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

NCT ID: NCT05156320

Last Updated: 2026-01-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 188 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-04-14
• Study Completion Date: 2024-12-18

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Apitegromab

Intervention Type: 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.

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.

Group Type: EXPERIMENTAL

Apitegromab

Intervention Type: 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.

Main Efficacy Population (Placebo)

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

Exploratory Subpopulation (Apitegromab)

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

Group Type: EXPERIMENTAL

Apitegromab

Intervention Type: 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.

Exploratory Subpopulation (Placebo)

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

Interventions

Apitegromab

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.

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

Other Intervention Names

SRK-015

Eligibility Criteria

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

• 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.

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Scholar Rock, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Children's of Alabama

Birmingham, Alabama, United States

Phoenix Children's Hospital

Phoenix, Arizona, United States

Children's Hospital of Los Angeles

Los Angeles, California, United States

Stanford University Medical Center

Palo Alto, California, United States

Rady's Children's Hospital/UCSD

San Diego, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Nemours Children's Hospital

Orlando, Florida, United States

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

Chicago, Illinois, United States

University of Iowa

Iowa City, Iowa, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

The Johns Hopkins University

Baltimore, Maryland, United States

Boston Children's Hospital

Boston, Massachusetts, United States

Helen DeVos Children's Hospital

Grand Rapids, Michigan, United States

Gillette Children's Specialty Healthcare

Saint Paul, Minnesota, United States

Washington University School of Medicine in St. Louis

St Louis, Missouri, United States

Columbia University, SMA Clinical Research Center

New York, New York, United States

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

Oregon Health & Sciences University

Portland, Oregon, United States

Childrens Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

St. Jude Children's Research Hospital

Memphis, Tennessee, United States

Children's Medical Center Dallas

Dallas, Texas, United States

University of Utah

Salt Lake City, Utah, United States

Children's Hospital of The King's Daughters

Norfolk, Virginia, United States

Seattle Children's Hospital

Seattle, Washington, United States

University of Wisconsin School of Medicine and Public Health

Madison, Wisconsin, United States

UZ Gent

Ghent, , Belgium

UZ Leuven

Leuven, , Belgium

Chr de La Citadelle

Liège, , Belgium

CHU Lille - Hôpital Jeanne de Flandre

Lille, , France

Hôpital Armand Trousseau, I-Motion

Paris, , France

CHU Toulouse - Hopital des Enfants

Toulouse, , France

Universitätsklinikum Bonn

Bonn, , Germany

Universitätsklinikum Essen

Essen, , Germany

Universitaetsklinikum Freiburg

Freiburg im Breisgau, , Germany

Dr. von Haunersches Kinderspital

Munich, , Germany

IRCCS Istituto Giannina Gaslini

Genoa, , Italy

A.O.U Policlinico G. Martino

Messina, , Italy

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

Milan, , Italy

ASST Grande Ospedale Metropolitano Niguarda

Milan, , Italy

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

Roma, , Italy

Universitair Medisch Centrum Utrecht

Utrecht, , Netherlands

Uniwersyteckie Centrum Kliniczne w Gdańsku

Gdansk, , Poland

Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu

Poznan, , Poland

Instytut Pomnik - Centrum Zdrowia Dziecka: CZD Warszawa

Warsaw, , Poland

Hospital Sant Joan de Déu

Barcelona, , Spain

Hospital Universitario y Politécnico La Fe

Valencia, , Spain

Leeds Teaching Hospitals NHS Trust

Leeds, , United Kingdom

Great Ormond Street Hospital for Children NHS Foundation Trust

London, , United Kingdom

University of Oxford

Oxford, , United Kingdom

Countries

United States; Belgium; France; Germany; Italy; Netherlands; Poland; Spain; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 40818473 (View on PubMed)

Other Identifiers

SRK-015-003

Identifier Type: -

Identifier Source: org_study_id