 15 mg / kg. 10 mg / kg, 5 mg / kg, 2 mg / kg, or 1 mg / kg), e.g., four weeks or one month after administration of the initial 20 mg / kg dose, e.g., wherein the one or more lower doses are administered once every four weeks or once monthly thereafter, or at longer intervals than was used for the loading dose.

[0353]

[0310] In some embodiments, the SMA therapy comprises intravenous administration of greater than 2 mg / kg and up to 20 mg / kg of apitegromab every four weeks or monthly. In some embodiments, the SMA therapy comprises intravenous administration of about 20 mg / kg of apitegromab every four weeks or monthly. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) may achieve disease stabilization such that a patient’s motorfunction is maintained overtime, or in other words, prevented from declining, contrary to the natural history of the disease, which predicts progression over time. In some embodiments, a net zero change in motor function scores over an appropriate baseline reflects disease stabilization. In some embodiments, the SMA therapy comprises intravenous administration of greater than 2 mg / kg and up to 20 mg / kg of apitegromab every four weeks or monthly. In some embodiments, the SMA therapy comprises intravenous administration of about 20 mg / kg of apitegromab every four weeks or monthly. In some embodiments, the SMA therapy comprises administering a therapeutically effective amount of apitegromab such that the administration is sufficient to increase the motor function of the subject by at least one milestone according to the WHO Motor Developmental Milestones. In some embodiments, the SMA therapy comprises administering a therapeutically effective amount of apitegromab such that the administration is sufficient to increase the motor function of the subject by one, two, orthree milestones according to the WHO Motor Developmental Milestones. In some embodiments, the WHO Motor Developmental Milestones include one or more of ability to walk independently, ability to stand independently, standing with assistance, hands and knees crawling, and / or walking with assistance.

[0354]

[0311] In some embodiments, the SMN therapy comprises intravenous administration of apitegromab at about 10 mg / kg to about 20 mg / kg once every four weeks for at least 52 weeks. In some embodiments, the SMN therapy comprises intravenous administration of apitegromab at about 10 mg / kg to about 20 mg / kg once monthly for at least 12 months. In some embodiments, the SMN therapy comprises intravenous administration of apitegromab at 10 mg / kg once every four weeks or monthly for at least 52 weeks or 12 months. In some embodiments, the SMN therapy comprises intravenous administration of apitegromab at 15 mg / kg once every four weeks or monthly for at least 52 weeks or 12 months. In some embodiments, the SMN therapy comprises intravenous administration of apitegromab at 20 mg / kg once every four weeks or monthly for at least 52 weeks or 12 months. In some embodiments, the SMN therapy comprises intravenous administration of apitegromab at about 10 mg / kg to about 20 mg / kg for 24 months or 2 years. In some embodiments, the SMN therapy comprises intravenous administration of apitegromab at 10 mg / kg for 24 months or 2 years. In some embodiments, the SMN therapy comprises intravenous administration of Attorney Docket No. 15094.0063-00304 apitegromab at 15 mg / kg for 24 months or 2 years. In some embodiments, the SMN therapy comprises intravenous administration of apitegromab at 20 mg / kg for 24 months or 2 years. In some embodiments, the SMN therapy comprises intravenous administration of apitegromab at about 10 mg / kg to 20 mg / kg for 36 months or 3 years. In some embodiments, the SMN therapy comprises intravenous administration of apitegromab at 10 mg / kg for 36 months or 3 years. In some embodiments, the SMN therapy comprises intravenous administration of apitegromab at 15 mg / kg for 36 months or 3 years. In some embodiments, the SMN therapy comprises intravenous administration of apitegromab at 20 mg / kg for 36 months or 3 years. In some embodiments, the SMN therapy comprises intravenous administration of apitegromab at about 10 mg / kg to about 20 mg / kg for 48 months or 4 years. In some embodiments, the SMN therapy comprises intravenous administration of apitegromab at 10 mg / kg for 48 months or 4 years. In some embodiments, the SMN therapy comprises intravenous administration of apitegromab at 15 mg / kg for 48 months or 4 years. In some embodiments, the SMN therapy comprises intravenous administration of apitegromab at 20 mg / kg for 48 months or 4 years.

[0355]

[0312] In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) may help maintain the disease status in a patient population that receives apitegromab, as compared to control group that does not. Maintenance of the disease status refers to preventing further deterioration of affected muscle, for example as assessed by changes in motor function overtime, in these patients. In some embodiments, treatment may slow the disease progression, e.g., as assessed by a slower rate of change in disease function as compared to a suitable baseline (e.g., an untreated patient). Therefore, even where no improvement in motor function test scores is shown, the apitegromab may provide clinical benefits by countering disease progression. Thus, such clinical benefits may present as a longer period of time observed where the patient population treated with the apitegromab maintains prior test scores or shows a slower rate of decrease in scores over time, as compared to a control group. In some embodiments, a patient or patient population receiving or in need of treatment with apitegromab may be compared to a control patient or patient population. In some embodiments, the control patient or patient population is a patient or patient population that does not receive apitegromab.

