information: Presentation of results at a congress
Announcement: presentation of results at the American Society of Clinical Oncology (ASCO) annual meeting, in Chicagoat the 2018 Annual Meeting of the American Academy of Neurology (AAN) Annual Meeting in Los Angeles
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
area: Rare diseases - Genetic diseases - Neuromuscular diseases
This phase 3 pivotal US trial is studying open-label intravenous administration of AVXS-101 in SMA Type 1 patients. The gene replacement therapy is evaluated in patients with spinal muscular atrophy (SMA) Type 1 who meet enrollment criteria and are genetically defined by nonfunctional survival motor neuron 1 gene (SMN1) with 1 or 2 copies of survival motor neuron 2 gene (SMN2). Fifteen (15) patients < 6 months (< 180 days) of age at the time of gene replacement therapy (Day 1) will be enrolled. (NCT03306277)
- • On April 24, 2018, AveXis announced that the company will present initial results from the Type 1 U.S. Pivotal trial (STR1VE) at the 2018 Annual Meeting of the American Academy of Neurology (AAN) Annual Meeting in Los Angeles. As of April 11, 2018, 11 patients were enrolled in the trial, and six patients were symptomatic and at least one-month post gene therapy treatment. All patients had homozygous deletion of SMN1 and two copies of SMN2; no patient had the known SMN2gene modifier mutation (c.859G>C). The patient population and baseline characteristics are closely matched to the Phase 1 trial.
- Event-free Survival and Safety: All patients (6/6) were alive and event-free as of April 11, 2018. AVXS-101 appeared to have a favorable safety profile and to be generally well tolerated. At the time of gene transfer, the mean age was 3.2 months, with the oldest patient being 5.0 months of age. In the six patients who were at least one-month post gene transfer, a cumulative total of 25 adverse events (AEs) were reported. Two patients experienced transient elevations in transaminases greater than 3x ULN that were not clinically significant and all resolved with prednisolone treatment without any clinical manifestations or sequelae. There were no serious adverse events (SAEs) reported.
- Motor Function Achievement: Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scores increased by an average of 7.8 at one month after gene transfer (in six patients) and 17.3 at three months after gene transfer (in three patients), reflecting improvement in motor function. These data correlate to CHOP-INTEND achievement by the proposed therapeutic dose cohort (Cohort 2) in the Phase 1 trial, which experienced mean increases of 9.8 points at one month and 15.4 points at three months. Early CHOP-INTEND increases have been observed to be associated with eventual milestone achievement.
- The open-label, single-arm, single-dose, multi-center trial – known as STR1VE – is designed to evaluate the efficacy and safety of a one-time IV infusion of AVXS-101 of 1.1 x 1014 vector genomes/kg in patients with SMA Type 1 who are less than six months of age at the time of gene therapy, have one or two copies of the SMN2 backup gene as determined by genetic testing, and have bi-allelic SMN1 gene deletion or point mutations. The intent-to-treat population is defined as patients who are less than six months of age and symptomatic at the time of gene therapy, with two copies of the SMN2 gene as determined by genetic testing, bi-allelic SMN1 gene deletion and no c.859G>C mutation in SMN2.
- The co-primary efficacy outcome measures include the achievement of the developmental milestone of independent sitting for at least 30 seconds at 18 months of age and event-free survival at 14 months of age, with an event 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 perioperative change. Co-secondary outcome measures include the ability to thrive and the ability to remain independent of ventilatory support at 18 months of age.
- • 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)
- Pivotal Trial of AVXS-101 in SMA Type 1 (STR1VE): The ongoing, open-label, single-arm, single-dose, multi-center trial is designed to evaluate the efficacy and safety of a one-time IV infusion of AVXS-101 in patients with SMA Type 1. The trial is expected to enroll a minimum of 15 patients with SMA Type 1 who are less than six months of age at the time of gene therapy, and who have one or two copies of the SMN2 backup gene as determined by genetic testing and bi-allelic SMN1 gene deletion or point mutations. Three patients have been dosed to date.