Abstract Details

Title STAGE 3 Clinical Trial of Ceftriaxone in Subjects with ALS

Topic Anterior Horn

Presentation(s) S36 - (-)

Poster/Presentation
Number 001

Objective

Background ALS is a uniformly progressive and fatal neurodegenerative disorder for which there is no known cure. The pathogenesis is largely unknown. Several studies implicate glutamate toxicity, free radical toxicity, toxicity from heavy metals and mitochondrial dysfunction as possible causes of both sporadic and familial ALS. Ceftriaxone showed hits in ALS-relevant assays during a NINDS-led screening program of 1040 FDA approved drugs. Ceftriaxone increased expression of the astrocytic glutamate transporter, EAAT2, and in models of superoxide dismutase mediated toxicity. Ceftriaxone also protects motor neurons in culture from excitotoxic cell death, and has antioxidant and anti-apoptotic activity.

Design/Methods A double-blind, placebo controlled clinical trial of ceftriaxone was conducted in 513 subjects with ALS. The study uses a sequential, non-stop drug development design. This design was chosen as a method to expedite drug development, while safely testing a new therapeutic agent in ALS. STAGE 1 investigated steady state levels and population kinetics of ceftriaxone in CSF, while STAGE 2 defined the safety and tolerability of ceftriaxone after 20 weeks of daily treatment. STAGE 3 investigated whether chronic treatment with 4 grams of ceftriaxone prolongs survival and slows the rate of decline in function (using ALSFRS-R). Study drug was given intravenously via an implanted central venous catheter. Ursodiol was also used in conjunction with Ceftriaxone to reduce the incidence of biliary adverse events.

Results Both 2 and 4 grams of Ceftriaxone achieved trough CSF levels of 1 uM, and were shown to be tolerable for long-term use. Survival (p= 0.3680) and rate of decline (p=0.1715) were not significantly different between 4 grams ceftriaxone and placebo.

Conclusions The three-stage study determined that Ceftriaxone does not significantly increase the survival time or significantly decrease the rate of decline in function for subjects with ALS.

Authors/Disclosures
Merit E. Cudkowicz, MD, MSC, FAAN (Massachusetts General Hospital) PRESENTER	Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for biogen. Dr. Cudkowicz has received personal compensation in the range of $0-$499 for serving as a Consultant for cytokinetics. Dr. Cudkowicz has received personal compensation in the range of $0-$499 for serving as a Consultant for immunitypharm. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for transposon. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Quralis. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Regeneron. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for vectorY. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for inflectis. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for novartis. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ono. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for otsuka. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for coya. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ac immune. Dr. Cudkowicz has received personal compensation in the range of $0-$499 for serving as a Consultant for pontifax. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Inflectis. Dr. Cudkowicz has received personal compensation in the range of $0-$499 for serving as a Consultant for ab science. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for aclipse. Dr. Cudkowicz has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Locust Walk. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pasithea. Dr. Cudkowicz has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Praxis Precision Medicine. Dr. Cudkowicz has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Annals of Neurology . The institution of Dr. Cudkowicz has received research support from NINDS. The institution of Dr. Cudkowicz has received research support from ALSFAC. The institution of Dr. Cudkowicz has received research support from UCB ra. The institution of Dr. Cudkowicz has received research support from Biohaven. The institution of Dr. Cudkowicz has received research support from Clene nanomedicine. The institution of Dr. Cudkowicz has received research support from prilenia. The institution of Dr. Cudkowicz has received research support from ALS one. The institution of Dr. Cudkowicz has received research support from Seelos. The institution of Dr. Cudkowicz has received research support from Calico. The institution of Dr. Cudkowicz has received research support from denali. The institution of Dr. Cudkowicz has received research support from ITB. The institution of Dr. Cudkowicz has received research support from PharmAust. The institution of Dr. Cudkowicz has received research support from woolsley. Dr. Cudkowicz has received research support from lilly. The institution of Dr. Cudkowicz has received research support from J& J. Dr. Cudkowicz has received publishing royalties from a publication relating to health care.
Jeremy M. Shefner, MD, PhD, FAAN (Barrow Neurological Institute)	Dr. Shefner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amylyx. Dr. Shefner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Uniqure. Dr. Shefner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Clene. Dr. Shefner has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Cytokinetics. Dr. Shefner has received personal compensation in the range of $0-$499 for serving as a Consultant for Mitsubishi Tanabe Pharma America. Dr. Shefner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for annexon. Dr. Shefner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Shefner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Shefner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurosense. Dr. Shefner has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Neuvivo. Dr. Shefner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nura BIo. Dr. Shefner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Prilenia. Dr. Shefner has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for swanbio. Dr. Shefner has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for vertex. Dr. Shefner has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. Dr. Shefner has received personal compensation in the range of $50,000-$99,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for UpToDate. The institution of Dr. Shefner has received research support from NIH. The institution of Dr. Shefner has received research support from Mitsubishi Tanabe Pharma America. The institution of Dr. Shefner has received research support from Amylyx. The institution of Dr. Shefner has received research support from BIogen. The institution of Dr. Shefner has received research support from Cytokinetics. The institution of Dr. Shefner has received research support from IONIS. The institution of Dr. Shefner has received research support from Healey Center for ALS. Dr. Shefner has received personal compensation in the range of $500-$4,999 for serving as a grant review chair with DOD- General Dynamics.
	No disclosure on file
	No disclosure on file

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