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

Abstract

OBJECTIVE 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. METHODS We performed a prospective open-label, multicenter screening trial of 36 ALS patients treated with 2mg 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. RESULTS 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). CONCLUSION Engagement of exploratory biomarkers and questions about comparability of baseline characteristics lead us to recommend a further placebo-controlled trial.

A Mitochondrial Biomarker-Based Study of S-Equol in Alzheimer’s Disease Subjects: Results of a Single-Arm, Pilot Trial

“…Blood represents an easily procurable tissue, although drug-mediated changes in blood-derived mitochondria does not ensure similar (or indeed any) changes in brain mitochondria have occurred. We recently reported a study in which lymphocyte mitochondria membrane potential values served as a biomarker of mitochondrial target engagement in amyotrophic lateral sclerosis patients treated with rasagiline [22]. …”

New Therapeutics to Modulate Mitochondrial Function in Neurodegenerative Disorders

“…Oxidative stress, measured by an Oxygen Radical Absorbance Capacity (ORAC) assay, was reduced. However, this study failed to find changes in the ALSFRS-R score [321]. Several larger clinical trials are in progress, which include functional and biomarker outcome measurements (clinicaltrials.gov IDs NCT01879241, NCT01786603).…”

Disparity of outcomes: the limits of modeling amyotrophic lateral sclerosis in murine models and translating results clinically

“…Thus measuring particular biomarkers related to mitochondrial function (e.g. changes in mitochondrial membrane potential, oxidative stress, and the relative abundance of pro-survival/proapoptotic signals) may allow for a biochemically-relevant measure of therapeutic effectiveness in ALS clinical trials (90). The trial did not demonstrate an improvement in the functional ALSFRS-R scores after 12 months compared to historical controls (when corrected for symptom duration).…”

“…A recently conducted clinical trial of rasagiline, an inhibitor of monoamine oxidase B, demonstrates the application of potential blood biomarkers in assessing the clinical outcome of a therapeutic agent (90). Prior work had demonstrated that the drug had specific beneficial effects on mitochondrial function, decreased oxidative damage, and inhibited apoptosis.…”

“…A major caveat to the use of peripheral biomarkers as a surrogate indicator for activity within the CNS is the degree to which the therapeutic agent is able to penetrate, and act on cells within the CNS. In the case of rasagiline, the use of a peripheral mitochondrial biomarker is expected to be an adequate indicator of CNS activity since the therapeutic agent has demonstrated peripheral distribution and CNS penetration (90).…”