Abstract Details

Title A Multicenter Phase II Open-Label Trial of L-Carnitine and Valproic Acid in Infants with Spinal Muscular Atrophy Type I

Topic Anterior Horn

Presentation(s) P03 - (-)

Poster/Presentation
Number 045

Objective

Background BACKGROUND: Valproic acid (VPA) has been demonstrated in vitro in SMA patient-derived cell lines to increase expression of full-length SMN and to prolong survival and improve neuromuscular phenotype in SMA animal models.

Design/Methods DESIGN/METHODS: Open label phase II multicenter trial design included 4 visits over 6 months, then 6 month telephone followup. Inclusion criteria: type I infants ages 2 weeks to 12 months with SMN deletion. Exclusion criteria: ventilator use > 12 hours, SMN enhancing medications within 30 days or illness within 2 weeks of entry. Exploratory outcomes: time to death and/or > 16 hours ventilator support (primary efficacy endpoint), Test of Infant Motor Performance Screening Inventory (TIMPSI), Type I Caregiver Questionnaire, maximum Ulnar Compound Muscle Action Potential Amplitude (CMAP), and SMN mRNA levels. Simple frequency and summary statistics used for most variables. Age/gender matching with subjects in the Utah database for primary efficacy outcome.

Results RESULTS: Thirty-eight infants were enrolled across 8 sites in the US, Canada and Germany. Mean age 5.5 months, gender 47% female. A significant proportion already had a feeding tube (11/38) or respiratory impairment (19/38). CMAP (0.68 mV) and TIMPSI (30.45) scores indicated significant baseline denervation/weakness. 261 adverse events included 83 SAEs (77% severe/life-threatening) and13/38 subjects (34.2%) died during the study. Time to death/ventilator dependence occurred in 37%.

Conclusions CONCLUSIONS: Recruitment/retention of sufficient numbers of type I infants for a multicenter clinical trial is feasible. A promising endpoint for measuring disease progression is time to death and/or more than 16 hours/day ventilator support per day. This study failed to support efficacy for VPA/L-carnitine in type I infants when compared to cohort of age and gender matched natural history subjects.

Authors/Disclosures
Kathryn J. Swoboda, MD PRESENTER	Dr. Swoboda has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Swoboda has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. The institution of Dr. Swoboda has received research support from Biogen.
	No disclosure on file
Thomas O. Crawford, MD (Johns Hopkins Hospital)	Dr. Crawford has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen.
John T. Kissel, MD, FAAN	Dr. Kissel has nothing to disclose.
Denise I. Campagnolo, MD, MS	Dr. Campagnolo has received personal compensation for serving as an employee of Biogen. Dr. Campagnolo has received stock or an ownership interest from Biogen.
	No disclosure on file
Mary K. Schroth, MD	Dr. Schroth has received personal compensation for serving as an employee of Cure SMA. The institution of Dr. Schroth has received research support from Biogen.
Gyula Acsadi, MD, FAAN (Connecticut Children'S Medical Center/UConn)	Dr. Acsadi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Acsadi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Avexis. Dr. Acsadi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Serepta. Dr. Acsadi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Acsadi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen.
Priya Kishnani, MD (Duke University)	Priya Kishnani, MD has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi/Genzyme. Priya Kishnani, MD has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Amicus Therapeutics. Priya Kishnani, MD has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Maze Therapeutics. Priya Kishnani, MD has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for JCR Pharmaceutical. Priya Kishnani, MD has received personal compensation in the range of $500,000-$999,999 for serving as a Consultant for Asklepios Biopharmaceutical Inc. (AskBio). Priya Kishnani, MD has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi/Genzyme. Priya Kishnani, MD has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Amicus Therapeutics. Priya Kishnani, MD has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Baebies, Inc.. The institution of Priya Kishnani, MD has received research support from Sanofi/Genzyme. Priya Kishnani, MD has received research support from Amicus Therapeutics. Priya Kishnani, MD has received intellectual property interests from a discovery or technology relating to health care. Priya Kishnani, MD has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
	No disclosure on file
Edward C. Smith, MD (Rare Disease Research - NC, LLC)	Dr. Smith has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Avidity Biosciences. Dr. Smith has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Solid Bioscences. Dr. Smith has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Catalyst.
Bakri Elsheikh, MD, FAAN (The Ohio State University Wexner Medical Center)	Dr. Elsheikh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen . Dr. Elsheikh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Argnex . The institution of Dr. Elsheikh has received research support from Biogen. The institution of Dr. Elsheikh has received research support from Cure SMA.
Louise R. Simard, PhD (University of Manitoba)	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Sandra P. Reyna, MD	Dr. Reyna has received personal compensation for serving as an employee of Novartis Gene Therapies.

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