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

Phase 3, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Apitegromab (SRK-015) in Patients With Later-Onset Spinal Muscular Atrophy Receiving Background Nusinersen or Risdiplam Therapy

This Phase 3 trial (Study SRK-015-003) is being 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 are 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Neuromuscular Diseases; Neuromuscular Manifestations; Atrophy; Muscular Atrophy; Spinal Muscular Atrophy; Muscular Atrophy, Spinal; Spinal Muscular Atrophy Type 3; SMA; Spinal Muscular Atrophy Type 2; Anti-myostatin
• Intervention / Treatment: Drug: Apitegromab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 188
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Main Efficacy Population (Apitegromab 10 mg/kg); Type 2 SMA and Nonambulatory Type 3 SMA, ages 2 through 12 years old at Screening. Participants will be randomized to receive apitegromab 10 mg/kg for up to 52 weeks.	Drug: 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 will be administered every 4 weeks by intravenous (IV) infusion.; Other Names: SRK-015
Experimental: Main Efficacy Population (Apitegromab 20 mg/kg); Type 2 SMA and Nonambulatory Type 3 SMA, ages 2 through 12 years old at Screening. Participants will be randomized to receive apitegromab 20 mg/kg for up to 52 weeks.	Drug: 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 will be administered every 4 weeks by intravenous (IV) infusion.; Other Names: SRK-015
Placebo Comparator: Main Efficacy Population (Placebo); Type 2 SMA and Nonambulatory Type 3 SMA, ages 2 through 12 years old at Screening. Participants will be randomized to receive placebo for up to 52 weeks.	Drug: Placebo; Placebo will be administered every 4 weeks by intravenous (IV) infusion.
Experimental: Exploratory Subpopulation (Apitegromab); Type 2 SMA and Nonambulatory Type 3 SMA, ages 13 through 21 years old at Screening. Participants will be randomized to receive apitegromab 20 mg/kg for up to 52 weeks.	Drug: 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 will be administered every 4 weeks by intravenous (IV) infusion.; Other Names: SRK-015
Placebo Comparator: Exploratory Subpopulation (Placebo); Type 2 SMA and Nonambulatory Type 3 SMA, ages 13 through 21 years old at Screening. Participants will be randomized to receive placebo for up to 52 weeks.	Drug: Placebo; Placebo will be administered every 4 weeks by intravenous (IV) infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline up to 12 months.
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.	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.
Main Efficacy Population and Exploratory Subpopulation combined: Circulating latent myostatin concentrations in blood samples.		Baseline up to 12 months.
Main Efficacy Population and Exploratory Subpopulation combined: Presence or absence of ADA against apitegromab in serum from blood samples.		Baseline up to 12 months.

Collaborators and Investigators

• Sponsor: Scholar Rock, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2022
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: December 1, 2021
• First Submitted That Met QC Criteria: December 1, 2021
• First Posted (Actual): December 14, 2021

Study Record Updates

• Last Update Posted (Actual): October 12, 2023
• Last Update Submitted That Met QC Criteria: October 11, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Genetic Diseases, Inborn; Neurodegenerative Diseases; Pathological Conditions, Anatomical; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Motor Neuron Disease; Muscular Atrophy; Atrophy; Muscular Atrophy, Spinal; Neuromuscular Manifestations; Neuromuscular Diseases; Spinal Muscular Atrophies of Childhood
• Other Study ID Numbers: SRK-015-003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No