OBJECTIVE We conducted a Phase IIa randomized, placebo-controlled trial of fingolimod to investig... more OBJECTIVE We conducted a Phase IIa randomized, placebo-controlled trial of fingolimod to investigate safety and tolerability and to explore biomarkers of immune change in people with ALS. BACKGROUND Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting primarily the motor neurons and causing progressive weakness. An increasing body of research implicates immune activation in the progression of the disease. Fingolimod, an FDA-approved oral medication for the treatment of multiple sclerosis, is a functional antagonist of the sphingosine-1-phosphate (S1P) receptor, and sequesters lymphocytes in secondary lymph organs. SOD1G93A mouse experiments at ALSTDI suggested possible benefit in ALS. DESIGN/METHODS Thirty participants with ALS were randomized 2:1 fingolimod to placebo. Participants were monitored clinically for 8 hours at baseline. Treatment duration was 4 weeks with follow up visits at day 1 and weeks 2 and 4, and a follow-up phone call at 8 weeks. Lymphocyte counts were monitored by an independent reviewer. Blood was collected for safety monitoring and lymphocyte subset analysis at each visit, and RNA was collected at baseline and week 4. The primary outcome was tolerability, defined by the number of participants remaining on study drug, and safety as measured by occurrence of adverse events. Secondary outcome measures included analysis of circulating lymphocyte populations and gene expression analysis from blood. RESULTS The study enrolled from August 2013 to September 2014 and completed in October 2014. Two participants were withdrawn after randomization but prior to study drug initiation (one developed QTc prolongation, the other developed an infection). One participant was removed after initiating study drug for possible QT prolongation. No serious adverse events (SAEs) were reported. CONCLUSIONS The study met its primary endpoint for tolerability. Final clinical data monitoring and RNA analysis are underway. Full results will be presented at the 2015 AAN meeting. STUDY SUPPORTED BY ALS Therapy Development Institute Disclosure: Dr. Berry has received personal compensation for activities with Oakstone Publishing as a speaker. Dr. Berry has received research support from the Muscular Dystrophy Association and ALS Therapy Alliance. Dr. Paganoni has nothing to disclose. Dr. Atassi has received personal compensation for activities with Biogen Idec as a consultant. Dr. Goyal has nothing to disclose. Dr. Rivner has received personal compensation for activities with Allergan, Inc. as a consultant. Dr. Rivner holds stock and/or stock options in Allergan Inc. Dr. Rivner has received research support from Allergan, Inc., and Cytokinetics. Dr. Simpson has received personal compensation for activities with Groefels as a speaker. Dr. Appel received personal compensation for activities with Neuraltus Pharmaceuticals, Inc. as a scientific advisory board member. Dr. Grasso has nothing to disclose. Dr. Mejia has nothing to disclose. Dr. Mateen has nothing to disclose. Dr. Cudkowicz has received personal compensation for activities with GlaxoSmithKline, Biogen Idec, Teva Neuroscience, and Cytokinetics. Dr. Cudkowicz has received personal compensation in an editorial capacity for JAMA Neurology. Dr. Perrin has received personal compensation for activities with Biogen Idec as an employee.
A 25-year-old woman with Kearns-Sayre syndrome (KSS) had complete external ophthalmoplegia, short... more A 25-year-old woman with Kearns-Sayre syndrome (KSS) had complete external ophthalmoplegia, short stature, ataxia, cardiac conduction defects, and pigmentary retinopathy. Muscle biopsy revealed ragged-red fibers. Electron microscopy showed increased numbers of mitochondria with disordered structure and paracrystalline inclusions. Enzymatic analysis revealed a deficiency of complex II of the mitochondrial respiratory chain, and, more specifically, a deficiency of succinic dehydrogenase, although both subunits of this enzyme proved to be present by immunologic analysis. Therapy with vitamin cofactors did not result in short-term improvement. This appears to be the first report of complex II deficiency in a patient with KSS.
Background and Objectives Myasthenia gravis (MG) is an autoimmune disease characterized by dysfun... more Background and Objectives Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CSs) and IV immunoglobulin (IVIG). This study was conducted to determine whether immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent patients with MG. Methods In this randomized double-blind placebo-controlled trial, CS-dependent patients with MG (Myasthenia Gravis Foundation of America Class II–Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/d) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every 3 weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (quantitative MG score ≥4 points from baseline). CS doses were increased (based on the current CS dose) in patients who worsened. Patients wer...
