Gene Replacement Therapy Clinical Trial for Participants With Spinal Muscular Atrophy Type 1

NCT03306277 | Completed Phase 3 Results DMC FDA Drug

• 3 other identifiers: AVXS-101-CL-3032020-000095-38COAV101A12302
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 16

Brief Summary

Phase 3 pivotal US trial studying open-label intravenous administration of onasemnogene abeparvovec-xioi in spinal muscular atrophy (SMA) Type 1 participants.

Conditions

SMA - Spinal Muscular Atrophy; Gene Therapy

Outcome Measures

Primary Outcomes (2)

• Achievement of Independent Sitting for at Least 30 Seconds

  Independent sitting is defined as sitting up straight with head erect for at least 30 seconds. This endpoint is a co-primary endpoint. The two co-primary efficacy endpoints were assessed in sequence: The endpoint of functional independent sitting was assessed first and, only when this assessment met statistical significance, was the endpoint of event-free survival assessed.

  Up to 18 months

• Event-free Survival

  Survival is defined by the avoidance of combined endpoint of either death or permanent ventilation, which is defined by tracheostomy or by the requirement of ≥ 16 hours of respiratory assistance per day for ≥ 14 consecutive days in the absence of an acute reversible illness, excluding perioperative ventilation. Permanent ventilation is considered a surrogate for death. An acute reversible illness is defined as any condition other than SMA that results in increased medical intervention. The endpoint is a co-primary endpoint. The two co-primary efficacy endpoints were assessed in sequence: The endpoint of functional independent sitting was assessed first and, only when this assessment met statistical significance was the survival endpoint assessed.

  14 months

Secondary Outcomes (2)

• Ability to Thrive

  18 months

• Ventilatory Support Independence

  Up to 18 months

Study Arms (1)

Onasemnogene Abeparvovec-xioi

EXPERIMENTAL

One-time Intravenous administration of onasemnogene abeparvovec-xioi at the therapeutic dose.

Biological: Onasemnogene Abeparvovec-xioi

Interventions

Onasemnogene Abeparvovec-xioi BIOLOGICAL

Non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the complimentary deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB). The AAV inverted terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, thus forming a double-stranded transgene ready for transcription.

Also known as: Zolgensma

Onasemnogene Abeparvovec-xioi

Eligibility Criteria

• Age: Up to 180 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Participants with SMA Type 1 as determined by the following features: a. Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or point mutations) and 1 or 2 copies of SMN2 (inclusive of the known SMN2 gene modifier mutation (c.859G\>C))2
• The first 3 participants enrolled must meet the criteria for the Intent-To-Treat Population
• Participants must be \< 6 months (\< 180 days) of age at the time of onasemnogene abeparvovec-xioi infusion
• Participants must have a swallowing evaluation test performed prior to administration of gene replacement therapy
• Up-to-date on childhood vaccinations. Seasonal vaccinations 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
• Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply with study procedures and visit schedule

You may not qualify if:

• Previous, planned or expected scoliosis repair surgery/procedure during the study assessment period
• Pulse oximetry \< 96% saturation at screening while the participant is awake or asleep without any supplemental oxygen or respiratory support, or for altitudes \> 1000 m, oxygen saturation \< 92% awake or asleep without any supplemental oxygen or respiratory support Pulse oximetry saturation may decrease to \< 96% after screening provided that the saturation does not decrease by ≥ 4 percentage points
• Tracheostomy or current use or requirement of non-invasive ventilatory support averaging ≥ 6 hours daily over the 7 days prior to the screening visit; or ≥ 6 hours/day on average during the screening period or requiring ventilatory support while awake over the 7 days prior to screening or at any point during the screening period prior to dosing
• Participants with signs of aspiration/inability to tolerate non-thickened- liquids based on a formal swallowing test performed as part of screening. Participants with a gastrostomy tube who pass the swallowing test will be allowed to enroll in the study
• Participants whose weight-for-age is below the third percentile based on World Health Organization (WHO) Child Growth Standards
• Active viral infection (includes human immunodeficiency virus \[HIV\] or positive serology for hepatitis B or C, or Zika virus)
• Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within 2 weeks prior to screening
• Upper or lower respiratory infection requiring medical attention, medical intervention, or increase in supportive care of any manner within 4 weeks prior to screening
• Severe non-pulmonary/respiratory tract infection within 4 weeks before administration of gene replacement therapy or concomitant illness that creates unnecessary risks for gene replacement therapy such as: a. Major renal or hepatic impairment b. Known seizure disorder c. Diabetes mellitus d. Idiopathic hypocalcuria e. Symptomatic cardiomyopathy
• Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients
• Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as adalimumab, immunosuppressive therapy within 3 months prior to gene replacement therapy
• Anti-adeno-associated virus serotype 9 (AAV9) antibody titer \> 1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay. Should a potential participant demonstrate Anti-AAV9 antibody titer \> 1:50, he or she may receive retesting within 30 days of the screening period and will be eligible to participate if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50
• Clinically significant abnormal laboratory values (gamma glutamyl- transpeptidase \[GGT\], ALT, and AST \> 3 × ULN, bilirubin ≥ 3.0 mg/dL, creatinine ≥ 1.0 mg/dL, hemoglobin \[Hgb\] \< 8 or \> 18 g/dL; white blood cell \[WBC\] \> 20,000 per cmm) prior to gene replacement therapy
• Participation in recent SMA treatment clinical study (with the exception of observational Cohort studies or non-interventional studies) or receipt of an investigational or commercial compound, product, or therapy administered with the intent to treat SMA at any time prior to screening for this study. Oral β-agonists must be discontinued at least 30 days before gene therapy dosing. Inhaled albuterol specifically prescribed for the purposes of respiratory (bronchodilator) management is acceptable and not a contraindication at any time prior to screening for this study
• Expectation of major surgical procedures during the study assessment period

Sponsors & Collaborators

• Novartis Gene Therapies: lead

Study Sites (16)

David Geffen School of Medicine at UCLA

Los Angeles, California, 90095, United States

Location

Stanford University

Stanford, California, 94305, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Nemours Children's Hospital

Orlando, Florida, 32827, United States

Location

Ann and Robert H Lurie Children's Hospital

Chicago, Illinois, 60611, United States

Location

Johns Hopkins Pediatric Neurology

Baltimore, Maryland, 21287, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Washington Unviersity School of Medicine

St Louis, Missouri, 63110, United States

Location

Columbia University

New York, New York, 10032, United States

Location

Duke University

Durham, North Carolina, 27713, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75235, United States

Location

University of Utah

Salt Lake City, Utah, 84112, United States

Location

University of Wisconsin (Madison)

Madison, Wisconsin, 53792, United States

Location

Related Publications (2)

• Day JW, Mendell JR, Mercuri E, Finkel RS, Strauss KA, Kleyn A, Tauscher-Wisniewski S, Tukov FF, Reyna SP, Chand DH. Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. Drug Saf. 2021 Oct;44(10):1109-1119. doi: 10.1007/s40264-021-01107-6. Epub 2021 Aug 12.

  PMID: 34383289 DERIVED

• Day JW, Finkel RS, Chiriboga CA, Connolly AM, Crawford TO, Darras BT, Iannaccone ST, Kuntz NL, Pena LDM, Shieh PB, Smith EC, Kwon JM, Zaidman CM, Schultz M, Feltner DE, Tauscher-Wisniewski S, Ouyang H, Chand DH, Sproule DM, Macek TA, Mendell JR. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021 Apr;20(4):284-293. doi: 10.1016/S1474-4422(21)00001-6. Epub 2021 Mar 17.

  PMID: 33743238 DERIVED

Related Links

• sponsor company website
• Novartis Results Record
• 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

The complete results are available via this link: https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=17657

Results Point of Contact

• Title: US Medical Information
• Organization: AveXis, Inc

medinfo@avexis.com

833-828-3947

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: One-time intravenous administration of onasemnogene abeparvovec-xioi.

Study Record Dates

• First Submitted: October 2, 2017
• First Posted: October 11, 2017
• Study Start: October 24, 2017
• Primary Completion: November 12, 2019
• Study Completion: November 12, 2019
• Last Updated: January 26, 2026
• Results First Posted: July 16, 2020

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share

Locations

US (16)