[0356]

[0313] In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) may slow the progression of the disease, e.g., by delaying a decrease in motor function as measured by a decreased score by HFMSE, RHS, MFM, MyoGrip or MyoPinch and / or by delaying a transition from ambulatory to non-ambulatory, delaying the need for respiratory aid or intervention, etc.

[0357]

[0314] Based on the surprising degree of clinical benefit achieved by selective inhibition of myostatin in human patients as demonstrated herein, it is contemplated that different myostatin-selective inhibitors (other than apitegromab) may be used in the treatment of SMA or other muscle disorders. Accordingly, the present disclosure includes a myostatin-selective inhibitor for use in the treatment of a muscle disorder, such as SMA, in a human subject, wherein optionally, the subject is further treated with a motor neuron- Attorney Docket No. 15094.0063-00304 directed therapy, wherein further optionally the motor neuron-directed therapy comprises an SMN upregulator therapy, such as SMN2 upregulator therapies and SMN1 gene therapies.

[0358] Biological Effects of Treatment

[0359]

[0315] In some embodiments, intravenous administration of apitegromab once every 4 weeks or once a month improves a patient’s HFMSE score by at least about 1 point as determined at 52 weeks or 12 months of apitegromab treatment as compared to baseline. In some embodiments, intravenous administration of apitegromab once every 4 weeks or once a month improves a patient’s HFMSE score by at least about 2 points (e.g., by 1.8 points) as determined at 52 weeks or 12 months of apitegromab treatment as compared to baseline. In some embodiments, the patient’s HFMSE score is improved by at least 3 points as determined at 52 weeks or 12 months of apitegromab treatment as compared to baseline. In some embodiments, the improvement in a patient’s HFMSE score is observed after 8 weeks or 2 months of apitegromab treatment. In some embodiments, the improvement in a patient’s HFMSE score is maintained after improving after 8 weeks or 2 months of apitegromab treatment to 52 weeks or 2 months. In some embodiments, the subject has declining motor function prior to the apitegromab treatment.

[0360]

[0316] In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) enhances motor function, such that an HFMSE score or an RHS score (e.g., an HFMSE score) measured at 24 months, 36 months, or 48 months after initiation of treatment is at least 1 , 3, 5, 7, or 10 points over a baseline, and wherein the baseline is obtained at or prior to initiation of the treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) produces at least a five-point increase in an HFMSE score relative to a baseline score after at least 24 months 36 months, or 48 months of treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) produces a 6-20 point or greater increase in an HFMSE score relative to a baseline score after at least 24 months of treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) produces at least a seven-point increase in an HFMSE score relative to a baseline score after at least 24 months 36 months, or 48 months of treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) produces an at least 2-point (e.g., at least 3-point, at least 4-point, or at least-5 point, at least 6-point) increase in an HFMSE score relative to a baseline after 12 months of apitegromab treatment, wherein the increase in HFMSE score is maintained at 24 months and at 36 months after initiating apitegromab treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) produces an at least 2-point (e.g., at least 3-point, at least 4-point, or at least-5 point, at least 6-point) increase in an HFMSE score relative to a baseline after 12 months of apitegromab treatment, wherein the increase in HFMSE score is maintained at 24 months, at 36 months, and 48 months after initiating apitegromab treatment. In some embodiments, the subject's improved HFMSE score over baseline as measured at 12 months after initiating apitegromab treatment is maintained or further increased at 24 months. In some embodiments, the subject's improved HFMSE score over baseline as measured at Attorney Docket No. 15094.0063-00304

[0361] 12 months after initiating apitegromab treatment is maintained or further increased at 36 months. In some embodiments, the subject's improved HFMSE score over baseline as measured at 12 months after initiating apitegromab treatment is maintained or further increased at 48 months. In some embodiments, the subject has declining motor function prior to the apitegromab treatment.

[0362]

[0317] In some embodiments, an improvement in a motor function score (e.g., an HFMSE or RHS score) may be positively correlated with SMA severity and / or the length of treatment time with an SMN-directed therapy (e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi). In some embodiments, an improvement in a motor function score (e.g., an HFMSE or RHS score) may be inversely correlated with age and / or characteristics of advanced disease. In some embodiments, a characteristic of advanced disease includes scoliosis and / or joint contractures. In some embodiments, joint contracture can occur due to shortening of muscles, tendons, ligaments, causing deformity and symptoms include pain and loss of movement in the joint. In some embodiments, a method of treating SMA comprises administering apitegromab therapy, either as monotherapy or in conjunction with (or in combination with) anothertherapy, to a patient lacking scoliosis and / or joint contracture. In some embodiments, apitegromab is used for treating SMA, either as monotherapy or in conjunction with (or in combination with) another therapy, in a patient lacking scoliosis and / or joint contracture.

