Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis

Fox, Robert J.; Coffey, Christopher S.; Conwit, Robin; Cudkowicz, Merit; Gleason, Trevis; Goodman, Andrew; Klawiter, Eric C.; Matsuda, Kazuko; McGovern, Michelle; Naismith, Robert T.; Ashokkumar, Akshata; Barnes, Janel; Ecklund, Dixie; Klingner, Elizabeth; Koepp, Maxine; Long, Jeffrey D.; Natarajan, Sneha; Thornell, Brenda; Yankey, Jon; Bermel, Robert; Debbins, Josef P.; Huang, Xinyi; Jagodnik, P.; Lowe, Mark J.; Nakamura, Kunio; Narayanan, Sridar; Sakaie, Kenneth Earl; Thoomukuntla, B.; Zhou, Xiaopeng; Krieger, Stephen; Alvarez, Enríque; Apperson, Michelle; Bashir, Khurram; Cohen, Bruce A.; Coyle, Patricia K.; Delgado, Silvia; DeWitt, L. D.; Flores, Angela; Giesser, Barbara; Goldman, Myla D.; Jubelt, Burk; Lava, Neil; Lynch, Sharon G.; Moses, Harold; Ontaneda, Daniel; Perumal, Jai; Racke, Michael K.; Repovic, Pavle; Riley, Claire; Severson, Christopher; Shinnar, Shlomo; Suski, Valerie; Weinstock‐Guttman, Bianca; Yadav, Vijayshree; Zabeti, Aram

doi:10.1056/nejmoa1803583

Cited by 222 publications

(184 citation statements)

References 30 publications

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“…Our findings also suggest that the pathology‐specific interaction between TRPC3 and Nox2 could be a general mechanism underlying wasting in a range of tissues. Indeed, ibudilast has pleiotropic effects on amyotrophic lateral sclerosis and multiple sclerosis (Crisafulli, Brajkovic, Cipolat Mis, Parente, & Corti, ; Fox et al, ). Further studies will elucidate the involvement of TRPC3‐Nox2 complexes in these intractable diseases and allow us to propose the inhibition of TRPC3‐Nox2 complex as an innovative therapeutic strategy for their prevention and treatment.…”

Section: Discussionmentioning

confidence: 99%

Ibudilast attenuates doxorubicin‐induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes

Nishiyama

Numaga‐Tomita

Fujimoto

et al. 2019

British J Pharmacology

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Background and Purpose Doxorubicin is a highly effective anticancer agent but eventually induces cardiotoxicity associated with increased production of ROS. We previously reported that a pathological protein interaction between TRPC3 channels and NADPH oxidase 2 (Nox2) contributed to doxorubicin‐induced cardiac atrophy in mice. Here we have investigated the effects of ibudilast, a drug already approved for clinical use and known to block doxorubicin‐induced cytotoxicity, on the TRPC3‐Nox2 complex. We specifically sought evidence that this drug attenuated doxorubicin‐induced systemic tissue wasting in mice. Experimental Approach We used the RAW264.7 macrophage cell line to screen 1,271 clinically approved chemical compounds, evaluating functional interactions between TRPC3 channels and Nox2, by measuring Nox2 protein stability and ROS production, with and without exposure to doxorubicin. In male C57BL/6 mice, samples of cardiac and gastrocnemius muscle were taken and analysed with morphometric, immunohistochemical, RT‐PCR and western blot methods. In the passive smoking model, cells were exposed to DMEM containing cigarette sidestream smoke. Key Results Ibudilast, an anti‐asthmatic drug, attenuated ROS‐mediated muscle toxicity induced by doxorubicin treatment or passive smoking, by inhibiting the functional interactions between TRPC3 channels and Nox2, without reducing TRPC3 channel activity. Conclusions and Implications These results indicate a common mechanism underlying induction of systemic tissue wasting by doxorubicin. They also suggest that ibudilast could be repurposed to prevent muscle toxicity caused by anticancer drugs or passive smoking.

