A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: Possible mitochondrial biomarker target engagement

Zachary Macchi; Yunxia Wang; Dan Moore; Jonathan Katz; David Saperstein; David Walk; Ericka Simpson; Angela Genge; Tulio Bertorini; J. Americo Fernandes; Andrea Swenson; Lauren Elman; Mazen Dimachkie; Laura Herbelin; Joann Miller; Jianghua Lu; Heather Wilkins; Russell H Swerdlow; Jeffrey Statland; Richard Barohn

doi:10.3109/21678421.2015.1026826

Journal article

A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: Possible mitochondrial biomarker target engagement

Zachary Macchi, Yunxia Wang, Dan Moore, Jonathan Katz, David Saperstein, David Walk, Ericka Simpson, Angela Genge, Tulio Bertorini, J. Americo Fernandes, …

Amyotrophic lateral sclerosis and frontotemporal degeneration, Vol.16(5-6), pp.345-352

08/27/2015

DOI: 10.3109/21678421.2015.1026826

PMCID: PMC4610861

PMID: 25832828

Files and links (1)

url

https://www.ncbi.nlm.nih.gov/pmc/articles/4610861View

Open Access

Abstract

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.

Apoptosis

Clinical Trials

rasagiline

Biomarker

mitochondria

Details

Title: Subtitle: A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: Possible mitochondrial biomarker target engagement
Creators: Zachary Macchi - University of Kansas Medical Center
Yunxia Wang - University of Kansas Medical Center
Dan Moore - California Pacific Medical Center
Jonathan Katz - California Pacific Medical Center
David Saperstein - Phoenix Neurological Associates
David Walk - University of Minnesota
Ericka Simpson - The Methodist Hospital
Angela Genge - McGill University
Tulio Bertorini - University of Tennessee
J. Americo Fernandes - University of Nebraska
Andrea Swenson - University of Iowa Health Care
Lauren Elman - University of Pennsylvania
Mazen Dimachkie - University of Kansas Medical Center
Laura Herbelin - University of Kansas Medical Center
Joann Miller - University of Kansas Medical Center
Jianghua Lu - University of Kansas Medical Center
Heather Wilkins - University of Kansas Medical Center
Russell H Swerdlow - University of Kansas Medical Center
Jeffrey Statland - University of Kansas Medical Center
Richard Barohn - University of Kansas Medical Center
Resource Type: Journal article
Publication Details: Amyotrophic lateral sclerosis and frontotemporal degeneration, Vol.16(5-6), pp.345-352
DOI: 10.3109/21678421.2015.1026826
PMID: 25832828
PMCID: PMC4610861
NLM abbreviation: Amyotroph Lateral Scler Frontotemporal Degener
ISSN: 2167-8421
eISSN: 2167-9223
Publisher: Informa Healthcare
Language: English
Date published: 08/27/2015
Academic Unit: Neurology
Record Identifier: 9984016335402771

Metrics

29 Record Views

22 Times Cited - Web of Science