[0363]

[0318] Despite chronic SMN-targeted treatments, SMA patients continue to lose function over time. SMN- targeted therapies prevent further degeneration of motor neurons, but do not directly address muscle atrophy. The current treatments available for SMA have limited effective duration in improving or stabilizing the disease as shown in Fig. 1 and Fig. 2. Patients receiving nusinersen or risdiplam experience improved motor function for approximately 1-2 years (for nusinersen), as measured by HFMSE score. Thereafter, motor function plateaus; after about 4 years, motor function shows a progressive loss over time, losing about 1 -point per year, despite being on SMN-targeted treatment, which is the current standard-of-care. The box indicating a similar time period to the patients in the SAPPHIRE clinical trial shows that the patients have declining motor function despite using the standard-of-care. Risdiplam shows a similar pattern of improved motor function followed by plateau and decline. Therefore, an unmet need exists for adjunct therapies to be used with SMN-directed therapies to provide long term improvement in motor function and / or stabilization of disease progression.

[0364]

[0319] In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) stabilizes disease progression, such that an HFMSE score or an RHS score measured at 6 months or 12 months after initiation of the treatment is no less than a baseline or no more than a 1 point decline, and wherein the baseline is obtained at or priorto initiation of the treatment, and optionally, wherein the stabilization is durable through at least 24 months, at least 36 months, or at least 48 months of treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) stabilizes disease progression, such that an RHS score comprises less than a one point, two point, or three point decline in the RHS score relative to a baseline score after at least 12 months of Attorney Docket No. 15094.0063-00304 treatment, and optionally, wherein the stabilization is durable through at least 24 months, at least 36 months, or at least 48 months of treatment. In some embodiments, the SMA therapy stabilizes the subject’s HFMSE score for at least 12 months or 52 weeks.

[0365]

[0320] In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) delays disease progression. In some embodiments, the delay in disease progression comprises a delay in the subject’s loss of motor function as compared to a subject who has not received apitegromab. In some embodiments, the delay in disease progression comprises a reduced rate of decline in the subject’s HFMSE score as compared to a subject who has not received apitegromab. In some embodiments, the treatment reduces the rate of decline in the subject’s HFMSE score by at least about 1 point per year (e.g., at least about 1 point per year, at least about 2 points per year, or at least 3 points per year) as compared to a subject who has not received apitegromab. In some embodiments, the delay of disease progression comprises a delay in the subject’s need for respiratory aid or intervention as compared to a subject who has not received apitegromab. In some embodiments, the delay of disease progression comprises a delay in a patient with ambulatory SMA from progressing from ambulatory SMA to nonambulatory SMA as compared to a subject who has not received apitegromab.

[0366]

[0321] In some embodiments, a patient with SMA (e.g., later-onset SMA) is evaluated using the Revised Upper Limb Module (RULM). The RULM is a 20-item assessment of upper limb function in non-ambulatory SMA patients (young children as well as adults) (Mazzone et al. (2017) Muscle Nerve. 55(6):869-874). The 19 scored items test functions that relate to everyday life, such as placing hands from lap, pressing a button, and picking up a token. The items are scored 0, 1 , 2, where 0 denotes unable, 1 denotes able with modification, and 2 denotes able with no difficulty. The maximum score achievable is 37. In some embodiments, the RULM is used to evaluate non-ambulatory SMA patients. In some embodiments, the RULM is completed by patients who are 30 months of age or older, e.g., at the time of the baseline assessment. In some embodiments, treatment with apitegromab improves a patient’s RULM score. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) produces an at least 0.5-point (e.g., at least 0.75, 1 , 1 .25, 1.5, 2., 2.25, or 2.5-point) increase in a RULM score relative to a baseline 12 months after initiating apitegromab treatment. In some embodiments, the increase in the RULM score compared to baseline is maintained at 24 months, at 36 months, or at 48 months after initiating apitegromab treatment. In some embodiments, the RULM score relative to baseline is further increased at 24 months, at 36 months, or at 48 months after initiating apitegromab treatment compared to the RULM score at 12 months after initiating apitegromab treatment. In some embodiments, the subject's improved RULM score over baseline as measured at 12 months after initiating apitegromab treatment is maintained or further increased at 24 months. In some embodiments, the subject's improved RULM score over baseline as measured at 12 months after initiating apitegromab treatment is maintained or further increased at 36 months. In some embodiments, the subject's improved RULM score over baseline as measured at 12 months after initiating apitegromab treatment is maintained or further increased at 48 months. In some embodiments, the subject has declining motor function prior to the apitegromab treatment. Attorney Docket No. 15094.0063-00304

[0367]

[0322] In some embodiments, intravenous administration of apitegromab once every 4 weeks or once a month improves a patient’s RULM score as determined at 52 weeks or 12 months of apitegromab treatment as compared to baseline. In some embodiments, the improvement in a patient’s RULM score is observed after 8 weeks or 2 months of apitegromab treatment. In some embodiments, the improvement in a patient’s RULM score is maintained after improving after 8 weeks or 2 months of apitegromab treatment to 52 weeks or 2 months.

