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CompletedNCT05156320SAPPHIREUpdated Jan 22, 2026

Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam

A Phase 3 interventional study of Apitegromab and Placebo in Spinal Muscular Atrophy, Spinal Muscular Atrophy Type 3 and Spinal Muscular Atrophy Type 2, sponsored by Scholar Rock, Inc.. Completed at 50 sites in 9 countries. Open to participants aged 2 Years to 21 Years. Per ClinicalTrials.gov, last updated 2026-01-22.

Sponsored by Scholar Rock, Inc. · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
188
Allocation
Randomized
Ages
2 Years to 21 Years
Sex
All
01

Study summary

This Phase 3 trial (Study SRK-015-003) was conducted in patients ≥2 years old at Screening, who were previously diagnosed with later-onset spinal muscular atrophy (SMA) (i.e., Type 2 and Type 3 SMA) and were receiving an approved survival motor neuron (SMN) upregulator therapy (i.e., either nusinersen or risdiplam), to confirm the efficacy and safety of apitegromab as an adjunctive therapy to nusinersen and evaluate the efficacy and safety of apitegromab as an adjunctive therapy to risdiplam.

02

Conditions studied

  • Spinal Muscular Atrophy
  • Spinal Muscular Atrophy Type 3
  • Spinal Muscular Atrophy Type 2
  • SMA
  • Neuromuscular Diseases
  • Muscular Atrophy
  • Atrophy
  • Muscular Atrophy, Spinal
  • Neuromuscular Manifestations
  • Anti-myostatin
03

Who can participate

Ages eligible
2 Years to 21 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Males and females 2 through 21 years old at Screening.
  • Documented diagnosis of 5q SMA.
  • Diagnosed with later-onset SMA (i.e., Type 2 and Type 3 SMA) before receiving an approved SMN upregulator therapy (i.e., either nusinersen or risdiplam).
  • Must be Nonambulatory at Screening. Nonambulatory patients must be able to sit independently (sits up straight with head erect for at least 10 seconds; does not use arms or hands to balance body or support position) per World Health Organization (WHO) motor milestones definition at Screening.
  • Receiving one background therapy for SMA (i.e., either nusinersen or risdiplam) for the time period specified below and anticipated to remain on that same treatment throughout the trial:

    1. If receiving the SMN upregulator therapy nusinersen, must have completed at least 10 months of dosing (i.e., completed the loading regimen and at least 2 maintenance doses) before Screening;
    2. If receiving the SMN upregulator therapy risdiplam, must have completed at least 6 months of dosing before Screening.
  • Motor Function Score (HFMSE) ≥10 and ≤45 at Screening.
  • Have no physical limitations that would prevent the patient from undergoing motor function outcome measures throughout the duration of the study.
  • Able to receive study drug infusions and provide blood samples through the use of a peripheral intravenous (IV) or a long-term IV access device that the patient has placed for reasons independent from the study throughout the duration of the study.
  • Able to adhere to the requirements of the protocol, including travel to the study center and completing all study procedures and study visits.
  • For patients who are expected to have reached reproductive maturity by the end of the study, adhere to study specific contraception requirements.

Exclusion criteria

Exclusion Criteria:

  • Received ZOLGENSMA® (onasemnogene abeparvovec-xioi) at any time and previous treatment with apitegromab.
  • Use of invasive ventilation and tracheostomy.
  • Use of chronic daytime non-invasive ventilatory support for >16 hours daily in the 2 weeks prior to dosing, or anticipated to regularly receive such daytime ventilator support chronically over the duration of the study.
  • Any acute or co-morbid condition interfering with the well-being of the patient within 7 days of screening, including active systemic infection, the need for acute treatment or inpatient observation due to any reason.
  • Severe scoliosis and/or contractures at screening. Based on clinical judgement, any scoliosis or contractures present must be stable over the past 6 months, anticipated to be stable for the duration of the study and not prevent the patient from being evaluated on any functional outcome measures throughout the duration of the study.
  • Pregnant or breastfeeding.
  • Major orthopedic or other interventional procedure, including spine or hip surgery, considered to have the potential to substantially limit the ability of the patient to be evaluated on any functional outcome measures, within 6 months prior to Screening, or anticipated for the duration of the study.
  • Prior history of a hypersensitivity reaction to a monoclonal antibody (mAb) or recombinant protein bearing an Fc domain (such as a soluble receptor-Fc fusion protein), apitegromab, or excipients of apitegromab.
  • Treatment with investigational drugs within 3 months prior to Screening.
  • Use of therapies with potentially significant muscle effects (such as androgens, insulin-like growth factor, growth hormone, systemic beta-agonist, botulinum toxin, or muscle relaxants or muscle-enhancing supplements) or potentially significant neuromuscular effects (such as acetylcholinesterase inhibitors) within 60 days prior to screening.
  • Nutritional status not stable over the past 6 months and not anticipated to be stable throughout the duration of the study.
  • Patient has any other condition, which in the opinion of the Investigator may compromise safety or compliance, would preclude the patient from successful completion of the study, or interfere with the interpretation of the results.
04

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
188 participants (actual)

Study arms

  • Experimental
    Main Efficacy Population (Apitegromab 10 mg/kg)

    Aged 2-12 years at Screening. Participants were randomized to receive apitegromab 10 mg/kg for up to 52 weeks.

