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

Spinal Muscular Atrophy Clinical Trial

— SAPPHIRE  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05156320
• Other study ID #: SRK-015-003
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: February 24, 2022
• Est. completion date: December 2024

Study information

• Verified date: October 2023
• Source: Scholar Rock, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 188
• Est. completion date: December 2024
• Est. primary completion date: October 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 21 Years

Eligibility

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.

Related Conditions & MeSH terms

• Atrophy
• Muscular Atrophy
• Muscular Atrophy, Spinal
• Neuromuscular Diseases
• Neuromuscular Manifestations
• SMA
• Spinal Muscular Atrophy
• Spinal Muscular Atrophy Type 2
• Spinal Muscular Atrophy Type 3

Intervention

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.
• Placebo
Placebo will be administered every 4 weeks by intravenous (IV) infusion.

Locations

Country	Name	City	State
Belgium	UZ Gent	Gent
Belgium	UZ Leuven	Leuven
Belgium	Chr de La Citadelle	Liège
France	CHU Lille - Hôpital Jeanne de Flandre	Lille
France	Hôpital Armand Trousseau, I-Motion	Paris
France	CHU Toulouse - Hopital des Enfants	Toulouse
Germany	Universitätsklinikum Bonn	Bonn
Germany	Universitätsklinikum Essen	Essen
Germany	Universitaetsklinikum Freiburg	Freiburg
Germany	Dr. von Haunersches Kinderspital	Munich
Italy	IRCCS Istituto Giannina Gaslini	Genoa
Italy	A.O.U Policlinico G. Martino	Messina
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milan
Italy	Foundation I.R.C.C.S. Carlo Besta Neurological Institute	Milan
Italy	Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico di Milano	Milano
Italy	Centro Clinico Nemo Pediatrico Policlinico A. Gemelli-Università Cattolica Sacro Cuore	Roma
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
Poland	Uniwersyteckie Centrum Kliniczne w Gdansku	Gdansk
Poland	Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu	Poznan
Poland	Instytut Pomnik - Centrum Zdrowia Dziecka: CZD Warszawa	Warsaw
Spain	Hospital Sant Joan de Déu	Barcelona
Spain	Hospital Universitario y Politécnico La Fe	Valencia
United Kingdom	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 States	Children's Hospital Colorado	Aurora	Colorado
United States	The Johns Hopkins University	Baltimore	Maryland
United States	Children's of Alabama	Birmingham	Alabama
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Children's Medical Center Dallas	Dallas	Texas
United States	Helen DeVos Children's Hospital	Grand Rapids	Michigan
United States	University of Iowa	Iowa City	Iowa
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Children's Hospital of Los Angeles	Los Angeles	California
United States	University of Wisconsin School of Medicine and Public Health	Madison	Wisconsin
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Columbia University, SMA Clinical Research Center	New York	New York
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Nemours Children's Hospital	Orlando	Florida
United States	Stanford University Medical Center	Palo Alto	California
United States	Childrens Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Oregon Health & Sciences University	Portland	Oregon
United States	Washington University School of Medicine in St. Louis	Saint Louis	Missouri
United States	Gillette Children's Specialty Healthcare	Saint Paul	Minnesota
United States	University of Utah	Salt Lake City	Utah
United States	Rady's Children's Hospital/UCSD	San Diego	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Scholar Rock, Inc.

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	Main Efficacy Population: Change from Baseline in number of WHO motor development milestones attained at 12 months.		Baseline up to 12 months.
Secondary	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.
Secondary	Main Efficacy Population and Exploratory Subpopulation combined: Apitegromab concentrations in serum from blood samples.		Baseline up to 12 months.
Secondary	Main Efficacy Population and Exploratory Subpopulation combined: Circulating latent myostatin concentrations in blood samples.		Baseline up to 12 months.
Secondary	Main Efficacy Population and Exploratory Subpopulation combined: Presence or absence of ADA against apitegromab in serum from blood samples.		Baseline up to 12 months.