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Section: Discussionmentioning

confidence: 99%

Ibudilast attenuates doxorubicin‐induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes

Nishiyama

Numaga‐Tomita

Fujimoto

et al. 2019

British J Pharmacology

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“…Additionally, Ibudilast recently demonstrated promising results in a phase 2 clinical trial of multiple sclerosis, where it is thought to have a protective effect by reducing brain atrophy, as compared to anti-inflammatory drugs commonly used to treat multiple sclerosis 35 .…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, MIF signaling through CXCR2 primarily activates PI3K/AKT pathways 32 . The pharmacologic targeting of MIF has also been of great interest in a variety of inflammatory conditions including multiple sclerosis, systemic lupus erythrematosus, rheumatoid arthritis, inflammatory bowel disease, and other inflammatory disorders 22,[33][34][35][36][37][38][39][40] . Additionally, clinically approved MIF inhibitors have been developed that could potentially be repurposed for GBM 33 .…”

Section: Introductionmentioning

confidence: 99%

Glioblastoma myeloid-derived suppressor cell subsets express differential macrophage migration inhibitory factor receptor profiles that can be targeted to reduce immune suppression

Alban

Bayık

Otvos

et al. 2019

Preprint

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The application of tumor immunotherapy to glioblastoma (GBM) is limited by an unprecedented degree of immune suppression due to factors that include high numbers of immune suppressive myeloid cells, the blood brain barrier, and T cell sequestration to the bone marrow. We previously identified an increase in immune suppressive myeloid-derived suppressor cells (MDSCs) in GBM patients, which correlated with poor prognosis and was dependent on macrophage migration inhibitory factor (MIF). Here we examine the MIF signaling axis in detail in murine MDSC models, GBM-educated MDSCs and human GBM. We found that the monocytic subset of MDSCs (M-MDSCs), expressed high levels of the MIF cognate receptor CD74 and was localized in the tumor microenvironment. In contrast, granulocytic MDSCs (G-MDSCs) expressed high levels of the MIF non-cognate receptor CXCR2 and showed minimal accumulation in the tumor microenvironment. Furthermore, targeting M-MDSCs with ibudilast, a brain penetrant MIF-CD74 interaction inhibitor, reduced MDSC function and enhanced CD8 T cell activity in the tumor microenvironment. These findings demonstrate the MDSC subsets differentially express MIF receptors and may be leveraged for specific MDSC targeting.

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“…4 Although, in general newer DMTs are considered to have better short-term outcomes than older DMTs, some cause adverse events that require careful monitoring (e.g., idubilast). 5 In relapsing-remitting multiple sclerosis, there are currently attempts to combine or sequentially administer the various options. So far, there are insufficient data about their long-term effectiveness and harms.…”

Section: In This Issuementioning

confidence: 99%

“…In one of the few phase III studies over a 2‐year period in patients below the age of 18, fingolimod, a spingosine‐1‐phosphate analogue was associated with a lower rate of relapse and less accumulation of lesions on magnetic resonance imaging than interferon beta‐1a, but a higher rate of serious adverse events was determined . Although, in general newer DMTs are considered to have better short‐term outcomes than older DMTs, some cause adverse events that require careful monitoring (e.g., idubilast) . In relapsing‐remitting multiple sclerosis, there are currently attempts to combine or sequentially administer the various options.…”

mentioning

confidence: 99%

Challenges in Neuropharmacology

Cascorbi

2019

Clin Pharma and Therapeutics

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Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis

Cited by 222 publications

References 30 publications

Ibudilast attenuates doxorubicin‐induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes

Ibudilast attenuates doxorubicin‐induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes

Glioblastoma myeloid-derived suppressor cell subsets express differential macrophage migration inhibitory factor receptor profiles that can be targeted to reduce immune suppression

Challenges in Neuropharmacology

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