Jerry Mendell, Samiah A. Al-Zaidy, Richard Shell, W. David Arnold, Louise R. Rodino-Klapac, Thomas W. Prior, Linda Lowes, Lindsay N. Alfano, Katherine Berry, Kathleen Church, John Kisse, Sukumar Nagendran, James L’Italien, Doug M. Sproule, Minna Du, Jessica A. Cardenas, Arthur Burghes, Kevin D. Foust, Kathrin Meyer, Shibi Likhite and Brian K. Kaspar. AVXS-101 Phase 1 Gene Therapy Clinical Trial in SMA Type 1: Event Free Survival and Achievement of developmental milestones (CT.003) Neurology April 18, 2017 vol. 88 no. 16 Supplement CT.003 http://www.neurology.org/content/88/16_Supplement/CT.003.short?sid=18d290af-ea7e-460e-a06e-2d70f0ce873b
Objective: Spinal muscular atrophy is a devastating, monogenic neurodegenerative disease that in its most severe form, SMA Type 1 (SMA1), afflicted children never sit unassisted, roll over or maintain head control. A natural history study of SMA1 children reported that none achieved a CHOP-INTEND score of ≥40 (with one transient exception at ~41) and 75% died or required permanent-ventilation by 13.6 months. This trial explores safety and efficacy of a single intravenous administration of gene therapy in SMA1.
Background: This is the first-ever gene therapy (AVXS-101) trial in SMA1, a rapidly lethal neurologic disease. AVXS-101 delivers the SMN gene in a single-dose via the AAV9 viral vector, which crosses the blood-brain-barrier.
Design/Methods: In this ongoing Phase 1 trial, 15 patients with SMA1 confirmed by genetic testing (with 2xSMN2 copies) were enrolled. Patients received an intravenous dose of AVXS-101 at 6.7e13 vg/kg (Cohort-1 n=3) or 2.0e14vg/kg (Cohort-2, n=12). The primary objective is safety and secondary objectives include survival (avoidance of death/permanent-ventilation) and ability to sit unassisted. CHOP-INTEND scores and motor milestones are additional objectives.
Results: AVXS-101 appears safe and to improve survival (15Sept16 cut-off). All patients are alive and only 1 patient, from Cohort 1, reached the pulmonary endpoint at 28.8 months of age. All patients reaching 13.6 months did so free of permanent ventilation. Patients in Cohort 2 demonstrated improvements in motor function: 11/12 have CHOP-INTEND scores >40 points, 11/12 have head control, and 8/12 sit unassisted. Two patients can crawl, stand and walk independently.
Conclusions: In contrast with the published natural history, a single intravenous administration of AVXS-101 appears to demonstrate a positive impact on the survival of both dosing cohorts and a dramatic, sustained impact on motor function in Cohort-2: 11/12 patients achieved CHOP-INTEND scores and motor milestones rarely or never seen in this population.
All 15 infants treated with gene therapy for spinal muscular atrophy type 1 (SMA-1) survived past the age at which 75 percent of untreated infants typically die or need at least 16 hours a day of ventilation support, according to results of an open-label phase 1 trial reported here in April at the AAN Annual Meeting.
The event-free survival of the infants to at least 13.6 months shows the promise of the proprietary gene therapy known as AVXS-101, for Avexis, the Illinois-based manufacturer that funded the study.
The drug uses an adeno-associated virus 9 – AAV9 – to deliver a fully functioning survival motor neuron gene to the patient's cells.
Researchers also found that all nine infants born at least 20 months before the January data cut-off reached the 20-months' time point. All of the patients in the trial are alive, and only one has required 16 or more hours per day of ventilator support at 28.8 months, according to the researchers…
In the current study, 12 of the 15 children were given the high dose of the drug. All of these infants have reached at least one milestone, and most have achieved several milestones, such as bringing their hands to their mouths, head control, and sitting. Two children stand and walk independently, and eight can talk.
These are milestones that are essentially never achieved in untreated children, said Dr. Mendell, who reported he has no financial interest in the drug.
“None of them ever learn to talk and as they approach their death march, they can no longer feed except by G-tube and they basically live in a vegetative state,” he said. “And all that has changed dramatically.”
Dr. Mendell emphasized the importance of early treatment. “The two best patients in our clinical trial were those who were treated very early, and they very rapidly reversed their course; they are now walking,” he said. “Many of the patients in the trial were treated early because they have a family history [for SMA] and were recognized prenatally. That is what facilitated the study and also what will make a difference in the long run.”
He added: “I'm hoping the results of this study will allow for newborn-screening for this disease. That will provide a pathway for early treatment.”
Last year, the FDA approved the new SMA drug nusinersen, an antisense oligonucleotide therapy, which uses targeted RNA binding to boost production of a protein in which SMA patients are deficient. Dr. Mendell said it's possible that the two drugs could work well together, although this hasn't been evaluated yet.
“What we all wonder about on the gene therapy side and on the oligonucleotide side is whether these treatments could be complementary,” he said. “We'll know the answer to that because some of our patients have requested opportunity to move to nusinersen.”