[0368]

[0323] In some embodiments, a patient with SMA (e.g., later-onset SMA) is evaluated using World Health Organization (WHO) Motor Development Milestones. The WHO Multicentre Growth Reference Study (MGRS) generated growth curves for assessing the growth and development of infants and young children around the world (de Onis et al. (2004) Food Nutr Bull. 25 Suppl:S1 -89). The MGRS had as its primary objective the construction of curves and related tools to assess growth and development in children from birth to five years of age. Another feature of the MGRS is that it included the collection of ages of achievement of motor milestones, including gross motor development milestones such as sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone, and walking alone (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, WHO MGRS performance criteria for gross motor development are utilized to assess motor development milestones, e.g., in patients with Type 2 and non-ambulatory Type 3 SMA. In some embodiments, treatment with apitegromab improves a patient’s WHO MGRS score. In some embodiments, intravenous administration of apitegromab once every 4 weeks or once a month increases the number of WHO motor development milestones attained by the patient as determined at 52 weeks or 12 months of apitegromab treatment as compared to baseline.

[0369]

[0324] Motor function may be assessed by suitable means, such as HFMSE and / or RHS, the latter of which is often used to assess the motor function of ambulatory patients. In some embodiments, HFMSE is more frequently used to assess the motor function of non-ambulatory patients. An increase in the respective score over an appropriate baseline indicates motor function improvement. In some embodiments, the increase is at least one point, at least two points, at least three points, at least four points, or at least five points. In some embodiments, the increase is one point or greater, two points or greater, three points or greater, four points or greater, or five points or greater. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) enhances motor function, such that an HFMSE score or an RHS score (e.g., an HFMSE score) measured at 6 months or 12 months, 24 months, 36 months, or 48 months after initiation of treatment is at least 1 , 3, 5, 7, or 10 points over a baseline, and wherein the baseline is obtained at or prior to initiation of the treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) produces at least a 2-point increase in an HFMSE score relative to a baseline score after at least 12 months (e.g., after at least 24 months, after at least 36 months, or after at least 48 months) of treatment. In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) produces a 3 point or greater increase in an HFMSE Attorney Docket No. 15094.0063-00304 score relative to a baseline score after at least 12 months (e.g., after at least 24 months, after at least 36 months, or after at least 48 months) of treatment.

[0370]

[0325] In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) improves muscle function, such that the patient’s HFMSE score is increased by at least about 2 points (e.g., by at least about 1 .8, about 2, about 2.5, about 3, about 3.5, about 4 points) at 12 months of treatment compared to baseline.

[0371]

[0326] In some embodiments, an SMA therapy disclosed herein (e.g., an SMA therapy comprising apitegromab) can improve quality of life of the subject at 52 weeks or 12 months of apitegromab treatment as compared to baseline. In some embodiments, the improvement in quality of life comprises an increase in a Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) score as determined at 52 weeks or 12 months of apitegromab treatment as compared to baseline, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528). In some embodiments, the improvement in quality of life comprises a reduced level of fatigue severity at 52 weeks or 12 months of apitegromab treatment as compared to baseline and / or compared to a subject who has not received apitegromab, wherein, optionally, the level of fatigue severity is determined by a Patient Reported Outcomes Measurement Information System (PROMIS) score of the subject, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528).

[0372] Quality of Life

[0373]

[0327] While a few previous studies reported on the effect of SMA treatment, e.g., nusinersen, on global quality of life, those results have so far demonstrated mixed results with no conclusive evidence of a significant improvement in quality of life. For instance, Montes et al. measured the six-minute walk test (6MWT) and fatigue in 14 ambulatory children 2-15 years old with Type II (1) or III (13) SMA after receiving their first dose of nusinersen. Fatigue was considered as the subtractive difference in meters walked in the first minute compared to the meters walked in the sixth minute. They observed only a modest decrease or stabilization of 6MWT fatigue after nusinersen treatment and concluded that this modest effect may represent a nusinersen treatment effect but qualified the finding by noting that further understanding of the underlying mechanisms of fatigue may help understand the merely modest effect (Montes et al. (2019) Muscle Nerve 60(4) :409-414).

[0374]

[0328] Yao et al. assessed quality of life in children aged 17 or younger who were diagnosed with SMA and treated with nusinersen. As compared to children who did not receive nusinersen treatment, children who received nusinersen treatment had higher average scores in the Neuromuscular Diseases and Family Resources domains of the Pediatric Quality of Life Inventory 3.0 Neuromuscular Module (PedsQL NMM). However, the authors of the study cautioned that the results may not be conclusive due to the small sample size of children receiving nusinersen treatment (n=6). (Yao et al. (2021) Orphanet Journal of Rare Diseases 16:7.) Attorney Docket No. 15094.0063-00304

[0375]

[0329] Mix et al. evaluated global quality of life, health-related quality of life, and depressive symptoms in adolescent and adult patients with SMA under treatment with nusinersen and reported improvement in the patients’ subject feeling of health over the first 6 months of treatment but not in the patients’ subjective wellbeing. (Mix et al. (2021) Front Neurol 12:626787).

[0376]

[0330] Other studies reported no change in quality of life in SMA patients as a result of the therapies provided in reported clinical trials. A literature review of the quality of life studies in patients with SMA (Landfeldt et al. (2019) Eur. J. Paediatric Neurology 23:347) found four relevant publications from reported clinical trials: a phase 1 trial of nusinersen, a phase 2 trial of olesoxime and a phase 2 trial of l-carnitine and valproic acid. None of the studies reported any significant change in quality of life.

