Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS
Abstract Background Laquinimod is an oral immunomodulator in clinical development to treat relapsing-remitting multiple sclerosis (RRMS). Laquinimod is in clinical development for the treatment of multiple sclerosis and Huntington Disease (HD). The objective of this study is to assess the safety, to...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-08-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-017-0945-z |
| _version_ | 1811280677487771648 |
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| author | Tjalf Ziemssen Hayrettin Tumani Tony Sehr Katja Thomas Friedemann Paul Nils Richter Emil Samara Ofer Spiegelstein Ella Sorani Oren Bar-Ilan Dorit Mimrod Liat Hayardeny |
| author_facet | Tjalf Ziemssen Hayrettin Tumani Tony Sehr Katja Thomas Friedemann Paul Nils Richter Emil Samara Ofer Spiegelstein Ella Sorani Oren Bar-Ilan Dorit Mimrod Liat Hayardeny |
| author_sort | Tjalf Ziemssen |
| collection | DOAJ |
| description | Abstract Background Laquinimod is an oral immunomodulator in clinical development to treat relapsing-remitting multiple sclerosis (RRMS). Laquinimod is in clinical development for the treatment of multiple sclerosis and Huntington Disease (HD). The objective of this study is to assess the safety, tolerability, pharmacokinetics (PK) and cytoimmunologic effects following escalating doses of laquinimod in patients with RRMS. Methods One hundred twelve patients were randomly assigned to laquinimod/placebo in a series of separate dose-escalating cohorts starting from a daily oral dose of 0.9 mg/1.2 mg escalating to 2.7 mg, in 0.3 mg increments. Results Twenty-eight patients received placebo and 84 received laquinimod ranging from 0.9 to 2.7 mg. No deaths occurred. One serious adverse event (SAE) of perichondritis was reported, which was unrelated to laquinimod (0.9 mg). There was no increased incidence of adverse events (AEs) with escalating doses. Laquinimod-treated patients showed more abnormal laboratory levels in liver enzymes, P-amylase, C-reactive protein (CRP), and fibrinogen, but most shifts were clinically non-significant. The exposure of laquinimod was dose proportional and linear in the tested dose range. An immunological substudy showed significant dose-dependent decreases in 6-sulpho LacNAc + dendritic cell (slanDC) frequency following laquinimod compared to placebo. Conclusion Laquinimod doses up to 2.7 mg were safely administered to patients with RRMS. An in vivo effect of laquinimod on the innate immune system was demonstrated. Trial registration EudraCT Number: 2009-011234-99 . Registered 23 June 2009. |
| first_indexed | 2024-04-13T01:19:05Z |
| format | Article |
| id | doaj.art-bdb3539f06e7433ab21434ff58506b17 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-13T01:19:05Z |
| publishDate | 2017-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-bdb3539f06e7433ab21434ff58506b172022-12-22T03:08:50ZengBMCJournal of Neuroinflammation1742-20942017-08-0114111010.1186/s12974-017-0945-zSafety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMSTjalf Ziemssen0Hayrettin Tumani1Tony Sehr2Katja Thomas3Friedemann Paul4Nils Richter5Emil Samara6Ofer Spiegelstein7Ella Sorani8Oren Bar-Ilan9Dorit Mimrod10Liat Hayardeny11Department of Neurology, MS Center Dresden, Center of Clinical Neuroscience, University Clinic Carl Gustav Carus DresdenMultiple Sclerosis Unit, Department of Neurology, University of UlmDepartment of Neurology, MS Center Dresden, Center of Clinical Neuroscience, University Clinic Carl Gustav Carus DresdenDepartment of Neurology, MS Center Dresden, Center of Clinical Neuroscience, University Clinic Carl Gustav Carus DresdenNeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center, Department of Neurology, Charité University MedicineNeurologische GemeinschaftspraxisPharmaPolaris InternationalTeva Pharmaceutical IndustriesTeva Pharmaceutical IndustriesTeva Pharmaceutical IndustriesTeva Pharmaceutical IndustriesTeva Pharmaceutical IndustriesAbstract Background Laquinimod is an oral immunomodulator in clinical development to treat relapsing-remitting multiple sclerosis (RRMS). Laquinimod is in clinical development for the treatment of multiple sclerosis and Huntington Disease (HD). The objective of this study is to assess the safety, tolerability, pharmacokinetics (PK) and cytoimmunologic effects following escalating doses of laquinimod in patients with RRMS. Methods One hundred twelve patients were randomly assigned to laquinimod/placebo in a series of separate dose-escalating cohorts starting from a daily oral dose of 0.9 mg/1.2 mg escalating to 2.7 mg, in 0.3 mg increments. Results Twenty-eight patients received placebo and 84 received laquinimod ranging from 0.9 to 2.7 mg. No deaths occurred. One serious adverse event (SAE) of perichondritis was reported, which was unrelated to laquinimod (0.9 mg). There was no increased incidence of adverse events (AEs) with escalating doses. Laquinimod-treated patients showed more abnormal laboratory levels in liver enzymes, P-amylase, C-reactive protein (CRP), and fibrinogen, but most shifts were clinically non-significant. The exposure of laquinimod was dose proportional and linear in the tested dose range. An immunological substudy showed significant dose-dependent decreases in 6-sulpho LacNAc + dendritic cell (slanDC) frequency following laquinimod compared to placebo. Conclusion Laquinimod doses up to 2.7 mg were safely administered to patients with RRMS. An in vivo effect of laquinimod on the innate immune system was demonstrated. Trial registration EudraCT Number: 2009-011234-99 . Registered 23 June 2009.http://link.springer.com/article/10.1186/s12974-017-0945-zLaquinimodMultiple sclerosisSafetyImmunologyslanDC |
| spellingShingle | Tjalf Ziemssen Hayrettin Tumani Tony Sehr Katja Thomas Friedemann Paul Nils Richter Emil Samara Ofer Spiegelstein Ella Sorani Oren Bar-Ilan Dorit Mimrod Liat Hayardeny Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS Journal of Neuroinflammation Laquinimod Multiple sclerosis Safety Immunology slanDC |
| title | Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS |
| title_full | Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS |
| title_fullStr | Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS |
| title_full_unstemmed | Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS |
| title_short | Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS |
| title_sort | safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with rrms |
| topic | Laquinimod Multiple sclerosis Safety Immunology slanDC |
| url | http://link.springer.com/article/10.1186/s12974-017-0945-z |
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