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

NCT05156320 | Completed Phase 3 DMC FDA Drug

• 1 other identifier: SRK-015-003
• Study Type: interventional
• Target: 188
• Locations: 9 countries
• Sites: 50

Brief 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.

Conditions

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

Outcome Measures

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.

  Baseline up to 12 months.

Secondary Outcomes (7)

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

  Baseline up to 12 months.

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

  Baseline up to 12 months.

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

  Baseline up to 12 months.

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

  Baseline up to 12 months.

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

  Baseline up to 12 months.

Study Arms (5)

Main Efficacy Population (Apitegromab 10 mg/kg)

EXPERIMENTAL

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

Drug: Apitegromab

Main Efficacy Population (Apitegromab 20 mg/kg)

EXPERIMENTAL

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

Drug: Apitegromab

Main Efficacy Population (Placebo)

PLACEBO COMPARATOR

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

Drug: Placebo

Exploratory Subpopulation (Apitegromab)

EXPERIMENTAL

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

Drug: Apitegromab

Exploratory Subpopulation (Placebo)

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Apitegromab DRUG

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

Exploratory Subpopulation (Apitegromab); Main Efficacy Population (Apitegromab 10 mg/kg); Main Efficacy Population (Apitegromab 20 mg/kg)

Placebo DRUG

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

Exploratory Subpopulation (Placebo); Main Efficacy Population (Placebo)

Eligibility Criteria

• Age: 2 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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:
• 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;
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Scholar Rock, Inc.: lead

Study Sites (50)

Children's of Alabama

Birmingham, Alabama, 35233, United States

Location

Phoenix Children's Hospital

Phoenix, Arizona, 85016, United States

Location

Children's Hospital of Los Angeles

Los Angeles, California, 90027, United States

Location

Stanford University Medical Center

Palo Alto, California, 94304, United States

Location

Rady's Children's Hospital/UCSD

San Diego, California, 92123, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Nemours Children's Hospital

Orlando, Florida, 32827, United States

Location

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

The Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Helen DeVos Children's Hospital

Grand Rapids, Michigan, 49503, United States

Location

Gillette Children's Specialty Healthcare

Saint Paul, Minnesota, 55101, United States

Location

Washington University School of Medicine in St. Louis

St Louis, Missouri, 63110, United States

Location

Columbia University, SMA Clinical Research Center

New York, New York, 10032, United States

Location

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, 27157, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Oregon Health & Sciences University

Portland, Oregon, 97239, United States

Location

Childrens Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Children's Medical Center Dallas

Dallas, Texas, 75235, United States

Location

University of Utah

Salt Lake City, Utah, 84112, United States

Location

Children's Hospital of The King's Daughters

Norfolk, Virginia, 23507, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

University of Wisconsin School of Medicine and Public Health

Madison, Wisconsin, 53705, United States

Location

UZ Gent

Ghent, 9000, Belgium

Location

UZ Leuven

Leuven, 3000, Belgium

Location

Chr de La Citadelle

Liège, 4000, Belgium

Location

CHU Lille - Hôpital Jeanne de Flandre

Lille, 59037, France

Location

Hôpital Armand Trousseau, I-Motion

Paris, 75012, France

Location

CHU Toulouse - Hopital des Enfants

Toulouse, 31059, France

Location

Universitätsklinikum Bonn

Bonn, 53127, Germany

Location

Universitätsklinikum Essen

Essen, 45147, Germany

Location

Universitaetsklinikum Freiburg

Freiburg im Breisgau, 79106, Germany

Location

Dr. von Haunersches Kinderspital

Munich, 80337, Germany

Location

IRCCS Istituto Giannina Gaslini

Genoa, Italy

Location

A.O.U Policlinico G. Martino

Messina, 98125, Italy

Location

Foundation I.R.C.C.S. Carlo Besta Neurological Institute

Milan, 20133, Italy

Location

ASST Grande Ospedale Metropolitano Niguarda

Milan, 20162, Italy

Location

Centro Clinico Nemo Pediatrico Policlinico A. Gemelli-Università Cattolica Sacro Cuore

Roma, 00168, Italy

Location

Universitair Medisch Centrum Utrecht

Utrecht, 3584, Netherlands

Location

Uniwersyteckie Centrum Kliniczne w Gdańsku

Gdansk, 80-001, Poland

Location

Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu

Poznan, 61-701, Poland

Location

Instytut Pomnik - Centrum Zdrowia Dziecka: CZD Warszawa

Warsaw, 04-736, Poland

Location

Hospital Sant Joan de Déu

Barcelona, Spain

Location

Hospital Universitario y Politécnico La Fe

Valencia, Spain

Location

Leeds Teaching Hospitals NHS Trust

Leeds, LS1 3EX, United Kingdom

Location

Great Ormond Street Hospital for Children NHS Foundation Trust

London, United Kingdom

Location

University of Oxford

Oxford, OX3 0ER, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 40818473 DERIVED

MeSH Terms

Conditions

Muscular Atrophy, Spinal; Spinal Muscular Atrophies of Childhood; Neuromuscular Diseases; Muscular Atrophy; Atrophy; Neuromuscular Manifestations

Interventions

apitegromab

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Neurologic Manifestations; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Active treatment, randomized, double-blind, placebo-controlled.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2021
• First Posted: December 14, 2021
• Study Start: April 14, 2022
• Primary Completion: December 18, 2024
• Study Completion: December 18, 2024
• Last Updated: January 22, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

FR (3); BE (3); NL (1); PL (3); US (26); ES (2); GB (3); DE (4); IT (5)