Abstract
Introduction: Immune activation has been implicated in progression of amytrophic lateral sclerosis (ALS). Oral fingolimod reduces circulating lymphocytes. The objective of this phase IIa, randomized, controlled trial was to test the short-term safety, tolerability, and target engagement of fingolimod in ALS. Methods: Randomization was 2:1 (fingolimod:placebo). Treatment duration was 4 weeks. Primary outcomes were safety and tolerability. Secondary outcomes included circulating lymphocytes and whole-blood gene expression. Results: Thirty participants were randomized; 28 were administered a drug (fingolimod 18, placebo 10). No serious adverse events occurred. Adverse events were similar by treatment arm, as was study discontinuation (2 fingolimod vs. 0 placebo, with no statistical difference). Forced expiratory volume in 1 second (FEV1) and FEV1/slow vital capacity changes were similar in the fingolimod and placebo arms. Circulating lymphocytes decreased significantly in the fingolimod arm (P < 0.001). Nine immune-related genes were significantly downregulated in the fingolimod arm, including forkhead box P3 (P < 0.001) and CD40 ligand (P = 0.003). Discussion: Fingolimod is safe and well-tolerated and can reduce circulating lymphocytes in ALS patients. Muscle Nerve 56: 1077–1084, 2017.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1077-1084 |
| Number of pages | 8 |
| Journal | Muscle and Nerve |
| Volume | 56 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 1 2017 |
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Keywords
- FOXP3
- RNA profiling
- circulating lymphocytes
- clinical trial
- neuroinflammation
- target engagement
ASJC Scopus subject areas
- Physiology
- Clinical Neurology
- Cellular and Molecular Neuroscience
- Physiology (medical)
Cite this
Phase IIa trial of fingolimod for amyotrophic lateral sclerosis demonstrates acceptable acute safety and tolerability. / Berry, James D.; Paganoni, Sabrina; Atassi, Nazem; Macklin, Eric A.; Goyal, Namita; Rivner, Michael; Simpson, Ericka; Appel, Stanley; Grasso, Daniela L.; Mejia, Nicte I.; Mateen, Farrah; Gill, Alan; Vieira, Fernando; Tassinari, Valerie; Perrin, Steven.
In: Muscle and Nerve, Vol. 56, No. 6, 01.12.2017, p. 1077-1084.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Phase IIa trial of fingolimod for amyotrophic lateral sclerosis demonstrates acceptable acute safety and tolerability
AU - Berry, James D.
AU - Paganoni, Sabrina
AU - Atassi, Nazem
AU - Macklin, Eric A.
AU - Goyal, Namita
AU - Rivner, Michael
AU - Simpson, Ericka
AU - Appel, Stanley
AU - Grasso, Daniela L.
AU - Mejia, Nicte I.
AU - Mateen, Farrah
AU - Gill, Alan
AU - Vieira, Fernando
AU - Tassinari, Valerie
AU - Perrin, Steven
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Introduction: Immune activation has been implicated in progression of amytrophic lateral sclerosis (ALS). Oral fingolimod reduces circulating lymphocytes. The objective of this phase IIa, randomized, controlled trial was to test the short-term safety, tolerability, and target engagement of fingolimod in ALS. Methods: Randomization was 2:1 (fingolimod:placebo). Treatment duration was 4 weeks. Primary outcomes were safety and tolerability. Secondary outcomes included circulating lymphocytes and whole-blood gene expression. Results: Thirty participants were randomized; 28 were administered a drug (fingolimod 18, placebo 10). No serious adverse events occurred. Adverse events were similar by treatment arm, as was study discontinuation (2 fingolimod vs. 0 placebo, with no statistical difference). Forced expiratory volume in 1 second (FEV1) and FEV1/slow vital capacity changes were similar in the fingolimod and placebo arms. Circulating lymphocytes decreased significantly in the fingolimod arm (P < 0.001). Nine immune-related genes were significantly downregulated in the fingolimod arm, including forkhead box P3 (P < 0.001) and CD40 ligand (P = 0.003). Discussion: Fingolimod is safe and well-tolerated and can reduce circulating lymphocytes in ALS patients. Muscle Nerve 56: 1077–1084, 2017.
AB - Introduction: Immune activation has been implicated in progression of amytrophic lateral sclerosis (ALS). Oral fingolimod reduces circulating lymphocytes. The objective of this phase IIa, randomized, controlled trial was to test the short-term safety, tolerability, and target engagement of fingolimod in ALS. Methods: Randomization was 2:1 (fingolimod:placebo). Treatment duration was 4 weeks. Primary outcomes were safety and tolerability. Secondary outcomes included circulating lymphocytes and whole-blood gene expression. Results: Thirty participants were randomized; 28 were administered a drug (fingolimod 18, placebo 10). No serious adverse events occurred. Adverse events were similar by treatment arm, as was study discontinuation (2 fingolimod vs. 0 placebo, with no statistical difference). Forced expiratory volume in 1 second (FEV1) and FEV1/slow vital capacity changes were similar in the fingolimod and placebo arms. Circulating lymphocytes decreased significantly in the fingolimod arm (P < 0.001). Nine immune-related genes were significantly downregulated in the fingolimod arm, including forkhead box P3 (P < 0.001) and CD40 ligand (P = 0.003). Discussion: Fingolimod is safe and well-tolerated and can reduce circulating lymphocytes in ALS patients. Muscle Nerve 56: 1077–1084, 2017.
KW - FOXP3
KW - RNA profiling
KW - circulating lymphocytes
KW - clinical trial
KW - neuroinflammation
KW - target engagement
UR - http://www.scopus.com/inward/record.url?scp=85033792241&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85033792241&partnerID=8YFLogxK
U2 - 10.1002/mus.25733
DO - 10.1002/mus.25733
M3 - Article
VL - 56
SP - 1077
EP - 1084
JO - Muscle and Nerve
JF - Muscle and Nerve
SN - 0148-639X
IS - 6
ER -