A Biomarker Study to Evaluate MN-166 in Subjects With Amyotrophic Literal Sclerosis (ALS)

Summary

This is a multi-center, open-label study of MN-166 (ibudilast) in subjects with ALS. To be eligible subjects must meet the El Escorial criteria of possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS. Safety, tolerability, blood, neuro-imaging biomarkers, and clinical outcomes will be collected on all subjects. Subjects will receive study drug for 36 weeks. The study will consist of a Screening Phase (up to 6 weeks), an Open-Label Treatment Phase (36 weeks) and an Off-Treatment Follow-up Phase (4 Weeks). Number of Subjects (Planned): Approximately 45 subjects are planned to be screened with the goal of enrolling 35 subjects.

Timeline

Start

2016-05-06

Primary completion

2019-12-31

Completion

2020-06-30

Publications

• Background Al-Chalabi A, Hardiman O. The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol. 2013 Nov;9(11):617-28. doi: 10.1038/nrneurol.2013.203. Epub 2013 Oct 15.
• Background Chio A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E, Traynor BG; Eurals Consortium. Prognostic factors in ALS: A critical review. Amyotroph Lateral Scler. 2009 Oct-Dec;10(5-6):310-23. doi: 10.3109/17482960802566824.
• Background Chio A, Logroscino G, Traynor BJ, Collins J, Simeone JC, Goldstein LA, White LA. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology. 2013;41(2):118-30. doi: 10.1159/000351153. Epub 2013 Jul 11.
• Background Turner MR, Hardiman O, Benatar M, Brooks BR, Chio A, de Carvalho M, Ince PG, Lin C, Miller RG, Mitsumoto H, Nicholson G, Ravits J, Shaw PJ, Swash M, Talbot K, Traynor BJ, Van den Berg LH, Veldink JH, Vucic S, Kiernan MC. Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol. 2013 Mar;12(3):310-22. doi: 10.1016/S1474-4422(13)70036-X.
• Background Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012 Mar 14;2012(3):CD001447. doi: 10.1002/14651858.CD001447.pub3.
• Background Henkel JS, Beers DR, Siklos L, Appel SH. The chemokine MCP-1 and the dendritic and myeloid cells it attracts are increased in the mSOD1 mouse model of ALS. Mol Cell Neurosci. 2006 Mar;31(3):427-37. doi: 10.1016/j.mcn.2005.10.016. Epub 2005 Dec 5.
• Background Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW. Onset and progression in inherited ALS determined by motor neurons and microglia. Science. 2006 Jun 2;312(5778):1389-92. doi: 10.1126/science.1123511.
• Background Butovsky O, Siddiqui S, Gabriely G, Lanser AJ, Dake B, Murugaiyan G, Doykan CE, Wu PM, Gali RR, Iyer LK, Lawson R, Berry J, Krichevsky AM, Cudkowicz ME, Weiner HL. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest. 2012 Sep;122(9):3063-87. doi: 10.1172/JCI62636. Epub 2012 Aug 6.
• Background Koval ED, Shaner C, Zhang P, du Maine X, Fischer K, Tay J, Chau BN, Wu GF, Miller TM. Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice. Hum Mol Genet. 2013 Oct 15;22(20):4127-35. doi: 10.1093/hmg/ddt261. Epub 2013 Jun 4.
• Background Brettschneider J, Del Tredici K, Toledo JB, Robinson JL, Irwin DJ, Grossman M, Suh E, Van Deerlin VM, Wood EM, Baek Y, Kwong L, Lee EB, Elman L, McCluskey L, Fang L, Feldengut S, Ludolph AC, Lee VM, Braak H, Trojanowski JQ. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol. 2013 Jul;74(1):20-38. doi: 10.1002/ana.23937. Epub 2013 Jun 19.
