Abstract Details

Title Early Diagnosis and Speed to Effect in Spinal Muscular Atrophy Type 1 (SMA1)

Topic Child Neurology and Developmental Neurology

Presentation(s) S25 - Child Neurology: Spinal Muscular Atrophy: Treatments and Outcomes (1:11 PM-1:22 PM)

Poster/Presentation
Number 002

Background SMA1 is a rapidly progressing disease resulting in death or need for permanent ventilation by 2 years of age; early intervention with disease-modifying treatment is critical. In ENDEAR, ~10% of patients died/required permanent ventilation within 2 months after initiation of therapy (time required for 4 loading doses); 39% of patients died/required permanent ventilation by 6 months from dosing. This may reflect a non-immediate therapeutic impact related to the loading dose schedule.

Objective

Explore rapidity of therapeutic effect of onasemnogene abeparvovec (AVXS-101) gene-replacement therapy (CL-101 phase 1 study), as measured by early changes in Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score, compared with response to nusinersen in the pivotal phase 3 study (ENDEAR; ≤5-point increase at 2 months postdosing).

Design/Methods

SMA1 patients were treated with a 1-time intravenous injection of AVXS-101 (NCT02122952; study cohort 2; N=12; followed up to 24 months). Outcomes of interest were event-free survival (AVXS-101: EFS, death or ≥16 hours ventilation/day for >2 consecutive weeks; ENDEAR: EFS, death, tracheostomy, or ventilatory support ≥16 hours ventilation/day for >21 continuous days) and motor function improvements (changes in CHOP-INTEND from baseline).

Results

All 12 patients treated with AVXS-101 survived and were event-free to end of study (24 months postdose), while 49/80 nusinersen patients showed EFS. Rapid increases in CHOP-INTEND of 9.8- and 15.4-points were observed at 1 and 3 months post–AVXS-101 dose, respectively (nusinersen: ≤5-points increase at 2 months postdose).

Conclusions

AVXS-101 appears to improve survival (100% vs. 61% for nusinersen) and induce more rapid improvement in motor function as measured by CHOP-INTEND score relative to nusinersen, consistent with rapid restoration of survival motor neuron gene expression in motor neurons with a single-dose administration. Advances in understanding SMA underscore the importance of early diagnosis and treatments with a near-immediate onset of action to maximize clinical improvements.

Authors/Disclosures
Omar Dabbous PRESENTER	Omar Dabbous has received personal compensation for serving as an employee of Novartis Gene Therapies. Omar Dabbous has received stock or an ownership interest from Novartis Gene Therapies.
Marcus Droege	No disclosure on file
Douglas Feltner	No disclosure on file
Aaron Novack	No disclosure on file
	No disclosure on file
	No disclosure on file
Richard S. Finkel, MD, FAAN (St. Jude Children's Research Hospital)	Dr. Finkel has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AveXis. Dr. Finkel has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Catabasis. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Capricor. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ReveraGen. Dr. Finkel has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Scholar Rock. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. Finkel has received research support from AveXis. The institution of Dr. Finkel has received research support from Biogen. The institution of Dr. Finkel has received research support from Capricor. The institution of Dr. Finkel has received research support from Catabasis. The institution of Dr. Finkel has received research support from ReveraGen. The institution of Dr. Finkel has received research support from Roche. The institution of Dr. Finkel has received research support from Scholar Rock. Dr. Finkel has received intellectual property interests from a discovery or technology relating to health care. An immediate family member of Dr. Finkel has received intellectual property interests from a discovery or technology relating to health care. Dr. Finkel has received personal compensation in the range of $0-$499 for serving as a Speaker in workshop with National Academy of Sciences. Dr. Finkel has a non-compensated relationship as a advisor with n-Lorem Foundation that is relevant to AAN interests or activities. Dr. Finkel has a non-compensated relationship as a Board Member with EveryLife Foundation that is relevant to AAN interests or activities.

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