    Drug: Apitegromab

  • Experimental
    Main Efficacy Population (Apitegromab 20 mg/kg)

    Aged 2-12 years at Screening. Participants were randomized to receive apitegromab 20 mg/kg for up to 52 weeks.

    Drug: Apitegromab

  • Placebo comparator
    Main Efficacy Population (Placebo)

    Aged 2-12 years at Screening. Participants were randomized to receive placebo for up to 52 weeks.

    Drug: Placebo

  • Experimental
    Exploratory Subpopulation (Apitegromab)

    Aged 13-21 years at Screening. Participants were randomized to receive apitegromab 20 mg/kg for up to 52 weeks.

    Drug: Apitegromab

  • Placebo comparator
    Exploratory Subpopulation (Placebo)

    Aged 13-21 years at Screening. Participants were randomized to receive placebo for up to 52 weeks.

    Drug: Placebo

Interventions

  • DrugApitegromab

    Apitegromab is a fully human anti-proMyostatin monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4)/lambda isotype that specifically binds to human pro/latent myostatin with high affinity inhibiting myostatin activation. SRK-015 was administered every 4 weeks by intravenous (IV) infusion.

    Also known as: SRK-015

  • DrugPlacebo

    Placebo was administered every 4 weeks by intravenous (IV) infusion.

05

What researchers measure

Primary outcomes

  1. Main Efficacy Population: Change from Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) total score.

    The HFMSE assesses the physical abilities of patients with Type 2 and Type 3 SMA. It comprises of 33 items graded on a scale of 0, 1, or 2, where 0 denotes unable, 1 denotes performed with modification or adaptation, and 2 denotes performed without modification or adaptation. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate increased motor function.

    Time frame: Baseline up to 12 months.

Secondary outcomes

  1. Main Efficacy Population: Change from Baseline in Revised Upper Limb Module (RULM) total score.

    The RULM is a 20 item assessment of upper limb function in nonambulatory patients with SMA that was performed for patients who were 30 months of age or older at baseline. The 19 scored items assess functions that relate to everyday life, such as pressing a button and picking up a token; these items are scored 0, 1, or 2, where 0 denotes unable, 1 denotes able with modification, and 2 denotes able with no modification. The maximum score achievable is 37. Higher scores increased great upper limb function.

    Time frame: Baseline up to 12 months.

  2. Main Efficacy Population: Proportion of patients with ≥3-point change from Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) total score.

    The HFMSE assesses the physical abilities of patients with Type 2 and Type 3 SMA. It comprises of 33 items graded on a scale of 0, 1, or 2, where 0 denotes unable, 1 denotes performed with modification or adaptation, and 2 denotes performed without modification or adaptation. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate increased motor function.

    Time frame: Baseline up to 12 months.

  3. Main Efficacy Population: Change from Baseline in number of WHO motor development milestones attained at 12 months.

    Time frame: Baseline up to 12 months.

  4. Main Efficacy Population and Exploratory Subpopulation combined: Incidence of Treatment Emergent Adverse Events (TEAEs) and Severe Adverse Events (SAEs) by severity.

    Time frame: Baseline up to 12 months.

  5. Main Efficacy Population and Exploratory Subpopulation combined: Apitegromab concentrations in serum from blood samples.

    Time frame: Baseline up to 12 months.

  6. Main Efficacy Population and Exploratory Subpopulation combined: Circulating latent myostatin concentrations in blood samples.

    Time frame: Baseline up to 12 months.

  7. Main Efficacy Population and Exploratory Subpopulation combined: Presence or absence of Antidrug Antibody (ADA) against apitegromab in serum from blood samples.

    Time frame: Baseline up to 12 months.

