Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide Hydrolase
Three patients had severe ataxia and memory impairment in a phase 1 trial of a fatty acid amide hydrolase inhibitor designed as an analgesic and antiinflammatory drug. One patient became brain dead. MRI of the brain showed lesions in the pons and hippocampi. A decrease in fatty acid amide hydrolase...
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| Published in | The New England journal of medicine Vol. 375; no. 18; pp. 1717 - 1725 |
|---|---|
| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Massachusetts Medical Society
03.11.2016
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0028-4793 1533-4406 1533-4406 |
| DOI | 10.1056/NEJMoa1604221 |
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| Abstract | Three patients had severe ataxia and memory impairment in a phase 1 trial of a fatty acid amide hydrolase inhibitor designed as an analgesic and antiinflammatory drug. One patient became brain dead. MRI of the brain showed lesions in the pons and hippocampi.
A decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids.
1
FAAH inhibitors have shown analgesic and antiinflammatory activity in animal models,
2
and some have been tested for these purposes in phase 1 and phase 2 studies.
3
Phase 3 studies were not pursued owing to a lack of efficacy. BIA 10-2474, with the chemical name 3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide, is a new reversible FAAH inhibitor. A phase 1 study was conducted in healthy volunteers to explore the safety profile of BIA 10-2474. Five of the six participants who had received the highest cumulative dose . . . |
|---|---|
| AbstractList | BackgroundA decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids. FAAH inhibitors have shown analgesic and antiinflammatory activity in animal models, and some have been tested in phase 1 and 2 studies. In a phase 1 study, BIA 10-2474, an orally administered reversible FAAH inhibitor, was given to healthy volunteers to assess safety.MethodsSingle doses (0.25 to 100 mg) and repeated oral doses (2.5 to 20 mg for 10 days) of BIA 10-2474 had been administered to 84 healthy volunteers in sequential cohorts; no severe adverse events had been reported. Another cohort of participants was then assigned to placebo (2 participants) or 50 mg of BIA 10-2474 per day (6 participants). This report focuses on neurologic adverse events in participants in this final cohort. A total of 4 of the 6 participants who received active treatment consented to have their clinical and radiologic data included in this report.ResultsAn acute and rapidly progressive neurologic syndrome developed in three of the four participants starting on the fifth day of drug administration. The main clinical features were headache, a cerebellar syndrome, memory impairment, and altered consciousness. Magnetic resonance imaging showed bilateral and symmetric cerebral lesions, including microhemorrhages and hyperintensities on fluid-attenuated inversion recovery and diffusion-weighted imaging sequences predominantly involving the pons and hippocampi. One patient became brain dead; the condition of two patients subsequently improved, but one patient had residual memory impairment, and the other patient had a residual cerebellar syndrome. One patient remained asymptomatic.ConclusionsAn unanticipated severe neurologic disorder occurred after ingestion of BIA 10-2474 at the highest dose level used in a phase 1 trial. The underlying mechanism of this toxic cerebral syndrome remains unknown. BACKGROUND A decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids. FAAH inhibitors have shown analgesic and antiinflammatory activity in animal models, and some have been tested in phase 1 and 2 studies. In a phase 1 study, BIA 10-2474, an orally administered reversible FAAH inhibitor, was given to healthy volunteers to assess safety. METHODS Single doses (0.25 to 100 mg) and repeated oral doses (2.5 to 20 mg for 10 days) of BIA 10-2474 had been administered to 84 healthy volunteers in sequential cohorts; no severe adverse events had been reported. Another cohort of participants was then assigned to placebo (2 participants) or 50 mg of BIA 10-2474 per day (6 participants). This report focuses on neurologic adverse events in participants in this final cohort. A total of 4 of the 6 participants who received active treatment consented to have their clinical and radiologic data included in this report. RESULTS An acute and rapidly progressive neurologic syndrome developed in three of the four participants starting on the fifth day of drug administration. The main clinical features were headache, a cerebellar syndrome, memory impairment, and altered consciousness. Magnetic