information: Treatment of the first patient
Announcement: treatment of the first patient
Company: Avexis (USA - IL)
Product: AVXS-101 (adeno-associated virus serotype 9 expressing the human Survival Motor Neuron gene)
- gene therapy. AVXS-101 is a proprietary gene therapy candidate of a one-time treatment for SMA Type 1 and is the only clinical-stage gene therapy in development for SMA. AVXS-101 is designed to address the monogenetic root cause of SMA and prevent further muscle degeneration by addressing the defective and/or loss of the primary SMN gene. AVXS-101 also targets motor neurons providing rapid onset of effect, and crosses the blood brain barrier allowing an IV dosing route and effective targeting of both central and systemic features.
- AVXS-101 - ChariSMA™ is a recombinant AAV9 in which most of the AAV9’s naturally-occurring components have been removed and replaced with the SMN transgene and other elements such as the CB promoter and the Bovine Growth Hormone polyadenylation signal (BGH pA) added for hydrolytic enzymatic protection and mRNA stability. The viral vector will deliver the SMN transgene into the motor neurons. Protein synthesis from the SMN transgene will produce full-length, functional SMN protein.
Disease: spinal muscular atrophy (SMA) Type 1, 2, 3
area: Rare diseases - Genetic diseases - Neuromuscular diseases
Country: Australia, Belgium, Israel, Japan, Republic of Korea, Spain, Taiwan, UK, USA
- Phase 3, open-label, single-arm study of a single, one-time dose of AVXS-101 (gene replacement therapy) in patients with spinal muscular atrophy (SMA) who meet enrollment criteria and are genetically defined by bi-allelic deletion of SMN1 with 2, 3, or 4 copies of survival motor neuron 2 gene (SMN2). Patients with SMN1 point mutations or the SMN2 gene modifier mutation (c.859G>C) may enroll but will not be included in the efficacy analysis sets.
- The study will enroll at least fifteen (15) patients with 2 copies of SMN2 that meet the Intent To Treat (ITT) criteria, at least twelve (12) patients with 3 copies of SMN2 that meet the ITT criteria and at least seventeen (17) patients with 4 copies of SMN2 that meet the ITT criteria. Patients in all three cohorts must be ?6 weeks of age at the time of gene replacement therapy (Day 1).
- U.S. sites include: Center for Rare Neurological Diseases; Clinic for Special Children; Columbia University; David Geffen School of Medicine at UCLA, Department of Neurology; Duke University; Massachusetts General; Nationwide Children's Hospital; Nemours Children’s Hospital; Stanford University Medical Center; University of Texas Southwestern Medical Center, Children's Medical Center Ambulatory Care Pavilion in Dallas; University of Utah, Utah Program For Inherited Neuromuscular Disorders; University of Wisconsin, Madison; and, Washington University School of Medicine.
Sites outside of the U.S. include: Agostino Gemelli; Area Genetica Clínica y Molecular; Belgium (Liege); Canada Children’s Hospital of Eastern Ontario; Dr. Von Haunersches Kinderspital; Fondazione Policlinico Universitario; Great Ormond Street Hospital for Children; Hospital Valle Hebron, Barcelona; Israel, Schneider Children's Medical Center of Israel, Institute of Child Neurology; National Taiwan University Hospital; Pusan National University Children's Hospital; Sydney Children’s Hospital; and, UMC Utrecht, Wilhelmina Kinderziekenhuis. (NCT03505099)
- • On April 25, 2018, AveXis announced that the first patient has been dosed in a Phase 3 trial evaluating AVXS-101 in pre-symptomatic patients with spinal muscular atrophy (SMA) Types 1, 2 and 3 (SPRINT). SPRINT is a multi-cohort, multi-national trial expected to enroll approximately 44 pre-symptomatic patients with a bi-allelic deletion of SMN1; two, three or four copies of SMN2; and who are less than six weeks of age at the time of gene therapy. The trial is designed to evaluate appropriate clinical endpoints, including developmental milestones, survival, bulbar function and safety of a one-time intravenous infusion of AVXS-101 of 1.1 x 1014 vg/kg.
- 2 Copy SMN2 Cohort: Primary Outcome: proportion of patients who achieve functional independent sitting for at least 30 seconds, up to 18 months of ageSecondary Outcomes: event-free survival at 14 months of age; and, ability to maintain weight at or above the third percentile without need for non-oral/mechanical feeding support up to 18 months of age
— An event is 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
3 Copy SMN2 Cohort: Primary Outcome: proportion of patients who achieve the ability to stand without support for at least three seconds, up to 24 months of age
Secondary Outcome: ability to walk without assistance by 24 months of age, defined as the ability to take at least five steps independently displaying coordination and balance
4 Copy SMN2 Cohort: Primary Outcome: proportion of patients who do not manifest symptoms consistent with SMA Type 3 based on a scaled score on Bayley V.3 Gross and Fine Motor Subtests within 1.5 standard deviations of chronological development reference standard, as assessed at 36 months of age.
The trial will be conducted at 26 sites in 13 countries.
- • On January 16, 2018, AveXis provided an overview of the expanded clinical development program for AVXS-101, for the treatment of spinal muscular atrophy (SMA). In addition to the ongoing pivotal trial in SMA Type 1 (STR1VE) and the ongoing Phase 1 trial in SMA Type 2 (STRONG), the company plans to initiate three studies to further evaluate AVXS-101, including in new SMA patient populations.
- Planned Trials in SMA : Pre-Symptomatic SMA Types 1, 2, 3 (SPRINT): The planned multi-national trial is expected to enroll approximately 44 patients with two, three and four copies of SMN2 who are less than six weeks of age and pre-symptomatic at the time of gene therapy. The trial is designed to evaluate appropriate clinical endpoints, including developmental milestones, survival, bulbar function and safety, of a one-time IV infusion of AVXS-101. AveXis expects to initiate the trial in the first half of 2018, and will provide more design details at the time of initiation.