• Background Henkel JS, Engelhardt JI, Siklos L, Simpson EP, Kim SH, Pan T, Goodman JC, Siddique T, Beers DR, Appel SH. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol. 2004 Feb;55(2):221-35. doi: 10.1002/ana.10805.
• Background Kuhle J, Lindberg RL, Regeniter A, Mehling M, Steck AJ, Kappos L, Czaplinski A. Increased levels of inflammatory chemokines in amyotrophic lateral sclerosis. Eur J Neurol. 2009 Jun;16(6):771-4. doi: 10.1111/j.1468-1331.2009.02560.x. Epub 2009 Feb 19.
• Background Moreau C, Devos D, Brunaud-Danel V, Defebvre L, Perez T, Destee A, Tonnel AB, Lassalle P, Just N. Elevated IL-6 and TNF-alpha levels in patients with ALS: inflammation or hypoxia? Neurology. 2005 Dec 27;65(12):1958-60. doi: 10.1212/01.wnl.0000188907.97339.76.
• Background Zurcher NR, Loggia ML, Lawson R, Chonde DB, Izquierdo-Garcia D, Yasek JE, Akeju O, Catana C, Rosen BR, Cudkowicz ME, Hooker JM, Atassi N. Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: assessed with [(11)C]-PBR28. Neuroimage Clin. 2015 Jan 19;7:409-14. doi: 10.1016/j.nicl.2015.01.009. eCollection 2015.
• Background Sanftner LM, Gibbons JA, Gross MI, Suzuki BM, Gaeta FC, Johnson KW. Cross-species comparisons of the pharmacokinetics of ibudilast. Xenobiotica. 2009 Dec;39(12):964-77. doi: 10.3109/00498250903254340.
• Background Cho Y, Crichlow GV, Vermeire JJ, Leng L, Du X, Hodsdon ME, Bucala R, Cappello M, Gross M, Gaeta F, Johnson K, Lolis EJ. Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast. Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11313-8. doi: 10.1073/pnas.1002716107. Epub 2010 Jun 8.
• Background Cox GM, Kithcart AP, Pitt D, Guan Z, Alexander J, Williams JL, Shawler T, Dagia NM, Popovich PG, Satoskar AR, Whitacre CC. Macrophage migration inhibitory factor potentiates autoimmune-mediated neuroinflammation. J Immunol. 2013 Aug 1;191(3):1043-54. doi: 10.4049/jimmunol.1200485. Epub 2013 Jun 24.
• Background Wakita H, Tomimoto H, Akiguchi I, Lin JX, Ihara M, Ohtani R, Shibata M. Ibudilast, a phosphodiesterase inhibitor, protects against white matter damage under chronic cerebral hypoperfusion in the rat. Brain Res. 2003 Nov 28;992(1):53-9. doi: 10.1016/j.brainres.2003.08.028.
• Background Suzumura A, Ito A, Yoshikawa M, Sawada M. Ibudilast suppresses TNFalpha production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS. Brain Res. 1999 Aug 7;837(1-2):203-12. doi: 10.1016/s0006-8993(99)01666-2.
• Background Mizuno T, Kurotani T, Komatsu Y, Kawanokuchi J, Kato H, Mitsuma N, Suzumura A. Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia. Neuropharmacology. 2004 Mar;46(3):404-11. doi: 10.1016/j.neuropharm.2003.09.009.
• Background Kiebala M, Maggirwar SB. Ibudilast, a pharmacologic phosphodiesterase inhibitor, prevents human immunodeficiency virus-1 Tat-mediated activation of microglial cells. PLoS One. 2011 Apr 8;6(4):e18633. doi: 10.1371/journal.pone.0018633.
• Background Kagitani-Shimono K, Mohri I, Fujitani Y, Suzuki K, Ozono K, Urade Y, Taniike M. Anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor, in demyelination of twitcher, a genetic demyelination model. J Neuroinflammation. 2005 Apr 6;2(1):10. doi: 10.1186/1742-2094-2-10.
