The neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic touched on the therapy’s performance in a phase II clinical trial.
Robert J. Fox, MD
Recently, ibudilast, a small molecule normally used in the treatment of asthma and post-stroke vertigo in Asia, was evaluated in a phase II trial, where it showed a powerful effect on slowing brain atrophy in progressive multiple sclerosis (MS).
While brain atrophy has not been validated as a biomarker in progressive MS, the results were promising for lead author Robert J. Fox, MD, and set it up nicely for a larger, phase III trial to assess the impact on disability progression. Coupled with a robust safety profile, the therapy has shown to be comparable to other agents in the pipeline thus far.
To provide further insight into the clinical relevance and implications of the trial’s findings, Fox spoke with NeurologyLive about the data’s takeaways and the assessments of ibudilast.
Robert J. Fox, MD: One is that we found a drug that slows progression of brain atrophy by about half, and although we don’t exactly know the clinical relevance of that because we haven’t validated brain atrophy in progressive MS—because we don’t have much in the way of therapies for progressive MS—it was still encouraging in pointing toward a potential therapy for progressive MS. The safety was quite strong, and the tolerability was quite good.
There were some adverse effects—gastrointestinal symptoms, headache, and depression—that were seen more commonly with ibudilast compared to placebo, but the drug discontinuation rate was only 5% different between the ibudilast and placebo, which suggests that, in general, it was quite well tolerated.
Now, the other thing that this study did was it evaluated 5 different imagining metrics in a multicenter, 28-site, clinical trial to identify which was the best imaging metric for progressive MS. That second part was a little bit beyond the scope of this paper—this paper was just recording the primary outcomes and wasn’t necessarily comparing one imaging modality to another—but we do have that data and it will inform future trials. Cortical atrophy, so shrinkage of the gray matter ribbon that surrounds the brain and runs the thinking of the brain, that looked quite promising as an outcome metric. This trial will help inform future progressive MS clinical trials to help make them faster and smaller so that we can test more drugs more quickly with the same amount of effort.
This was a phase II, proof-of-concept trial. It showed that brain shrinkage was slowed with ibudilast compared to placebo, but it wasn’t powered to show a benefit on clinical disability. That, of course, is what’s needed in a phase III trial to go to the FDA to seek potential approval, so it can be used in general clinical settings in patients with progressive MS. That will be the next study that needs to be done. That phase III study will be a larger trial so that we’re appropriately powered for clinical disability. That has to be set up and is hoped to be coming.
One thing that was encouraging, back to the advanced imaging, is even though these advanced imaging methods were quite complex and required an imaging physicist team in order to implement and to monitor the magnet, we were able to do it. We were able to use quite advanced imaging modalities in 28 sites across the US and maintain them over a period of time. The advanced imaging methods were not just a sub-study done at 1 or 2 sites but were implemented at all the sites across the entire study, and so it really demonstrates the potential utility of these advanced imaging measures for use in future clinical trials.
Now, particularly, the one that looked most attractive, as I mentioned, was the cortical atrophy. Further studies will need to look at if that truly is a useful outcome metric in progressive MS, and then further evaluate it for potential generalization to other neurodegenerative processes. But this really is a big step forward in utilizing advanced imaging measures to understand neurodegeneration. Now I say that for a neurology community. The patient community may not really understand that so much, but for the neurology community, I think that’s a helpful and useful lesson from this trial, that we can actually do these things. They’re not just neat tools that some academic institution keeps off in a corner somewhere. But it is something we can implement out on a widespread scale.
Well, it’s sort of hard to know the study results before the study is done, and that study that I’m referring to, of course, is the phase III study that would use disability as the main outcome. However, what’s encouraging is that the comparison—and it’s hard to do cross-trial comparisons, but we can use it as a little bit of a guidepost. The only approved therapy for progressive MS, ocrelizumab, only slowed brain atrophy by 17.5%. There’s another drug that is in development for secondary progressive MS, siponimod, and that slowed brain atrophy by 15%. In terms of the magnitude, this is very encouraging that the slowing of brain atrophy was quite robust—almost cut in half. This was not just driven by a couple outliers, this wasn’t driven by a hydration shift in the first few months then everything was the same, it was really an ongoing, continued consistent effect over the course of the entire 96-week study. That’s as encouraging as it can be. The caveat is that we have not validated atrophy as a biomarker for progressive disability in progressive MS, so we really don’t know if this will translate to slowed disability progression. I’m hoping it does—that’s why we do these studies—but we really have to wait for a phase III trial before we can say that with any confidence.
The one thing I would point out is, up to this point, ibudilast has been studied primarily at the 10-mg to 30-mg per day dose. That is generally used in Japan for asthma and post-stroke symptoms. Our dose of 100 mg was quite a bit higher than that. It was based on some pharmacokinetic profiles which suggested that would allow even higher levels to get into the brain, and that was thought to be beneficial, but we really didn’t have long-term experience with this drug at that dose. This study informs us in a new way of the long-term safety of ibudilast in 100 mg a day over almost 2 years, and it’s a very encouraging result, too. It’s easy to use a drug for just a short term and then stop it. To use it for 96 weeks is a different issue, and we didn’t see any surprising or new safety signals.
Transcript edited for clarity.
Fox RJ, Coffey CS, Conwitt R, et al. Phase 2 trial of ibudilast in progressive multiple sclerosis. N Engl J Med. 2018; 379:846-855.