[0377]

[0331] Thimm et al. (2022) Frontiers in Neurology 12:8120 studied adult Type 2 or Type 3 SMA patients treated with nusinersen who were prospectively included in an assessment of health-related quality of life, measured by the short form of the Neuro-QoL for upper and lower extremity function prior to initiation of treatment and after 2, 6, 10 and 14 months of nusinersen treatment. The study did not show an improvement at any of the measured timepoints.

[0378]

[0332] An earlier study reported on HRQoL in children aged 2-4 years who were diagnosed with Type 2 or Type 3 SMA, where a slight but not significant increase was observed after 85 days of treatment with nusinersen (Chiriboga et al. (2016) Neurology 86:890-7). A comprehensive literature review (Yang et al. (2022) Adv Ther 39:1915) found that, while the SMN-targeted therapies have improved the prognosis of survival for SMA patients, no treatments, other than those of Chiriboga, demonstrated a significant improvement in HRQoL.

[0379]

[0333] In some embodiments, in contrast, the present disclosure demonstrates that apitegromab is the first muscle- directed treatment of SMA to provide improvements to the quality of life in patients with SMA. In some embodiments, these improvements are durable through at least 24 months of treatment. In some embodiments, these improvements are durable through at least 36 months of treatment. In some embodiments, these improvements are durable through at least 48 months of treatment.

[0380]

[0334] In some embodiments, quality of life is assessed by conducting an interview with the subject using a semi-structured interview guide that includes questions about the subject’s expectations about a meaningful improvement in their condition and their perception as to why they did or did not experience a meaningful improvement. The subject may be interviewed about their experiences with SMA and their treatment with respect to certain aspects of life, such as physical functioning, social impact, and emotional impact. Subjects may be asked to rate their quality of life by providing a score, e.g., on a scale of 0-10, where a score of zero indicates minimal impact on quality of life and a score of ten indicates extremely severe impact on quality of life.

[0381]

[0335] In some embodiments, a patient with SMA (e.g., later-onset SMA) is evaluated using one of the family of instruments developed by the EUROQOL, such as the EQ-5d-3L. EQ-5D-5L, EQ-5D-Y and EQ- Attorney Docket No. 15094.0063-00304

[0382] HWB. These multiutility instruments measure health-related quality of life. For example, the EQ-5D-5L is a descriptive system that comprises the dimensions of mobility, self-care, usual activities, pain / discomfort, and anxiety / depression.

[0383]

[0336] In some embodiments, treatment with apitegromab improves a subject’s Clinical Global Impression of Change (CGI-C). The CGI-C scores a clinician’s impression of the subject’s change in global health (Staunton et al. (2021) Health Qual Life Outcomes 19:184). In some embodiments, treatment with apitegromab improves a subject’s Pediatric QoL Inventory (PedsQL). The PedsQL consists of generic core scales and disease-specific modules, e.g., the neuromuscular module, which can be used to evaluate health-related QoL in children 2-18 years old with neuromuscular diseases, including SMA (lannaccone et al. (2009) Neuromus Disord 19:805-812). In some embodiments, treatment with apitegromab improves a subject’s Neuromuscular Gross Motor Outcome (GRO) score. The GRO is a gross motor outcome measure designed to assess whole body strength and function for all level of abilities across the lifespan of those with neuromuscular disease and has been validated in SMA types 1-3 (Alfano et al. (2021) Pediatric Neurology 122:21-26).

[0384]

[0337] In some embodiments, treatment with apitegromab is sufficient to improve one or more measures of quality of life in an SMA subject, e.g., at 24 months after initiating the apitegromab treatment, at 36 months after initiating the apitegromab treatment, and / or 48 months after initiating apitegromab treatment.

[0385]

[0338] In some embodiments, a patient with SMA (e.g., later-onset SMA) is evaluated, e.g., before and / or after treatment comprising apitegromab, using the Patient-reported Outcomes Measurement Information System (PROMIS). The PROMIS is a person-centered measure intended to be completed by the patient or parent proxy without help from anyone (Ader (2007) Med Care. 5(5):S1-S2). The fatigue profile domain measures a range of symptoms, from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion. The self-report measures are suitable for children 8-17 years old and the parent proxy report measures are suited for children 5-17 years old. Patients aged 18-21 may complete an adult form of PROMIS. In some embodiments, the PROMIS is completed by patients who are > 2 years of age, > 5 years of age or 5-21 years of age. In some embodiments, treatment with apitegromab improves a patient’s PROMIS score, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528).

[0386]

[0339] The Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) is a questionnaire completed by the caregiver that assesses the patient’s ability to perform daily functions (Haley et al. (2005) Arch Phys Med Rehabil. 86(5):932-939). A domain directed to activities of daily living (ADL) comprises 68 items directed to areas that include getting dressed, keeping clean, home tasks, etc. A domain directed to mobility comprises 75 items directed to areas that include basic movement and transfers, standing and walking, steps and inclines, etc. The answers are scored on a four-point scale (unable to easy) and the test is suitable to assess function in newborns to 21 -year-olds. Properties of the PEDI-CAT have been studied in and the test has been validated in the SMA population; a Rasch analysis revealed that the distribution of abilities for the Mobility and Daily Activities domains of the PEDI-CAT are Attorney Docket No. 15094.0063-00304 best represented in the Type 2 and Type 3 populations (Pasternak et al. (2016) Muscle Nerve. 54(6):1097- 1107).

