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

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

Neurology

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25 Scopus citations

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.

Original language	English (US)
Pages (from-to)	345-352
Number of pages	8
Journal	Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Volume	16
Issue number	5-6
DOIs	https://doi.org/10.3109/21678421.2015.1026826
State	Published - Aug 27 2015

Bibliographical note

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.

Keywords

Biomarker
apoptosis
clinical trials
mitochondria
rasagiline

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Macchi, Z., Wang, Y., Moore, D., Katz, J., Saperstein, D., Walk, D., Simpson, E., Genge, A., Bertorini, T., Fernandes, J. A., Swenson, A., Elman, L., Dimachkie, M., Herbelin, L., Miller, J., Lu, J., Wilkins, H., Swerdlow, R. H., Statland, J., & Barohn, R. (2015). A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: Possible mitochondrial biomarker target engagement. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 16(5-6), 345-352. https://doi.org/10.3109/21678421.2015.1026826

A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: Possible mitochondrial biomarker target engagement. / Macchi, Zachary; Wang, Yunxia; Moore, Dan et al.
In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, Vol. 16, No. 5-6, 27.08.2015, p. 345-352.

Research output: Contribution to journal › Article › peer-review

Macchi, Z, Wang, Y, Moore, D, Katz, J, Saperstein, D, Walk, D, Simpson, E, Genge, A, Bertorini, T, Fernandes, JA, Swenson, A, Elman, L, Dimachkie, M, Herbelin, L, Miller, J, Lu, J, Wilkins, H, Swerdlow, RH, Statland, J & Barohn, R 2015, 'A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: Possible mitochondrial biomarker target engagement', Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, vol. 16, no. 5-6, pp. 345-352. https://doi.org/10.3109/21678421.2015.1026826

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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.",

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AU - Fernandes, J. Americo

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

Abstract

Bibliographical note

Keywords

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