Study of Intrathecal Administration of Onasemnogene Abeparvovec-xioi for Spinal Muscular Atrophy

NCT03381729 | Terminated Phase 1 Results DMC FDA Drug

• 3 other identifiers: AVXS-101-CL-1022020-003678-28COAV101A12102
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 11

Brief Summary

The purpose of this trial is to evaluate the safety and tolerability of intrathecal administration of onasemnogene abeparvovec-xioi in infants and children with Spinal Muscular Atrophy with 3 copies of SMN2 and deletion of SMN1.

Conditions

Spinal Muscular Atrophy

Keywords

Gene Transfer; Gene Therapy; Adeno-associated virus; Survival Motor Neuron; SMN; AAV9

Outcome Measures

Primary Outcomes (3)

• Age 6 to <24 Months Only: Number of Participants Who Achieved the Ability to Stand Alone

  Defined by the Bayley Scales of Infant and Toddler Development (BSID) Gross Motor (GM) subtest performance criteria number 40, confirmed by video recording, as a participant who stands alone for at least 3 seconds unsupported.

  From Day 1 up to Month 12

• Age 24 to <60 Months Only: Change From Baseline in Hammersmith Functional Motor Scale-Expanded (HFMSE) Score at Month 12

  The HFMSE contained 33 items which were scored on a scale of 0-2 with a total achievable score ranging from 0, if all activities are failed, to 66, if all the activities are achieved. A positive change from baseline indicates a better outcome.

  Baseline and Month 12

• Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)

  A TEAE was defined as any event that began or worsened in severity on or after the administration of AVXS-101 through the last study visit. Evaluation of TEAEs included the number of participants with at least one: * TEAE * Serious TEAE * TEAE related to AVXS-101 * TEAE with Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 (grade 3 = severe or medically significant to grade 5 = death related to TEAE)

  Adverse events were collected from the single dose of study treatment until the end of study visit (12 months for Cohort 1 and 2 and 15 months for Cohort 3)

Secondary Outcomes (2)

• Number of Participants Who Achieved the Ability to Walk Alone

  From Day 1 up to Month 12

• Average Number of Hours Per Day of Non-invasive Ventilatory Support

  Months 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12

Study Arms (3)

Dose A

EXPERIMENTAL

Intrathecal administration 6.0 X 10\^13 vg of onasemnogene abeparvovec-xioi

Biological: Onasemnogene Abeparvovec-xioi

Dose B

EXPERIMENTAL

Intrathecal administration 1.2 X 10\^14 vg of onasemnogene abeparvovec-xioi

Biological: Onasemnogene Abeparvovec-xioi

Dose C

EXPERIMENTAL

Intrathecal administration 2.4 X 10\^14 vg of onasemnogene abeparvovec-xioi

Biological: Onasemnogene Abeparvovec-xioi

Interventions

Onasemnogene Abeparvovec-xioi BIOLOGICAL

Self-complementary AAV9 carrying the SMN gene under the control of a hybrid CMV enhancer/chicken-β-actin promoter

Also known as: Zolgensma

Dose A; Dose B; Dose C

Eligibility Criteria

• Age: 6 Months - 60 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Patients ≥6 months and up to 60 months (1800 days) of age at time of dosing following diagnostic confirmation during screening period by genotype who demonstrate the ability to sit unassisted for 10 or more seconds but cannot stand or walk
• Diagnostic confirmation by genotype includes lab documentation of homozygous absence of SMN1 exon 7; with exactly three copies of SMN2
• Negative gene testing for SMN2 gene modifier mutation (c.859G\>C)
• Onset of clinical signs and symptoms consistent with spinal muscular atrophy (SMA) at \< 12 months of age
• Able to sit independently and not standing or walking independently. Definition of sitting independently is defined by the World Health Organization Multicentre Growth Reference Study (WHO-MGRS) criteria of being able to sit up unsupported with head erect for at least 10 seconds. Child should not use arms or hands to balance body or support position (Wijnhoven 2004)
• Be up-to-date on childhood vaccines that include palivizumab prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) infections are also recommended in accordance with American Academy of Pediatrics (AAP 2009)

You may not qualify if:

• Current or historical ability to stand or walk independently
• Contraindications for spinal tap procedure or administration of intrathecal therapy or presence of an implanted shunt for the drainage of CSF or an implanted central venous (CNS) catheter
• Severe contractures as determined by designated Physical Therapist(s) at screening that interfere with either the ability to attain/demonstrate functional measures or interferes with ability to receive intrathecal (IT) dosing
• Severe scoliosis (defined as ≥ 50° curvature of spine) evident on X-ray examination
• Previous, planned or expected scoliosis repair surgery/procedure within 1 year of dose administration
• Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse oximetry \< 95% saturation at screening while the patient is awake, or for high altitudes \> 1000 m, oxygen saturation \< 92% while the patient is awake
• Pulse oximetry saturation must not decrease ≥ four (4) percentage points between screening and highest value on day of dosing
• Use or requirement of non-invasive ventilatory support for 12 or more hours daily over the two (2) weeks prior to dosing
• Use or requirement of non-invasive ventilatory support for 12 or more hours daily over the two (2) weeks prior to dosing
• Active viral infection (includes human immunodeficiency virus (HIV) or serology positive for hepatitis B or C, or Zika virus)
• Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within two (2) weeks prior to study entry
• Respiratory infection requiring medical attention, medical intervention or increase in supportive care of any manner within four (4) weeks prior to study entry
• Severe non-pulmonary/respiratory tract infection within four (4) weeks before study dosing or concomitant illness that in the opinion of the Principal Investigator (PI) creates unnecessary risks for gene transfer such as:
• Major renal or hepatic impairment
• Known seizure disorder

Sponsors & Collaborators

• Novartis Gene Therapies: lead

Study Sites (11)

UCLA

Los Angeles, California, 90095, United States

Location

Stanford University

Stanford, California, 94305, United States

Location

Nemours Children's Hospital

Orlando, Florida, 32827, United States

Location

Ann & Robert H. Lurie Children's Hospital

Chicago, Illinois, 60611, United States

Location

Johns Hopkins

Baltimore, Maryland, 21287, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Washington University

St Louis, Missouri, 63130, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

UT Southwestern

Dallas, Texas, 75390, United States

Location

University of Utah

Salt Lake City, Utah, 84112, United States

Location

Related Publications (3)

• Duque SI, Arnold WD, Odermatt P, Li X, Porensky PN, Schmelzer L, Meyer K, Kolb SJ, Schumperli D, Kaspar BK, Burghes AH. A large animal model of spinal muscular atrophy and correction of phenotype. Ann Neurol. 2015 Mar;77(3):399-414. doi: 10.1002/ana.24332. Epub 2015 Feb 9.

  PMID: 25516063 BACKGROUND

• Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM, Le TT, Morales PR, Rich MM, Burghes AH, Kaspar BK. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010 Mar;28(3):271-4. doi: 10.1038/nbt.1610. Epub 2010 Feb 28.

  PMID: 20190738 BACKGROUND

• Meyer K, Ferraiuolo L, Schmelzer L, Braun L, McGovern V, Likhite S, Michels O, Govoni A, Fitzgerald J, Morales P, Foust KD, Mendell JR, Burghes AH, Kaspar BK. Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: a dose-response study in mice and nonhuman primates. Mol Ther. 2015 Mar;23(3):477-87. doi: 10.1038/mt.2014.210. Epub 2014 Oct 31.

  PMID: 25358252 BACKGROUND

Related Links

• The Novartis Clinical Trial Results
• A Plain Language Trial Summary is available on www.novctrd.com

MeSH Terms

Conditions

Muscular Atrophy, Spinal

Interventions

Zolgensma

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases

Limitations and Caveats

A comparison of the results from this study to the results from the natural history observational study (Pediatric Neuromuscular Clinical Research Network (PNCR), Finkel et al, 2014) are included in the Novartis Clinical Trial Results, as a historical control. These full results are available via this link: https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=17933

Results Point of Contact

• Title: EMEA Medical Information
• Organization: Novartis Gene Therapies EU Limited

medinfoemea.gtx@novartis.com

+353 (1) 566-2364

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 13, 2017
• First Posted: December 22, 2017
• Study Start: December 14, 2017
• Primary Completion: November 18, 2021
• Study Completion: November 18, 2021
• Last Updated: January 26, 2026
• Results First Posted: February 16, 2023

Record last verified: 2026-01

Locations

US (11)