• Background Fujimoto T, Sakoda S, Fujimura H, Yanagihara T. Ibudilast, a phosphodiesterase inhibitor, ameliorates experimental autoimmune encephalomyelitis in Dark August rats. J Neuroimmunol. 1999 Mar 1;95(1-2):35-42. doi: 10.1016/s0165-5728(98)00251-3.
• Background Barkhof F, Hulst HE, Drulovic J, Uitdehaag BM, Matsuda K, Landin R; MN166-001 Investigators. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010 Mar 30;74(13):1033-40. doi: 10.1212/WNL.0b013e3181d7d651. Epub 2010 Mar 3.
• Background Gibson LC, Hastings SF, McPhee I, Clayton RA, Darroch CE, Mackenzie A, Mackenzie FL, Nagasawa M, Stevens PA, Mackenzie SJ. The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. Eur J Pharmacol. 2006 May 24;538(1-3):39-42. doi: 10.1016/j.ejphar.2006.02.053. Epub 2006 Mar 13.
• Background Tominaga Y, Nakamura Y, Tsuji K, Shibata T, Kataoka K. Ibudilast protects against neuronal damage induced by glutamate in cultured hippocampal neurons. Clin Exp Pharmacol Physiol. 1996 Jun-Jul;23(6-7):519-23. doi: 10.1111/j.1440-1681.1996.tb02772.x.
• Background Takuma K, Lee E, Enomoto R, Mori K, Baba A, Matsuda T. Ibudilast attenuates astrocyte apoptosis via cyclic GMP signalling pathway in an in vitro reperfusion model. Br J Pharmacol. 2001 Jul;133(6):841-8. doi: 10.1038/sj.bjp.0704146.
• Background Yoshioka A, Shimizu Y, Hirose G, Kitasato H, Pleasure D. Cyclic AMP-elevating agents prevent oligodendroglial excitotoxicity. J Neurochem. 1998 Jun;70(6):2416-23. doi: 10.1046/j.1471-4159.1998.70062416.x.
• Background Fox RJ. Primary neuroprotection: the Holy Grail of multiple sclerosis therapy. Neurology. 2010 Mar 30;74(13):1018-9. doi: 10.1212/WNL.0b013e3181d6b165. Epub 2010 Mar 3. No abstract available.
• Background Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, Rhodes C, Pulford DJ, Bennacef I, Parker CA, StJean PL, Cardon LR, Mooser VE, Matthews PM, Rabiner EA, Rubio JP. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab. 2012 Jan;32(1):1-5. doi: 10.1038/jcbfm.2011.147. Epub 2011 Oct 19.
• Background Kreisl WC, Jenko KJ, Hines CS, Lyoo CH, Corona W, Morse CL, Zoghbi SS, Hyde T, Kleinman JE, Pike VW, McMahon FJ, Innis RB; Biomarkers Consortium PET Radioligand Project Team. A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. J Cereb Blood Flow Metab. 2013 Jan;33(1):53-8. doi: 10.1038/jcbfm.2012.131. Epub 2012 Sep 12.
• Background Butovsky O, Jedrychowski MP, Cialic R, Krasemann S, Murugaiyan G, Fanek Z, Greco DJ, Wu PM, Doykan CE, Kiner O, Lawson RJ, Frosch MP, Pochet N, Fatimy RE, Krichevsky AM, Gygi SP, Lassmann H, Berry J, Cudkowicz ME, Weiner HL. Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann Neurol. 2015 Jan;77(1):75-99. doi: 10.1002/ana.24304. Epub 2014 Nov 27.
• Babu S, Hightower BG, Chan J, Zurcher NR, Kivisakk P, Tseng CJ, Sanders DL, Robichaud A, Banno H, Evora A, Ashokkumar A, Pothier L, Paganoni S, Chew S, Dojillo J, Matsuda K, Gudesblatt M, Berry JD, Cudkowicz ME, Hooker JM, Atassi N. Ibudilast (MN-166) in amyotrophic lateral sclerosis- an open label, safety and pharmacodynamic trial. Neuroimage Clin. 2021;30:102672. doi: 10.1016/j.nicl.2021.102672. Epub 2021 Apr 15.

Drugs

Indications