06

Study locations

50 sites
  • Children's of Alabama
    Birmingham, Alabama 35233, United States
  • Phoenix Children's Hospital
    Phoenix, Arizona 85016, United States
  • Children's Hospital of Los Angeles
    Los Angeles, California 90027, United States
  • Stanford University Medical Center
    Palo Alto, California 94304, United States
  • Rady's Children's Hospital/UCSD
    San Diego, California 92123, United States
  • Children's Hospital Colorado
    Aurora, Colorado 80045, United States
  • Nemours Children's Hospital
    Orlando, Florida 32827, United States
  • Ann & Robert H. Lurie Children's Hospital of Chicago
    Chicago, Illinois 60611, United States
  • University of Iowa
    Iowa City, Iowa 52242, United States
  • University of Kansas Medical Center
    Kansas City, Kansas 66160, United States
  • The Johns Hopkins University
    Baltimore, Maryland 21287, United States
  • Boston Children's Hospital
    Boston, Massachusetts 02115, United States
  • Helen DeVos Children's Hospital
    Grand Rapids, Michigan 49503, United States
  • Gillette Children's Specialty Healthcare
    Saint Paul, Minnesota 55101, United States
  • Washington University School of Medicine in St. Louis
    St Louis, Missouri 63110, United States
  • Columbia University, SMA Clinical Research Center
    New York, New York 10032, United States
  • Wake Forest Baptist Medical Center
    Winston-Salem, North Carolina 27157, United States
  • Nationwide Children's Hospital
    Columbus, Ohio 43205, United States
  • Oregon Health & Sciences University
    Portland, Oregon 97239, United States
  • Childrens Hospital of Philadelphia
    Philadelphia, Pennsylvania 19104, United States
  • St. Jude Children's Research Hospital
    Memphis, Tennessee 38105, United States
  • Children's Medical Center Dallas
    Dallas, Texas 75235, United States
  • University of Utah
    Salt Lake City, Utah 84112, United States
  • Children's Hospital of The King's Daughters
    Norfolk, Virginia 23507, United States
  • Seattle Children's Hospital
    Seattle, Washington 98105, United States
  • University of Wisconsin School of Medicine and Public Health
    Madison, Wisconsin 53705, United States
  • UZ Gent
    Ghent, 9000, Belgium
  • UZ Leuven
    Leuven, 3000, Belgium
  • Chr de La Citadelle
    Liège, 4000, Belgium
  • CHU Lille - Hôpital Jeanne de Flandre
    Lille, 59037, France
  • Hôpital Armand Trousseau, I-Motion
    Paris, 75012, France
  • CHU Toulouse - Hopital des Enfants
    Toulouse, 31059, France
  • Universitätsklinikum Bonn
    Bonn, 53127, Germany
  • Universitätsklinikum Essen
    Essen, 45147, Germany
  • Universitaetsklinikum Freiburg
    Freiburg im Breisgau, 79106, Germany
  • Dr. von Haunersches Kinderspital
    Munich, 80337, Germany
  • IRCCS Istituto Giannina Gaslini
    Genoa, Italy
  • A.O.U Policlinico G. Martino
    Messina, 98125, Italy
  • Foundation I.R.C.C.S. Carlo Besta Neurological Institute
    Milan, 20133, Italy
  • ASST Grande Ospedale Metropolitano Niguarda
    Milan, 20162, Italy
  • Centro Clinico Nemo Pediatrico Policlinico A. Gemelli-Università Cattolica Sacro Cuore
    Roma, 00168, Italy
  • Universitair Medisch Centrum Utrecht
    Utrecht, 3584, Netherlands
  • Uniwersyteckie Centrum Kliniczne w Gdańsku
    Gdansk, 80-001, Poland
  • Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu
    Poznan, 61-701, Poland
  • Instytut Pomnik - Centrum Zdrowia Dziecka: CZD Warszawa
    Warsaw, 04-736, Poland
  • Hospital Sant Joan de Déu
    Barcelona, Spain
  • Hospital Universitario y Politécnico La Fe
    Valencia, Spain
  • Leeds Teaching Hospitals NHS Trust
    Leeds, LS1 3EX, United Kingdom
  • Great Ormond Street Hospital for Children NHS Foundation Trust
    London, United Kingdom
  • University of Oxford
    Oxford, OX3 0ER, United Kingdom
07

References and documents

Publications

  • Crawford TO, Servais L, Mercuri E, Kolbel H, Kuntz N, Finkel RS, Krueger J, Batley K, Young SD, Marantz JL, Song G, Yao B, Zhao G, Rossello J, Tirucherai GS, Mazzone ES, Butterfield RJ, de la Banda MGG, Seferian AM, Sansone VA, De Waele L, van der Pol WL, Cances C, Pechmann A, Darras BT; SAPPHIRE Study Group. Safety and efficacy of apitegromab in nonambulatory type 2 or type 3 spinal muscular atrophy (SAPPHIRE): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2025 Sep;24(9):727-739. doi: 10.1016/S1474-4422(25)00225-X. PubMed 40818473 ↗

Individual participant data

Plan to share: No

08

Registry details

Key details

Study ID
NCT05156320
Lead sponsor
Scholar Rock, Inc.
Responsible party
Sponsor
First posted
Dec 14, 2021
Start date
Apr 14, 2022
Primary completion
Dec 18, 2024
Completion
Dec 18, 2024
Last update
Jan 22, 2026

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
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