[0387]

[0340] In some embodiments, a patient with SMA (e.g., later-onset SMA) is evaluated using the PEDI- CAT. In some embodiments, a caregiver (who may or may not be a parent and / or legal guardian) completes the PEDI-CAT assessment. In some embodiments, the PEDI-CAT assessment is not administered to the patient or if a caregiver is not present. In some embodiments, the PEDI-CAT is filled out by the caregiver in a location where they are not watching the patient perform any functional assessment tests. In some embodiments, treatment with apitegromab improves a patient’s PEDI-CAT score, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528).

[0388]

[0341] In some embodiments, treatment with apitegromab improves a subject’s quality of life as evaluated on the PEDI-CAT scale, wherein, optionally, the subject’s PEDI-CAT score may comprise a PEDI-CAT activities score and a PEDI-CAT mobility score. In some embodiments, treatment with apitegromab improves a subject’s quality of life by evaluating the subject’s level of fatigue, wherein, optionally, the subject’s fatigue may be evaluated by a Patient Reported Outcomes Measurement Information System (PROMIS) score and / or an Endurance Shuttle Block and Box Test (ESBBT) score. In some embodiments, treatment with apitegromab for 12 months is sufficient to increase the subject’s PEDI-CAT activities score as compared to before starting apitegromab treatment, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528). In some embodiments, treatment with apitegromab for 12 months is sufficient to increase the subject’s PEDI-CAT activities score by at least 1 .9 points (e.g., increase the subject’s PEDI-CAT activity score by about 2 points to about 4 points), increase the subject’s PEDI-CAT mobility score by at least 0.4 points (e.g., increase the subject’s PEDI-CAT mobility score by about 0.5 points to about 3 points), and / or decrease the subject’s PROMIS score by at least 5.5 points (e.g., decrease the subject’s PROMIS score by about 6 points to about 10 points) as compared to before starting apitegromab treatment, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528). wherein, optionally, the subject has non-ambulatory type 2 SMA and is at least two years of age. In some embodiments, the subject’s PEDI-CAT activities score is further increased at 24 months as compared to 12 months after starting apitegromab treatment, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528). In some embodiments, the subject’s PEDI- CAT activities score is further increased at 36 months as compared to 12 months after starting apitegromab treatment, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528). In some embodiments, the subject’s PEDI-CAT activities score is further increased at 48 months as compared to 12 months after starting apitegromab treatment e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528). In some embodiments, the subject’s PEDI-CAT activities score is maintained at 36 months as compared to 24 months after starting apitegromab treatment, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528). In some embodiments, the subject’s PEDI-CAT activities score is not decreased at 36 months as compared to 24 months after starting apitegromab treatment, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528). In some embodiments, the subject’s PEDI-CAT activities score is maintained at 48 months as compared to 36 months after starting apitegromab treatment, e.g., as seen in Attorney Docket No. 15094.0063-00304 subjects in the TOPAZ clinical trial (NCT03921528). In some embodiments, the subject’s PEDI-CAT activities score is not decreased at 48 months as compared to 36 months after starting apitegromab treatment, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528). In some embodiments, the subject has previously received an SMN upregulator / corrector therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi treatment, wherein the subject was first treated with the SMN upregulator / corrector therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi, before five years of age.

[0389]

[0342] In some embodiments, treatment with apitegromab for 12 months is sufficient to increase the subject’s PEDI-CAT activities score by at least 0.9 points (e.g., increase the subject’s PEDI-CAT score by about 1 point to about 3 points) and / or decrease the subject’s PROMIS score by at least 0.6 points (e.g., decrease the subject’s PROMIS score by about 1 point to about 6 points, or by about 4 points to about 35 points), e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528), wherein, optionally, the subject has non-ambulatory Type 2 SMA and is aged 5-21 years. In some embodiments, the subject’s PROMIS score is further decreased at 24 months as compared to 12 months after starting apitegromab treatment, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528). In some embodiments, the subject’s PROMIS score is further decreased at 36 months as compared to 12 months after starting apitegromab treatment, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528). In some embodiments, the subject’s PROMIS score is maintained at 36 months as compared to 24 months after starting apitegromab treatment, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528). In some embodiments, the subject’s PROMIS score is not increased at 36 months as compared to 24 months after starting apitegromab treatment, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528). In some embodiments, the subject’s PROMIS score is further decreased at 36 months as compared to 24 months after starting apitegromab treatment, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528). In some embodiments, the subject has previously received an SMN upregulator / corrector therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi treatment, wherein the subject was first treated with the SMN upregulator / corrector therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi after five years of age.