resonance imaging showed bilateral and symmetric cerebral lesions, including microhemorrhages and hyperintensities on fluid-attenuated inversion recovery and diffusion-weighted imaging sequences predominantly involving the pons and hippocampi. One patient became brain dead; the condition of two patients subsequently improved, but one patient had residual memory impairment, and the other patient had a residual cerebellar syndrome. One patient remained asymptomatic. CONCLUSIONS An unanticipated severe neurologic disorder occurred after ingestion of BIA 10-2474 at the highest dose level used in a phase 1 trial. The underlying mechanism of this toxic cerebral syndrome remains unknown. Three patients had severe ataxia and memory impairment in a phase 1 trial of a fatty acid amide hydrolase inhibitor designed as an analgesic and antiinflammatory drug. One patient became brain dead. MRI of the brain showed lesions in the pons and hippocampi. A decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids. 1 FAAH inhibitors have shown analgesic and antiinflammatory activity in animal models, 2 and some have been tested for these purposes in phase 1 and phase 2 studies. 3 Phase 3 studies were not pursued owing to a lack of efficacy. BIA 10-2474, with the chemical name 3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide, is a new reversible FAAH inhibitor. A phase 1 study was conducted in healthy volunteers to explore the safety profile of BIA 10-2474. Five of the six participants who had received the highest cumulative dose . . . A decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids. FAAH inhibitors have shown analgesic and antiinflammatory activity in animal models, and some have been tested in phase 1 and 2 studies. In a phase 1 study, BIA 10-2474, an orally administered reversible FAAH inhibitor, was given to healthy volunteers to assess safety. Single doses (0.25 to 100 mg) and repeated oral doses (2.5 to 20 mg for 10 days) of BIA 10-2474 had been administered to 84 healthy volunteers in sequential cohorts; no severe adverse events had been reported. Another cohort of participants was then assigned to placebo (2 participants) or 50 mg of BIA 10-2474 per day (6 participants). This report focuses on neurologic adverse events in participants in this final cohort. A total of 4 of the 6 participants who received active treatment consented to have their clinical and radiologic data included in this report. An acute and rapidly progressive neurologic syndrome developed in three of the four participants starting on the fifth day of drug administration. The main clinical features were headache, a cerebellar syndrome, memory impairment, and altered consciousness. Magnetic resonance imaging showed bilateral and symmetric cerebral lesions, including microhemorrhages and hyperintensities on fluid-attenuated inversion recovery and diffusion-weighted imaging sequences predominantly involving the pons and hippocampi. One patient became brain dead; the condition of two patients subsequently improved, but one patient had residual memory impairment, and the other patient had a residual cerebellar syndrome. One patient remained asymptomatic. An unanticipated severe neurologic disorder occurred after ingestion of BIA 10-2474 at the highest dose level used in a phase 1 trial. The underlying mechanism of this toxic cerebral syndrome remains unknown. A decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids. FAAH inhibitors have shown analgesic and antiinflammatory activity in animal models, and some have been tested in phase 1 and 2 studies. In a phase 1 study, BIA 10-2474, an orally administered reversible FAAH inhibitor, was given to healthy volunteers to assess safety.BACKGROUNDA decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids. FAAH inhibitors have shown analgesic and antiinflammatory activity in animal models, and some have been tested in phase 1 and 2 studies. In a phase 1 study, BIA 10-2474, an orally administered reversible FAAH inhibitor, was given to healthy volunteers to assess safety.Single doses (0.25 to 100 mg) and repeated oral doses (2.5 to 20 mg for 10 days) of BIA 10-2474 had been administered to 84 healthy volunteers in sequential cohorts; no severe adverse events had been reported. Another cohort of participants was then assigned to placebo (2 participants) or 50 mg of BIA 10-2474 per day (6 participants). This report focuses on neurologic adverse events in participants in this final cohort. A total of 4 of the 6 participants who received active treatment consented to have their clinical and radiologic data included in this report.METHODSSingle doses (0.25 to 100 mg) and repeated oral doses (2.5 to 20 mg for 10 days) of BIA 10-2474 had been administered