PMID- 28859672 OWN - NLM STAT- MEDLINE DCOM- 20180514 LR - 20181113 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 14 IP - 1 DP - 2017 Aug 31 TI - Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS. PG - 172 LID - 10.1186/s12974-017-0945-z [doi] LID - 172 AB - 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. FAU - Ziemssen, Tjalf AU - Ziemssen T AD - Department of Neurology, MS Center Dresden, Center of Clinical Neuroscience, University Clinic Carl Gustav Carus Dresden, Dresden, Germany. Tjalf.Ziemssen@uniklinikum-dresden.de. FAU - Tumani, Hayrettin AU - Tumani H AD - Multiple Sclerosis Unit, Department of Neurology, University of Ulm, Ulm, Germany. hayrettin.tumani@uni-ulm.de. AD - Fachklinik fur Neurologie Dietenbronn, Schwendi, Germany. hayrettin.tumani@uni-ulm.de. FAU - Sehr, Tony AU - Sehr T AD - Department of Neurology, MS Center Dresden, Center of Clinical Neuroscience, University Clinic Carl Gustav Carus Dresden, Dresden, Germany. FAU - Thomas, Katja AU - Thomas K AD - Department of Neurology, MS Center Dresden, Center of Clinical Neuroscience, University Clinic Carl Gustav Carus Dresden, Dresden, Germany. FAU - Paul, Friedemann AU - Paul F AD - NeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center, Department of Neurology, Charite University Medicine, Berlin, Germany. AD - Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charite University Medicine Berlin, Berlin, Germany. FAU - Richter, Nils AU - Richter N AD - Neurologische Gemeinschaftspraxis, Dusseldorf, Germany. FAU - Samara, Emil AU - Samara E AD - PharmaPolaris International, Davis, CA, USA. FAU - Spiegelstein, Ofer AU - Spiegelstein O AD - Teva Pharmaceutical Industries, Netanya, Israel. FAU - Sorani, Ella AU - Sorani E AD - Teva Pharmaceutical Industries, Netanya, Israel. FAU - Bar-Ilan, Oren AU - Bar-Ilan O AD - Teva Pharmaceutical Industries, Netanya, Israel. FAU - Mimrod, Dorit AU - Mimrod D AD - Teva Pharmaceutical Industries, Netanya, Israel. FAU - Hayardeny, Liat AU - Hayardeny L AD - Teva Pharmaceutical Industries, Netanya, Israel. AD - Galmed Pharmaceuticals, Tel Aviv, Israel. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial DEP - 20170831 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (Immunologic Factors) RN - 0 (Quinolones) RN - 908SY76S4G (laquinimod) SB - IM MH - Administration, Oral MH - Adolescent MH - Adult MH - Cohort Studies MH - Dose-Response Relationship, Drug MH - Double-Blind Method MH - Female MH - Follow-Up Studies MH - Humans MH - Immunity, Innate/drug effects/*immunology MH - Immunologic Factors/*administration & dosage MH - Male MH - Middle Aged MH - Multiple Sclerosis, Relapsing-Remitting/*drug therapy/*immunology MH - Quinolones/*administration & dosage MH - Young Adult PMC - PMC5577769 OTO - NOTNLM OT - Immunology OT - Laquinimod OT - Multiple sclerosis OT - Safety OT - slanDC COIS- AUTHORS' INFORMATION: Not applicable. ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The study was conducted in accordance with the Declaration of Helsinki, the protocol was approved by the Independent Ethics Committee at each study site (Ethikkommission der Universitat Ulm), and written informed consent was obtained from each patient as a condition of entry. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: T.Z. received grants from Novartis during the conduct of the study; grants and personal fees from Bayer HealthCare, Biogen Idec, Teva Pharmaceutical Industries Ltd., Genzyme and Novartis outside the submitted work; and personal fees from Merck Serono, Almirall, GlaxoSmithKline and Roche outside the submitted work. H.T. serves on a scientific advisory board as a consultant for, and/or received funding for research projects and travel from Bayer Healthcare, Biogen Idec, Genzyme Virotec, Merck Serono, Novartis, Roche, Teva Pharmaceutical Industries Ltd., and Siemens Health Diagnostics. F.P. received research support and personal compensation for activities with Alexion, Bayer, Biogen Idec, Teva Pharmaceutical Industries Ltd., Merck Serono, Novartis, Sanofi-Aventis/Genzyme, MedImmune and Shire and is a member of the SCs for the OCTIMS study (Novartis) and the MedImmune 551 study. K.T. received personal compensation fees from Novartis and Biogen Idec for oral presentations outside the submitted work. E.S. received consultant fees from Teva Pharmaceutical Industries Ltd. O.S., E.S., O.B., D. M., and L.H. are or were employees of Teva Pharmaceutical Industries Ltd. at the time the study was conducted. T. Sehr and N. Richter have nothing to declare. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2017/09/02 06:00 MHDA- 2018/05/15 06:00 PMCR- 2017/08/31 CRDT- 2017/09/02 06:00 PHST- 2017/06/02 00:00 [received] PHST- 2017/08/16 00:00 [accepted] PHST- 2017/09/02 06:00 [entrez] PHST- 2017/09/02 06:00 [pubmed] PHST- 2018/05/15 06:00 [medline] PHST- 2017/08/31 00:00 [pmc-release] AID - 10.1186/s12974-017-0945-z [pii] AID - 945 [pii] AID - 10.1186/s12974-017-0945-z [doi] PST - epublish SO - J Neuroinflammation. 2017 Aug 31;14(1):172. doi: 10.1186/s12974-017-0945-z.