[0390]

[0343] In some embodiments, treatment with apitegromab for 24 months is sufficient to increase the subject’s PEDI-CAT activities score by at least 1.8 points (e.g., increase the subject’s PEDI-CAT activities score by about 2 to about 4 points), increase the subject’s PEDI-CAT mobility score by at least 0.4 points (e.g., increase the subject’s PEDI-CAT mobility score by about 0.4 to about 5 points), and / or decrease the subject’s PROMIS score by at least 5.0 points (e.g., decrease the subject’s PROMIS score by about 5 points to about 9 points), e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528), wherein, optionally, the subject has non-ambulatory Type 2 SMA and is at least two years of age. In some embodiments, the subject has previously received an SMN upregulator / corrector therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi treatment, wherein the subject was first treated with the Attorney Docket No. 15094.0063-00304

[0391] SMN upregulator / corrector therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi before five years of age.

[0392]

[0344] In some embodiments, treatment with apitegromab for 36 months is sufficient to increase the subject’s PEDI-CAT activities score by at least 1.7 points (e.g., increase the subject’s PEDI-CAT activities score by about 2 points to about 4 points), increase the subject’s PEDI-CAT mobility score by at least 1 .0 points (e.g., increase the subject’s PEDI-CAT mobility score by about 0.5 points to about 3 points), and / or decrease the subject’s PROMIS score by at least 5.0 points (e.g., decrease the subject’s PROMIS score by about 5 points to about 9 points), e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528), wherein, optionally, the subject has non-ambulatory Type 2 SMA and is at least two years of age. In some embodiments, the subject has previously received an SMN upregulator / corrector therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi treatment, wherein the subject was first treated with the SMN upregulator / corrector therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi before five years of age.

[0393]

[0345] In some embodiments, treatment with apitegromab for 24 months is sufficient to increase the subject’s PEDI-CAT activities score by at least 0.7 points (e.g., increase the subject’s PEDI-CAT activities score by about 1 point to about 3 points) and / or decrease the subject’s PROMIS score by at least 1.3 points (e.g., decrease the subject’s PROMIS score by about 2 points to about 7 points or by about 4 points to about 10 points), e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528), wherein, optionally, the subject has non-ambulatory Type 2 SMA and is aged 5-21 years. In some embodiments, the subject has previously received an SMN upregulator / corrector therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi treatment, wherein the subject was first treated with the SMN upregulator / corrector therapy, e.g., nusinersen, risdiplam, and / or onasemnogene abeparvovec-xioi after five years of age.

[0394]

[0346] In some embodiments, treatment with apitegromab is sufficient to increase the subject’s PEDI-CAT activities of daily living score at 12 months compared to baseline, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528), wherein, optionally, the subject’s PEDI-CAT activities of daily living score is further increased at 24 months compared to 12 months and, wherein, further optionally, the subject’s PEDI- CAT activities of daily living score at 36 months or 48 months is not decreased (e.g., maintained) compared to the subject’s PEDI-CAT activities of daily living score at 24 months. In some embodiments, treatment with apitegromab is sufficient to increase the subject’s PEDI-CAT mobility score at 12 months compared to baseline, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528), wherein, optionally, the subject’s PEDI-CAT mobility score is further increased at 24 months compared to 12 months and, wherein, further optionally, the subject’s PEDI-CAT mobility score is not decreased (e.g., maintained) at 36 months or 48 months compared to the subject’s PEDI-CAT mobility score at 24 months.

[0395]

[0347] In some embodiments, treatment with apitegromab is sufficient to decrease the subject’s PROMIS fatigue score at 12 months compared to baseline, e.g., as seen in subjects in the TOPAZ clinical trial Attorney Docket No. 15094.0063-00304

[0396] (NCT03921528), wherein, optionally, the subject’s PROMIS fatigue score is further decreased at 24 months compared to 12 months. In some embodiments, the subject's improvement in PROMIS fatigue score is maintained at 36 months, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528). In some embodiments, the subject's improvement in PROMIS fatigue score is further decreased at 36 months compared to 12 months, and / or 24 months, e.g., as seen in subjects in the TOPAZ clinical trial (NCT03921528).

[0397]

[0348] In some embodiments, treatment with apitegromab is sufficient to increase the subject’s ESBBT score at 12 months compared to baseline, wherein, optionally, the subject’s ESBBT score is further increased at 24 months compared to 12 months.

[0398]

[0349] The Columbia Suicide Severity Rating Scale (C-SSRS) measur...

Claims

1. Attorney Docket No. 15094.0063-00304CLAIMS1 . A composition comprising apitegromab for use in treating spinal muscular atrophy (SMA) in a subject in need thereof, wherein the treatment comprises intravenously administering to the subject 10 mg / kg to 20 mg / kg of apitegromab, wherein the subject has declining motor function prior to starting the apitegromab treatment, wherein the subject started receiving a survival motor neuron (SMN)-targeted therapy prior to starting the apitegromab treatment, and optionally wherein the treatment: a) stabilizes or delays disease progression in the subject as compared to a subject who has not received apitegromab; b) improves or stabilizes / maintains motor function in the subject as compared to baseline; and / or c) improves or stabilizes / maintains quality of life in the subject as compared to baseline.

