TY - JOUR
T1 - A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis
T2 - Possible mitochondrial biomarker target engagement
AU - Macchi, Zachary
AU - Wang, Yunxia
AU - Moore, Dan
AU - Katz, Jonathan
AU - Saperstein, David
AU - Walk, David
AU - Simpson, Ericka
AU - Genge, Angela
AU - Bertorini, Tulio
AU - Fernandes, J. Americo
AU - Swenson, Andrea
AU - Elman, Lauren
AU - Dimachkie, Mazen
AU - Herbelin, Laura
AU - Miller, Joann
AU - Lu, Jianghua
AU - Wilkins, Heather
AU - Swerdlow, Russell H.
AU - Statland, Jeffrey
AU - Barohn, Richard
N1 - Funding Information:
Funding provided in part by an investigator initiated grant from TEvA Pharmaceuticals (yunxia Wang), a grant from Project ALS, and an and an Institutional Clinical andTranslational Science award (NIH/NCATS grant #UL1TR000001). Work on this project was supported by the University of Kansas Medical Center. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Biomarker studies were partly supported by the University of Kansas Alzheimer’s Disease Center (P30Ag035982).TEvA Pharmaceuticals performed a medical accuracy review of this manuscript.
Funding Information:
Work by JS was supported by the University of Kansas Medical Center for Frontiers:The Heartland Institute for Clinical and Translation Research (KL2TR000119).TEvA Pharmaceuticals performed a medical accuracy review of this manuscript.
Publisher Copyright:
© 2015 Informa Healthcare.
PY - 2015/8/27
Y1 - 2015/8/27
N2 - Rasagiline, a monoamine oxidase B inhibitor, slowed disease progression in the SOD1 mouse, and in a case series of patients with amyotrophic lateral sclerosis (ALS). Here we determine whether rasagiline is safe and effective in ALS compared to historical placebo controls, and whether it alters mitochondrial biomarkers. We performed a prospective open-label, multicenter screening trial of 36 ALS patients treated with 2 mg oral rasagiline daily for 12 months. Outcomes included the slope of deterioration of the revised ALS Functional Rating Scale (ALSFRS-R), adverse event monitoring, time to treatment failure, and exploratory biomarkers. Participants experienced no serious drug-related adverse events, and the most common adverse event was nausea (11.1%). Rasagiline did not improve the rate of decline in the ALSFRS-R; however, differences in symptom duration compared to historical placebo controls differentially affected ALSFRS-R slope estimates. Rasagiline changed biomarkers over 12 months, such that the mitochondrial membrane potential increased (JC-1 red/green fluorescent ratio 1.92, p = 0.0001) and apoptosis markers decreased (Bcl-2/Bax ratio 0.24, p < 0.0001). In conclusion, engagement of exploratory biomarkers and questions about comparability of baseline characteristics lead us to recommend a further placebo-controlled trial.
AB - Rasagiline, a monoamine oxidase B inhibitor, slowed disease progression in the SOD1 mouse, and in a case series of patients with amyotrophic lateral sclerosis (ALS). Here we determine whether rasagiline is safe and effective in ALS compared to historical placebo controls, and whether it alters mitochondrial biomarkers. We performed a prospective open-label, multicenter screening trial of 36 ALS patients treated with 2 mg oral rasagiline daily for 12 months. Outcomes included the slope of deterioration of the revised ALS Functional Rating Scale (ALSFRS-R), adverse event monitoring, time to treatment failure, and exploratory biomarkers. Participants experienced no serious drug-related adverse events, and the most common adverse event was nausea (11.1%). Rasagiline did not improve the rate of decline in the ALSFRS-R; however, differences in symptom duration compared to historical placebo controls differentially affected ALSFRS-R slope estimates. Rasagiline changed biomarkers over 12 months, such that the mitochondrial membrane potential increased (JC-1 red/green fluorescent ratio 1.92, p = 0.0001) and apoptosis markers decreased (Bcl-2/Bax ratio 0.24, p < 0.0001). In conclusion, engagement of exploratory biomarkers and questions about comparability of baseline characteristics lead us to recommend a further placebo-controlled trial.
KW - Biomarker
KW - apoptosis
KW - clinical trials
KW - mitochondria
KW - rasagiline
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U2 - 10.3109/21678421.2015.1026826
DO - 10.3109/21678421.2015.1026826
M3 - Article
C2 - 25832828
AN - SCOPUS:84945116255
SN - 2167-8421
VL - 16
SP - 345
EP - 352
JO - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
JF - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
IS - 5-6
ER -