to 84 healthy volunteers in sequential cohorts; no severe adverse events had been reported. Another cohort of participants was then assigned to placebo (2 participants) or 50 mg of BIA 10-2474 per day (6 participants). This report focuses on neurologic adverse events in participants in this final cohort. A total of 4 of the 6 participants who received active treatment consented to have their clinical and radiologic data included in this report.An acute and rapidly progressive neurologic syndrome developed in three of the four participants starting on the fifth day of drug administration. The main clinical features were headache, a cerebellar syndrome, memory impairment, and altered consciousness. Magnetic resonance imaging showed bilateral and symmetric cerebral lesions, including microhemorrhages and hyperintensities on fluid-attenuated inversion recovery and diffusion-weighted imaging sequences predominantly involving the pons and hippocampi. One patient became brain dead; the condition of two patients subsequently improved, but one patient had residual memory impairment, and the other patient had a residual cerebellar syndrome. One patient remained asymptomatic.RESULTSAn acute and rapidly progressive neurologic syndrome developed in three of the four participants starting on the fifth day of drug administration. The main clinical features were headache, a cerebellar syndrome, memory impairment, and altered consciousness. Magnetic resonance imaging showed bilateral and symmetric cerebral lesions, including microhemorrhages and hyperintensities on fluid-attenuated inversion recovery and diffusion-weighted imaging sequences predominantly involving the pons and hippocampi. One patient became brain dead; the condition of two patients subsequently improved, but one patient had residual memory impairment, and the other patient had a residual cerebellar syndrome. One patient remained asymptomatic.An unanticipated severe neurologic disorder occurred after ingestion of BIA 10-2474 at the highest dose level used in a phase 1 trial. The underlying mechanism of this toxic cerebral syndrome remains unknown.CONCLUSIONSAn unanticipated severe neurologic disorder occurred after ingestion of BIA 10-2474 at the highest dose level used in a phase 1 trial. The underlying mechanism of this toxic cerebral syndrome remains unknown. |
| Author | Kerbrat, Anne Edan, Gilles Fillatre, Pierre Le Tulzo, Yves Lavoué, Sylvain Vérin, Marc Gauvrit, Jean-Yves Ferré, Jean-Christophe Vannier, Stéphane Ronzière, Thomas Carsin-Nicol, Béatrice |
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Ronzière, Thomas organization: From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d’Investigation Clinique–Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) — all in Rennes, France – sequence: 5 givenname: Stéphane surname: Vannier fullname: Vannier, Stéphane organization: From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d’Investigation Clinique–Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) — all in Rennes, France – sequence: 6 givenname: Béatrice surname: Carsin-Nicol fullname: Carsin-Nicol, Béatrice organization: From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d’Investigation Clinique–Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) — all in Rennes, France – sequence: 7 givenname: Sylvain surname: Lavoué fullname: Lavoué, Sylvain organization: From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d’Investigation Clinique–Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) — all in Rennes, France – sequence: 8 givenname: Marc surname: Vérin fullname: Vérin, Marc organization: From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d’Investigation Clinique–Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) — all in Rennes, France – sequence: 9 givenname: Jean-Yves surname: Gauvrit fullname: Gauvrit, Jean-Yves organization: From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d’Investigation Clinique–Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) — all in Rennes, France – sequence: 10 givenname: Yves surname: Le Tulzo fullname: Le Tulzo, Yves organization: From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d’Investigation Clinique–Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) — all in Rennes, France – sequence: 11 givenname: Gilles surname: Edan fullname: Edan, Gilles organization: From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d’Investigation Clinique–Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) — all in Rennes, France |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27806235$$D View this record in MEDLINE/PubMed https://univ-rennes.hal.science/hal-01412967$$DView record in HAL |