2. The composition for use of claim 1 , wherein the subject has non-ambulatory SMA.

3. The composition for use of claim 1 , wherein the subject has ambulatory SMA.

4. The composition for use of claim 1 or claim 2, wherein the subject has Type 2 SMA.

5. The composition for use of any one of claims 1 -3, wherein the subject has Type 3 SMA.

6. The composition for use of any one of claims 1 -5, wherein the subject has been diagnosed with5q SMA.

7. The composition for use of any one of claims 1 -6, wherein the subject is 2-12 years of age.

8. The composition for use of any one of claims 1 -6, wherein the subject is 13-21 years of age.

9. The composition for use of any one of claims 1 -8, wherein the subject has at least 2 copies of survival motor neuron 2 (SMN2), optionally wherein the subject has 2-5 copies of SMN2 (e.g., 3 copies of SMN2).

10. The composition for use of any one of claims 1 -9, wherein the subject has a Hammersmith Functional Motor Scale-Expanded (HFMSE) score of about 8 to about 48 at baseline.11 . The composition for use of any one of claims 1 -10, wherein the subject’s motor function is determined by an HFMSE score, a 32-item Motor Function Measure (MFM32) score, a Revised Upper Limb Module (RULM) score, a Revised Hammersmith Scale (RHS) score, and / or a WHO developmental motor milestone.

12. The composition for use of any one of claims 1-11 , wherein the subject’s motor function is determined by an HFMSE score, and wherein the subject’s HFMSE score is declining at a rate of at least 1 point per year (e.g., at least 1 point per year, at least 2 points per year, or at least 3 points per year).

13. The composition for use of any one of claims 1 -12, wherein the subject’s motor function has been declining for at least 24 weeks or at least 6 months prior to starting the apitegromab treatment.Attorney Docket No. 15094.0063-0030414. The composition for use of any one of claims 1 , 2, and 5-13, wherein the subject’s decline in motor function comprises a progression of the subject’s SMA from ambulatory SMA to non-ambulatory SMA prior to starting to the apitegromab treatment.

15. The composition for use of any one of claims 1-14, wherein the subject is treated with apitegromab at an interval of once every four weeks or once a month.

16. The composition for use of any one of claims 1 -15, wherein the subject is treated with apitegromab for at least 52 weeks or at least 12 months (e.g., at least 48 months or at least 4 years).

17. The composition for use of any one of claims 1 -16, wherein the apitegromab is administered in an amount of 10 mg / kg.

18. The composition for use of any one of claims 1 -16, wherein the apitegromab is administered in an amount of 20 mg / kg.

19. The composition for use of any one of claims 1 -18, wherein the subject started receiving the SMN-targeted therapy before 5 years of age.

20. The composition for use of any one of claims 1 -18, wherein the subject started receiving the SMN-targeted therapy at or after 5 years of age.21 . The composition for use of any one of claims 1 -20, wherein the SMN-targeted therapy comprises nusinersen and / or risdiplam.

22. The composition for use of any one of claims 1 -21 , wherein the SMN-targeted therapy comprises nusinersen.

23. The composition for use of claim 22, wherein the subject has received nusinersen for at least 10 months (e.g., about 1 year to about 10 years or about 4 years to about 7 years) before starting the apitegromab treatment.

24. The composition for use of any one of claims 1 -21 , wherein the SMN-targeted therapy comprises risdiplam.

25. The composition for use of claim 24, wherein the subject has received risdiplam for at least 6 months (e.g., about 6 months to about 6 years or about 2 years to about 4 years) before starting the apitegromab treatment.

26. The composition for use of any one of claims 1 -25, wherein the treatment stabilizes or delays disease progression in a subject as compared to a subject who has not received apitegromab.

27. The composition for use of claim 26, wherein: a) the treatment stabilizes the subject’s HFMSE score at 8 weeks or 2 months after starting apitegromab treatment;Attorney Docket No. 15094.0063-00304 b) the treatment stabilizes the subject’s HFMSE score for at least 52 weeks or 12 months; c) the treatment results in a delay in the subject’s loss of motor function as compared to a subject who has not received apitegromab, optionally wherein motor function is determined by an HFMSE score; and / or d) the treatment results in a reduced rate of decline in the subject’s HFMSE score as compared to a subject who has not received apitegromab.

28. The composition for use of any one of claims 25-26, wherein the treatment reduces the rate of decline in the subject’s HFMSE score by at least about 1 point per year (e.g., at least about 1 point per year, at least about 2 points per year, or at least 3 points per year) as compared to a subject who has not received apitegromab.

29. The composition for use of any one of claims 1 , 3-13, and 15-27, wherein the subject has ambulatory SMA, and wherein the treatment results in a delay in the progression of the subject’s ambulatory SMA to non-ambulatory SMA as compared to a subject who has not received apitegromab.

30. The composition for use of any one of claims 1 -28, wherein the treatment comprises administering an amount of apitegromab sufficient to achieve one or more (e.g., all) of the following in the subject at 52 weeks or 12 months after starting apitegromab administration: a) an increase in HFMSE score of at least about 1 point (e.g., at least about 1 point, at least about 2 points, at least 3 points, at least 4 points) as compared to baseline; b) an increase in RULM score as compared to baseline; c) additional WHO motor milestones as compared to baseline; and d) a reduction in a rate of decline in the subject’s HFMSE score as compared to a subject who has not received apitegromab.

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