Ibudilast (MN-166) in amyotrophic lateral sclerosis- an open label, safety and pharmacodynamic trial

Abstract

Ibudilast (MN-166) is an inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterases 3,4,10 and 11 (Gibson et al., 2006; Cho et al., 2010). Ibudilast attenuates CNS microglial activation and secretion of pro-inflammatory cytokines (Fujimoto et al., 1999; Cho et al., 2010). In vitro evidence suggests that ibudilast is neuroprotective by suppressing neuronal cell death induced by microglial activation. People with ALS have increased microglial activation measured by [11C]PBR28-PET in the motor cortices. The primary objective is to determine the impact of ibudilast on reducing glial activation and neuroaxonal loss in ALS, measured by PBR28-PET and serum Neurofilament light (NfL). The secondary objectives included determining safety and tolerability of ibudilast high dosage (up to 100 mg/day) over 36 weeks. In this open label trial, 35 eligible ALS participants underwent ibudilast treatment up to 100 mg/day for 36 weeks. Of these, 30 participants were enrolled in the main study cohort and were included in biomarker, safety and tolerability analyses. Five additional participants were enrolled in the expanded access arm, who did not meet imaging eligibility criteria and were included in the safety and tolerability analyses. The primary endpoints were median change from baseline in (a) PBR28-PET uptake in primary motor cortices, measured by standard uptake value ratio (SUVR) over 12-24 weeks and (b) serum NfL over 36-40 weeks. The secondary safety and tolerability endpoints were collected through Week 40. The baseline median (range) of PBR28-PET SUVR was 1.033 (0.847, 1.170) and NfL was 60.3 (33.1, 219.3) pg/ml. Participants who completed both pre and post-treatment scans had PBR28-PET SUVR median(range) change from baseline of 0.002 (-0.184, 0.156) , P = 0.5 (n = 22). The median(range) NfL change from baseline was 0.4 pg/ml (-1.8, 17.5), P = 0.2 (n = 10 participants). 30(86%) participants experienced at least one, possibly study drug related adverse event. 13(37%) participants could not tolerate 100 mg/day and underwent dose reduction to 60-80 mg/day and 11(31%) participants discontinued study drug early due to drug related adverse events. The study concludes that following treatment with ibudilast up to 100 mg/day in ALS participants, there were no significant reductions in (a) motor cortical glial activation measured by PBR28-PET SUVR over 12-24 weeks or (b) CNS neuroaxonal loss, measured by serum NfL over 36-40 weeks. Dose reductions and discontinuations due to treatment emergent adverse events were common at this dosage in ALS participants. Future pharmacokinetic and dose-finding studies of ibudilast would help better understand tolerability and target engagement in ALS.

Trial registration: ClinicalTrials.gov NCT02714036.

Keywords: Biomarker endpoint; Clinical trial; Ibudilast; MIF; Neurofilament; PBR28; Phase 1b; TNF-alpha.

Conflict of interest statement

Nazem Atassi is an employee of Sanofi.

Baileigh Hightower, Pia Kivisäkk, Nicole R Zürcher, Chieh-En J Tseng, Danica L Sanders, Ashley Robichaud, Armineuza Evora, Akshata Ashokkumar and Lindsay Pothier report no COI related to this trial.

Suma Babu reports research support from American Academy of Neurology, AANEM Foundation, The ALS Association., Muscular Dystrophy Association, Biogen Inc, Orion Corporation, Voyager Therapeutics and Novartis pharmaceuticals.

James D. Berry has attended advisory boards at Alexion, Biogen and Clene Nanomedicine, has received research support from Alexion, Amylyx Therapeutics, Biogen, MT Pharma of America, Anelixis Therapeutics, Brainstorm Cell Therapeutics, Genentech, nQ Medical, ALS Finding a Cure, NINDS, Muscular Dystrophy Association, and ALS One.

Sabrina Paganoni reports research grants from Amylyx Therapeutics, Revalesio Corporation, Ra Pharma/UCB, Biohaven Pharmaceuticals, Clene Nanomedicine, Prilenia Therapeutics, The ALS Association, the American Academy of Neurology, ALS Finding a Cure, the Salah Foundation, the Spastic Paraplegia Foundation and reports personal consulting fees for advisory panels from Orion Corporation.

Sheena Chew is a full-time employee of Biogen and reports research support from the American Academy of Neurology and Biogen Inc.

Haruhiko Banno reports research grant from Time Therapeutics and scientific advising fee from Sumitomo Dainippon Pharma.

Jacob Hooker holds equity or stock options and/or has received income from Eikonizo Therapetics, Psy Therapeutics, Fuzionaire Diagnostics, and Delix Therapeutics.

Merit Cudkowicz reports consulting fees from Biogen, Takeda, Sunovion, Cytokinetics, Immunitypharm, and Wave.

Kazuko Matsuda is an employee of MediciNova.

Joanna Dojillo is an employee of MediciNova.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1

Consort diagram Some participants had more than one reason for screen failure.

Fig. 2

[11C]PBR28-PET uptake in bilateral motor cortices for Ibudilast pre-treatment and post-treatment groups (n = 22 participants). [A] Group median [11C]PBR28 SUVRocc for pre-treatment (top) and 12–24 weeks from baseline (bottom) groups. The median pre-treatment SUVRocc in the motor cortices was 1.033 (range 0.847, 1.170). All images are projected onto standard MNI space at coordinates (x = −8, y =  − 20, z = +64). The color bar represents the group median [11C]PBR28 SUVRocc values in the motor cortices. [B] The box plots show that there were no significant changes from baseline observed in median [11C]PBR28 SUVRocc in the motor cortices at 12–24 weeks of ibudilast treatment [n = 22, median 0.002 (range −0.184, 0.156), Wilcoxon-Signed-Rank-Test V = 149, p = 0.5] [C] The spaghetti plot represents individual changes from baseline in median [11C]PBR28 SUVRocc in the motor cortices following 12–24 weeks of ibudilast treatment.

Fig. 3

[Fig. 3A]: Baseline serum NfL was 60.6 (range 33.1, 219.3) pg/ml. The box plots show median serum NfL levels at (a) baseline (b) 24 weeks of ibudilast treatment [n = 10 participants, median(range) change 1.7 pg/ml (−2.7, 27.3), Wilcoxon-Signed-Rank-Test V = 41, p = 0.19] and (c) 36–40 weeks of ibudilast treatment [n = 10 participants, median (range) change 0.4 pg/ml (−1.8, 17.5), Wilcoxon-Signed-Rank-Test V = 40, p = 0.23] and. [Fig. 3B] The spaghetti plot represents individual changes from baseline in median serum NfL following 36–40 weeks of ibudilast treatment.