Zolgensma

Zolgensma, formerly AVXS-101, is a gene therapy, also called gene transfer. Gene transfer may increase SMN levels by using a virus, called a vector, to deliver the SMN1 gene to affected cells. AVXS-101 is being developed by AveXis, a clinical-stage gene therapy company. The company was acquired by Novartis in mid-2018.

AveXis is currently developing two delivery methods for AVXS-101. One is intravenous (IV) delivery for infants with SMA type I who are under nine months of age. On October 18, AveXis announced that it had filed for FDA approval for IV delivery of its gene therapy for SMA. 

AveXis is also testing intrathecal (IT) delivery of AVXS-101—that is, dosage given via an intrathecal injection directly into the cerebrospinal fluid (CSF). This delivery could make the treatment accessible to older and bigger patients. The STRONG trial of this delivery method is ongoing and enrolling children with SMA type II, up to 5 years of age.

Gene Therapy Trials Currently Recruiting

STRONG Phase 1 Trial in SMA Type II

In December 2017, AveXis announced the start of their Phase 1 trial of AVXS-101 in SMA type II using the intrathecal (IT) formulation product from new GMP Commercial manufacturing process. The open-label, dose-comparison, multi-center Phase 1 trial—also known as STRONG—is designed to evaluate the safety, optimal dosing and proof of concept for efficacy of AVXS-101 in two distinct age groups of patients with SMA Type II, utilizing a one-time IT route of administration. The trial will enroll 27 infants and children with a genetic diagnosis consistent with SMA, including three copies of SMN2, who are able to sit but have no historical or current ability to stand or walk.

Three dosage strengths will be evaluated and patients will be stratified into two age groups: patients less than 24 months, and patients at least 24 months but less than 60 months. There will be at least a four-week interval between the dosing of the first three patients for each dose being studied and, based on the available safety data, a decision will be made whether to proceed. The low- and mid-dose cohorts have been fully enrolled. Enrollment is ongoing for the high-dose cohort.

The trial is being conducted at 11 sites in the United States, including: Ann and Robert H. Lurie Children's Hospital of Chicago, Boston Children's Hospital, Children's Hospital of Philadelphia, David Geffen School of Medicine at UCLA, Johns Hopkins Pediatric Neurology, Nationwide Children's Hospital, Stanford University Medical Center, University of Central Florida College of Medicine, University of Texas Southwestern Medical Center, University of Utah and Washington University School of Medicine. 

If you would like additional information about the AVXS-101 trial, please visit https://studysmanow.com/ or https://clinicaltrials.gov/ct2/show/NCT03381729

SPR1NT Pivotal Trial

SPR1NT is a Phase 3, multi-national study that will evaluate IV delivery of AVXS-101 in approximately 44 patients less than 6 weeks old with SMA Types 1, 2 or 3 who have 2 or 3 copies of SMN2 – often called the SMA back-up gene – and have not yet shown symptoms of the disease, also referred to as being "pre-symptomatic."

The intention of SPR1NT is to further understanding of both the safety of AVXS-101, and how well AVXS-101 may work in SMA patients. This study is currently enrolling. If you would like additional information about the SPR1NT trial, please visit https://studysmanow.com/ or https://clinicaltrials.gov/ct2/show/NCT03505099.

Fully Enrolled and Completed Trials

STR1VE Pivotal Trial in SMA Type I 

In October 2017, AveXis announced the start of their pivotal trial of AVXS-101 in SMA type I using the intravenous (IV) formulation product from new GMP Commercial manufacturing process. The open-label, single-arm, single-dose, multi-center trial – known as STR1VE — was designed to evaluate the efficacy and safety of a one-time IV infusion of AVXS-101. As of mid-2018, this trial is fully enrolled.

The trial is being conducted at 16 sites in the United States, including: Ann and Robert H. Lurie Children's Hospital of Chicago, Boston Children's Hospital, Children's Hospital Colorado, Children's Hospital of Philadelphia, Columbia University, David Geffen School of Medicine at UCLA, Duke University, Johns Hopkins Pediatric Neurology, Nationwide Children's Hospital, Oregon Health and Science University, Stanford University Medical Center, University of Central Florida College of Medicine, University of Texas Southwestern Medical Center, University of Utah, University of Wisconsin, and Washington University School of Medicine.

If you would like additional information about the AVXS-101 trial, please visit https://studysmanow.com/ or https://clinicaltrials.gov/ct2/show/NCT03306277.

Results from the Phase 1 Trial in SMA Type I

The Phase 1, open-label, dose-escalating study was designed to evaluate the safety and tolerability of AVXS-101 in patients with SMA Type 1. The key measures of efficacy were the time from birth to an “event,” which was defined as either death or at least 16 hours per day of required ventilation support for breathing for 14 consecutive days in the absence of acute reversible illness or perioperatively, and video confirmed achievement of ability to sit unassisted. Additionally, several exploratory objective measures were assessed, including a standard motor milestone development survey and Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND).

Data as of August 7, 2017, showed all patients (100%) were alive and event-free at 20 months of age. Patients in Cohort 2 continued to demonstrate improvements in motor milestones, including:

  • 15 of 15 (100%) patients were event-free at 13.6 months. The expected event-free survival rate at 13.6 months based on the natural history of the disease is 25%. 
  • AVXS-101 appears to have a favorable safety profile and to be generally well tolerated, with no new treatment-related safety or tolerability concerns identified. 
  • Nine of 12 patients (75%) could sit unassisted for 30 seconds or more. 
  • Eleven of 12 (92%) patients have sustained CHOP-INTEND scores more than 40 for a mean of 18.8 months.

Slide presentations of Phase I trial data can be found here.

Resources and Further Information

Cure SMA Funds Multiple Gene Therapy Approaches

Beginning in 2010, Cure SMA made a series of grants to Nationwide Children’s Hospital to study gene therapy, also called gene transfer. Spinal muscular atrophy (SMA) is caused by a mutation in the survival motor neuron 1 gene (SMN1). Because of this mutation, the individual does not produce enough survival motor neuron (SMN) protein. Gene transfer may increase SMN levels by using a virus, called a vector, to deliver the SMN1 gene to affected cells.

Currently, two approaches are being studied: an injection into a vein, known as systemic delivery, and delivery directly into the cerebrospinal spinal fluid (CSF), a process known as CSF-delivered gene therapy. CSF-delivered gene therapy has shown promise for reducing the amount of drug required for larger and older patients. This could eventually make the treatment accessible to a wider population. 

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