Two new papers of clinical trial data for spinal muscular atrophy were published today in the November issue of the New England Journal of Medicine (NEJM). NEJM is one of the most prestigious scientific journals in the US, and this dual publication reflects the scientific community’s increasing interest in and engagement with SMA research. 

“Nusinersen Versus Sham Control in Infantile-Onset Spinal Muscular Atrophy” details results from Biogen’s ENDEAR trial, a Phase 3 trial testing SPINRAZA in infants with SMA type I.

“Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy” detailed results from AveXis’s Phase 1 trial of AVXS-101, also in infants with SMA type I. SPINRAZA is the first FDA-approved therapy to treat SMA. AVXS-101 is currently being tested in Str1ve, a Phase 3 clinical trial at 16 sites across the US.

More About the Data on SPINRAZA

The two pre-specified ENDEAR primary endpoints were percentage of motor milestone responders, defined as improvements in motor milestone categories in the Hammersmith Infant Neurological Examination (HINE), and time to death or permanent ventilation. The final analysis demonstrated that a greater proportion of infants treated with SPINRAZA were motor milestone responders, compared to untreated infants (51% vs. 0%, PSPINRAZA also met the pre-specified primary endpoint of death or permanent ventilation in the end of study analysis, demonstrating a statistically significant 47% reduction in the risk of death or use of permanent assisted ventilation (P=0.005) and 76% reduction for those with shorter disease duration.

SPINRAZA demonstrated a favorable benefit-risk profile. Safety data was consistent with those expected in the general SMA infant population and were similar to those reported in an open-label study in infantile-onset SMA.

More About the Data on AVXS-101

The data published today demonstrates that all patients who received a one-time intravenous dose of AVXS-101 are alive and event-free at 20 months of age. Natural history indicates that only eight percent of untreated patients with SMA Type 1 will survive event-free at 20 months of age.

The NEJM publication provides detailed data as of August 7, 2017, from the Phase 1, open-label, dose-escalating study, 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).

Cure SMA Funds Multiple Therapeutic Approaches

From 2003 to 2006, Cure SMA provided the very first research funding needed to begin investigation into the therapeutic approach behind SPINRAZA. We would like to thank and acknowledge Cold Spring Harbor Laboratory (CSHL) and the University of Massachusetts Medical School for generating critical intellectual property for the program that was licensed to Ionis Pharmaceuticals. We specifically thank Drs. Adrian Krainer, Yimin Hua and colleagues at CSHL for years of dedication to and hard work on the preclinical development of Spinraza for SMA, and Drs. Ravindra Singh and Elliot Androphy for their work funded by Cure SMA in originally identifying the ISSN1 gene sequence, which is the sequence targeted in Spinraza.

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. In total, Cure SMA has granted $845,000 for gene therapy, including support for both the systemic program and the CSF program.