Ibudilast for PPMS better than for SPMS

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Response to ibudilast treatment according to progressive multiple sclerosis disease phenotype

https://onlinelibrary.wiley.com/doi/ful ... acn3.51251

Discussion

The impetus to study ibudilast in progressive MS derived from the trial of ibudilast in relapsing MS.9 Although that study failed to demonstrate an effect on the focal inflammatory pathology characteristic of relapsing disease, the favorable effects observed on brain atrophy suggested a neuroprotective effect.

Prior to the publication of standardized definitions of the MS phenotypes that described SPMS and PPMS in 1996,3 no distinction was recognized between MS with gradually worsening neurological function, whether there had been relapsing activity at the outset of the disease (SPMS) or not (PPMS). More recently, some reports have suggested biological differences between these clinically determined disease phenotypes, and others have not.4 Examples of therapies demonstrating beneficial responses in brain atrophy in progressive MS phenotypes include siponimod10 and simvastatin11 (not a registered therapy for MS) in SPMS and ocrelizumab12 in PPMS. In contrast, fingolimod was not found to slow the progression of brain atrophy in PPMS.13 Since these trials assessed treatment effect in separate clinical phenotypes, it remains unclear whether differential treatment effects occur between these phenotypes.5

We performed a post hoc analysis of SPRINT‐MS data to assess whether the previously reported1 treatment effect of ibudilast was similar in PPMS and SPMS. The results of this analysis suggest that the response to treatment observed in the BPF atrophy outcome within the PPMS group and not the SPMS group is driving the overall ibudilast‐related treatment difference. This difference held when the variables that were significantly different between the groups at baseline (age, LD, RNFL, T2 lesion volume, EDSS and 25‐foot walk) were accounted for in the model. Baseline brain size did not account for the PPMS versus SPMS difference, nor did it have a measurable influence on treatment effect.

We also evaluated the effect of disease duration (short vs. long). This model’s estimate suggests that disease duration does not explain the differential effect in treatment by disease phenotype. If disease duration was a driving factor, we would expect that PPMS subjects with longer disease duration would exhibit a lesser or no treatment effect of ibudilast and SPMS subjects with shorter disease duration would have a greater treatment effect. The results suggested the opposite: the estimated treatment effect for PPMS patients with long disease duration did not differ from short disease duration. In fact, the estimated effect was larger, albeit not statistically significantly. The estimated treatment effect for SPMS patients with short disease duration did not differ from long disease duration: the estimated effect for short disease duration suggested ibudilast had a lower effect, but was not statistically significant.

We also explored an alternative methodology for the assessment of cerebral atrophy using the SIENA method to assess change in total brain size over the course of the trial. We found a similar pattern of differential effect although this did not reach statistical significance. In addition, the initial trial results showed an overall reduction in the rate of cortical thickness loss,1 and we again found a similar pattern according to phenotype: this effect was principally driven by the PPMS subjects. Results of conventional imaging outcomes are reported in a separate publication.2

To our knowledge, the differential treatment effect on brain atrophy that we observed between SPMS and PPMS has not been described previously. Interestingly, there was a significantly higher rate of atrophy progression in PPMS versus SPMS seen in the placebo arm similar to the pattern observed in the literature.

We believe that this could account, at least in part, for our observations. Another possible explanation is that the PPMS phenotype was more susceptible to a specific treatment effect of ibudilast because of a more active disease process manifest as an approximately double rate of atrophy progression compared to SPMS.

Since this was a post hoc exploratory analysis, additional investigation is warranted to assess the reproducibility and generalizability of these results. Furthermore, the clinical relevance of these imaging findings needs to be evaluated. If confirmed and found to be clinically relevant, these findings will need to be considered in future trial designs for progressive MS