Ibudilast in Progressive MS: Hope with the size of a peanut

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Neuroprotection has been a tough nut to crack in MS, and essentially we are still eagerly waiting for the first drug that improves neuronal survival without impacting on inflammation (such as our beloved CD20 antibodies or siponimod). Ibudilast is one of the latest molecules that has tried to influence progression in pwMS…

In the 2018, Ibudilast (n=129) was compared with placebo (n=126) in a randomised controlled phase 2 trial published in the New England Journal of Medicine. The primary endpoint was reducing the rate of brain atrophy measured by brain parenchymal fraction. Roughly speaking, this is the volume of your brain divided by the volume of your skull. Ibudilast managed to reduce brain parenchymal fraction with 48% compared to placebo, or put differently with 2.5mL. As these results were promising, a secondary analysis of these data has now been published in Neurology. It demonstrated that Ibudilast reduced grey matter atrophy with 35%. There was no significant effect on the number of inflammatory T2 lesions. 

I can hear your thoughts out loud: 2.5 mL, is that the size of a metaphorical ‘peanut’? 

Obviously, reduction of grey matter atrophy with 35% compared to placebo is a good result, that we – theoretically – would be happy to take forward into a phase 3 trial. In comparison, siponimod which has now been licensed for clinical use in secondary progressive MS showed a reduction of 43% in grey matter volume and a reduction of 17% in whole brain volume compared to placebo at 96 weeks. Although the type of MRI analysis were not identical, these numbers seem to be in the same ballpark – at first instance. 

However, we need to take into account that ibudilast failed on all other measures of axonal loss in vivo

  • Ibudilast did not have an effect on neurofilament light measured in the cerebrospinal fluid nor serum compared to placebo. Neurofilament light is released into the cerebrospinal fluid when neurons die, and considered to be a substitute for brain volume loss. 
  • Ibudilast did not have an effect on retinal thinning measured with optical coherence tomography. The retina represents the most proximal part of optic nerve with a unique structure composed of unmyelinated axons. 
  • Ibudilast did not have a consistent effect on the reduction in T1 hypointense lesion or “black holes” volume. As opposed to the more non-specific substrate of T2 lesions, T1-hypointense lesions are established areas of axonal loss and severe tissue destruction. 

In addition, ibudilast failed on all clinical outcome measures (but we cannot blame it for it)

  • Ibudilast did not have an effect the percentage of patients that were free from disability progression measured by EDSS (this score ranges from 0 to 10). Importantly, the mean EDSS of pwMS included in this study was 6. EDSS 6 implies being able to walk 50 m with unilateral support or 120 m with bilateral support. EDSS 7 implies being unable to walk 5 metres and being dependent on a wheelchair. It is needless to say the this outcome measure is insensitive to clinically meaningful progression. This is why the CHARIOT-MS trial uses upper limb tests such as the 9-hole peg test as an outcome. Alternatively, cognitive measures such as the single digit modality test might be more appropriate. 

Moreover, inflammation could have been a potential confounder

  • Although the difference was not statistically significant, new or enlarging T2 lesions were observed in 37.2% on ibudilast and 29.0% on placebo. As new lesions have typically higher levels of inflammation they might potentially lead to cerebral swelling or oedema. In turn, this might corrupt conclusions on brain volumetric outcomes such as brain parenchymal fraction and grey matter fraction. If not accounted for appropriately, more inflammation on average could result contradictory in less brain volume loss. 

But how do we explain the effect on grey matter volume then? 

In summary, we have a drug that impacts on grey matter volume loss but not necessarily on axonal volume loss. A possible conclusion would be that ibudilast influences the volume of non-neuronal grey matter. Grey matter indeed contains a significant amount of neuronal cell bodies but also contains glial cells (macrophages, oligodendrocytes) and myelin. As ibudilast is a ‘Jack-of-all-trades’ on a molecular level with anti-(neuro)inflammatory, vasorelaxant, bronchodilator, analgesic, neuroprotective and potential anti-tumor activities, we have to acknowledge that we actually do not know how it exactly impacts on the brain. Off-target non-neuronal effects are definitely a possibility, and make this drug a much less attractive candidate for a follow-up phase 3 study. 

Twitter: @SmetsIde

Effects of Ibudilast on MRI Measures in the Phase 2 SPRINT-MS Study

Robert T Naismith, Robert A Bermel, Christopher S Coffey, Andrew D Goodman, Janel Fedler, Marianne Kearney, Eric C Klawiter, Kunio Nakamura, Sridar Narayanan, Christopher Goebel, Jon Yankey, Elizabeth Klingner, Robert J Fox , SPRINT-MS investigatorsCollaborators

PMID: 33268562

DOI: 10.1212/WNL.0000000000011314

Abstract

Objective: To determine whether ibudilast has an effect on brain volume and new lesions in progressive forms of multiple sclerosis (MS).

Methods: A randomized, placebo-controlled, blinded study evaluated ibudilast at a dose of up to 100 mg over 96 weeks in primary and secondary progressive MS. In this secondary analysis of a previously reported trial, secondary and tertiary endpoints included gray matter atrophy, new or enlarging T2 lesions as measured every 24 weeks, and new T1 hypointensities at 96 weeks. Whole brain atrophy measured by structural image evaluation, using normalization, of atrophy (SIENA) was a sensitivity analysis.

Results: A total of 129 participants were assigned to ibudilast and 126 to placebo. New or enlarging T2 lesions were observed in 37.2% on ibudilast and 29.0% on placebo (p = 0.82). New T1 hypointense lesions at 96 weeks were observed in 33.3% on ibudilast and 23.5% on placebo (p = 0.11). Gray matter atrophy was reduced by 35% for those on ibudilast vs placebo (p = 0.038). Progression of whole brain atrophy by SIENA was slowed by 20% in the ibudilast group compared with placebo (p = 0.08).

Conclusion: Ibudilast treatment was associated with a reduction in gray matter atrophy. Ibudilast treatment was not associated with a reduction in new or enlarging T2 lesions or new T1 lesions. An effect on brain volume contributes to prior data that ibudilast appears to affect markers associated with neurodegenerative processes, but not inflammatory processes.

Classification of evidence: This study provides Class II evidence that for people with MS, ibudilast does not significantly reduce new or enlarging T2 lesions or new T1 lesions.

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Ide Smets

2 comments

Leave a Reply to Kit Cancel reply

    • I think so, phase 3 trials are super expensive and I don’t think there are sufficient scientific arguments out there to back up the investment. Anyway, it’s clear that the trial design for any progressive drug will have to be significantly different to exclude the confounding effect of inflammation. Probably, it would be best to treat pwMS first with an immune reconstitution therapy such as cladribine and then add a neuroprotective agent such as ibudilast. But then 96 weeks will not suffice to establish the effect 🙁

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