OBJECTIVE We conducted a Phase IIa randomized, placebo-controlled trial of fingolimod to investig... more OBJECTIVE We conducted a Phase IIa randomized, placebo-controlled trial of fingolimod to investigate safety and tolerability and to explore biomarkers of immune change in people with ALS. BACKGROUND Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting primarily the motor neurons and causing progressive weakness. An increasing body of research implicates immune activation in the progression of the disease. Fingolimod, an FDA-approved oral medication for the treatment of multiple sclerosis, is a functional antagonist of the sphingosine-1-phosphate (S1P) receptor, and sequesters lymphocytes in secondary lymph organs. SOD1G93A mouse experiments at ALSTDI suggested possible benefit in ALS. DESIGN/METHODS Thirty participants with ALS were randomized 2:1 fingolimod to placebo. Participants were monitored clinically for 8 hours at baseline. Treatment duration was 4 weeks with follow up visits at day 1 and weeks 2 and 4, and a follow-up phone call at 8 weeks. Lymphocyte counts were monitored by an independent reviewer. Blood was collected for safety monitoring and lymphocyte subset analysis at each visit, and RNA was collected at baseline and week 4. The primary outcome was tolerability, defined by the number of participants remaining on study drug, and safety as measured by occurrence of adverse events. Secondary outcome measures included analysis of circulating lymphocyte populations and gene expression analysis from blood. RESULTS The study enrolled from August 2013 to September 2014 and completed in October 2014. Two participants were withdrawn after randomization but prior to study drug initiation (one developed QTc prolongation, the other developed an infection). One participant was removed after initiating study drug for possible QT prolongation. No serious adverse events (SAEs) were reported. CONCLUSIONS The study met its primary endpoint for tolerability. Final clinical data monitoring and RNA analysis are underway. Full results will be presented at the 2015 AAN meeting. STUDY SUPPORTED BY ALS Therapy Development Institute Disclosure: Dr. Berry has received personal compensation for activities with Oakstone Publishing as a speaker. Dr. Berry has received research support from the Muscular Dystrophy Association and ALS Therapy Alliance. Dr. Paganoni has nothing to disclose. Dr. Atassi has received personal compensation for activities with Biogen Idec as a consultant. Dr. Goyal has nothing to disclose. Dr. Rivner has received personal compensation for activities with Allergan, Inc. as a consultant. Dr. Rivner holds stock and/or stock options in Allergan Inc. Dr. Rivner has received research support from Allergan, Inc., and Cytokinetics. Dr. Simpson has received personal compensation for activities with Groefels as a speaker. Dr. Appel received personal compensation for activities with Neuraltus Pharmaceuticals, Inc. as a scientific advisory board member. Dr. Grasso has nothing to disclose. Dr. Mejia has nothing to disclose. Dr. Mateen has nothing to disclose. Dr. Cudkowicz has received personal compensation for activities with GlaxoSmithKline, Biogen Idec, Teva Neuroscience, and Cytokinetics. Dr. Cudkowicz has received personal compensation in an editorial capacity for JAMA Neurology. Dr. Perrin has received personal compensation for activities with Biogen Idec as an employee.
A 25-year-old woman with Kearns-Sayre syndrome (KSS) had complete external ophthalmoplegia, short... more A 25-year-old woman with Kearns-Sayre syndrome (KSS) had complete external ophthalmoplegia, short stature, ataxia, cardiac conduction defects, and pigmentary retinopathy. Muscle biopsy revealed ragged-red fibers. Electron microscopy showed increased numbers of mitochondria with disordered structure and paracrystalline inclusions. Enzymatic analysis revealed a deficiency of complex II of the mitochondrial respiratory chain, and, more specifically, a deficiency of succinic dehydrogenase, although both subunits of this enzyme proved to be present by immunologic analysis. Therapy with vitamin cofactors did not result in short-term improvement. This appears to be the first report of complex II deficiency in a patient with KSS.
Background and Objectives Myasthenia gravis (MG) is an autoimmune disease characterized by dysfun... more Background and Objectives Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CSs) and IV immunoglobulin (IVIG). This study was conducted to determine whether immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent patients with MG. Methods In this randomized double-blind placebo-controlled trial, CS-dependent patients with MG (Myasthenia Gravis Foundation of America Class II–Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/d) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every 3 weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (quantitative MG score ≥4 points from baseline). CS doses were increased (based on the current CS dose) in patients who worsened. Patients wer...
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