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| ContentType | Journal Article |
| Copyright | Copyright © 2016 Massachusetts Medical Society. All rights reserved. Distributed under a Creative Commons Attribution 4.0 International License |
| Copyright_xml | – notice: Copyright © 2016 Massachusetts Medical Society. All rights reserved. – notice: Distributed under a Creative Commons Attribution 4.0 International License |
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| DOI | 10.1056/NEJMoa1604221 |
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| References | Hu, SS, Mackie, K (r006) 2015; 231 Cravatt, BF, Demarest, K, Patricelli, MP (r001) 2001; 98 Sharma, P, Eesa, M, Scott, JN (r005) 2009; 193 r004 Roques, BP, Fournié-Zaluski, MC, Wurm, M (r002) 2012; 11 Huggins, JP, Smart, TS, Langman, S, Taylor, L, Young, T (r003) 2012; 153 r006 r001 r002 Huggins JP (r003) 2012; 153 r005 28121500 - N Engl J Med. 2017 Jan 26;376(4):393-4 28124887 - N Engl J Med. ;376(4):392 28121501 - N Engl J Med. 2017 Jan 26;376(4):393 28124888 - N Engl J Med. ;376(4):292-3 28124889 - N Engl J Med. ;376(4):393 27806239 - N Engl J Med. 2016 Nov 3;375(18):1788-1789 |
| References_xml | – volume: 231 start-page: 59 year: 2015 end-page: 93 ident: r006 article-title: Distribution of the endocannabinoid system in the central nervous system. publication-title: Handb Exp Pharmacol – volume: 98 start-page: 9371 year: 2001 end-page: 9376 ident: r001 article-title: Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. publication-title: Proc Natl Acad Sci U S A – volume: 193 start-page: 879 year: 2009 end-page: 886 ident: r005 article-title: Toxic and acquired metabolic encephalopathies: MRI appearance. publication-title: AJR Am J Roentgenol – ident: r004 article-title: Report by the Temporary Specialist Scientific Committee (TSSC), “FAAH (Fatty Acid Amide Hydrolase)”, on the causes of the accident during a Phase 1 clinical trial in Rennes in January 2016. Saint-Denis, France: Agence Nationale de Sécurité du Médicament et des Produits de Santé ( http://ansm.sante.fr/var/ansm_site/storage/original/application/744c7c6daf96b141bc9509e2f85c227e.pdf ). – volume: 11 start-page: 292 year: 2012 end-page: 310 ident: r002 article-title: Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain. publication-title: Nat Rev Drug Discov – volume: 153 start-page: 1837 year: 2012 end-page: 1846 ident: r003 article-title: An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee. publication-title: Pain – ident: r005 doi: 10.2214/AJR.08.2257 – ident: r001 doi: 10.1073/pnas.161191698 – volume: 153 start-page: 1837 year: 2012 ident: r003 publication-title: Pain doi: 10.1016/j.pain.2012.04.020 – ident: r002 doi: 10.1038/nrd3673 – ident: r006 doi: 10.1007/978-3-319-20825-1_3 – reference: 28124888 - N Engl J Med. ;376(4):292-3 – reference: 28121500 - N Engl J Med. 2017 Jan 26;376(4):393-4 – reference: 28124887 - N Engl J Med. ;376(4):392 – reference: 28121501 - N Engl J Med. 2017 Jan 26;376(4):393 – reference: 27806239 - N Engl J Med. 2016 Nov 3;375(18):1788-1789 – reference: 28124889 - N Engl J Med. ;376(4):393 |
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| Snippet | Three patients had severe ataxia and memory impairment in a phase 1 trial of a fatty acid amide hydrolase inhibitor designed as an analgesic and... A decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids. FAAH inhibitors... BackgroundA decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids. FAAH... BACKGROUND A decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids. FAAH... |
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| SubjectTerms | Acute Disease Administration, Oral Adult Amidohydrolases - antagonists & inhibitors Analgesics Animal models Brain Death Cannabinoids Cerebellar Diseases - chemically induced Cerebellum Cerebellum - pathology Cerebral Hemorrhage - chemically induced Cerebral Hemorrhage - diagnosis Consciousness Disorders - chemically induced Cyclic N-Oxides - administration & dosage Cyclic N-Oxides - adverse effects Double-Blind Method Drug dosages Enzymes Fatty acids Fatty-acid amide hydrolase Gait Ataxia - chemically induced Headache Headache - chemically induced Healthy Volunteers Hippocampus Hippocampus - pathology Human health and pathology Humans Hydrolase Inhibitor drugs Life Sciences Magnetic Resonance Imaging Male Memory Memory Disorders - chemically induced Middle Aged Neuroimaging Neurological disorders Neurons and Cognition Oral administration Patient safety Patients Pons Pons - pathology Psychiatrics and mental health Pyridines - administration & dosage Pyridines - adverse effects Toxicity |
| Title | Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide Hydrolase |
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