New developments in secondary-progressive MS – ECTRIMS 2019



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Recent positive trials in primary- and secondary-progressive MS (ORATORIO, EXPAND) have fuelled interest in the etiology, pathophysiology and treatment of progressive MS (reviewed in Secondary-progressive MS: conceptual and practical challenges, NeuroSens, April 17, 2019; and Progressive MS trials – design and interpretation, NeuroSens, September 4, 2019). In Part 3 of this series, we summarize some emerging concepts in PMS and new trial data in SPMS.

Pathophysiology of progressive MS

Evidence has emerged over the past two decades that neuropathological changes occur early in the course of MS and may remain clinically silent until a threshold of cumulative axonal loss is reached (Bruck W. ECTRIMS 2019; abstract 207). As such, axonal loss appears to be the primary pathological substrate in progressive MS, with the reduction in axonal density in demyelinated regions being more extensive in PPMS compared to SPMS (Tallantyre et al. Brain 2009;132(Pt 5):1190-1199).

A number of mechanisms may contribute to the onset of progressive MS, such as failed remyelination, diffuse inflammation in normal-appearing white matter, loss of trophic support and Ca2+ accumulation (Bruck 2019; Dutta & Trapp. Neurology 2007;68(22 suppl 3):S22-S31). Of particular interest are the mechanisms underlying the compartmentalized inflammation seen in PMS. Activation of innate immune cells in the CNS appears to underlie slowly expanding chronic active lesions and the development of grey-matter lesions (Bruck 2019). A recent suggestion is that the molecular signature changes as chronic active lesions develop, with alterations in microglia and astrocyte gene expression that may affect lesion formation and myelin repair (Elkjaer et al. ECTRIMS 2019; abstract 211).

Innate immune activation in the CNS appears to be initiated and/or sustained by meningeal inflammation, notably the lymphoid-like B cell follicles first described in SPMS patients (Magliozzi et al. Brain 2007;130(Pt 4):1089-1104). The observation that meningeal follicles lie adjacent to subpial cortical lesions suggests that soluble factors have a role in cortical lesion formation. Meningeal inflammation has since been reported in acute RRMS and was shown to be associated with activation of microglia/macrophages and loss of neurons (Bevan et al. Ann Neurol 2018;84:829-842).

Microglia activation can occur before the development of severe motor deficits in EAE (Ajami B. Nat Neurosci 2011;14:1142-1149), which has led some to speculate that peripheral immune activation is secondary to CNS degenerative events, such as myelin destruction, neurodegeneration and reactive gliosis (Behrangi et al. Cells 2019;8:24). Indeed, it has been suggested that the oligodendrocyte loss at the centre of pattern III lesions described by Lucchinetti and colleagues (Ann Neurol 2000;47:707-717) may be due to resident CNS events (Bruck 2019). This “inside-out” process was investigated in cuprizone fed mice, a model that produces demyelination and oligodendrocyte death in the absence of peripheral immune activation. Coadministration of siponimod during cuprizone intoxication reduced demyelination, glia activation and acute axonal injury (Behrangi et al. ECTRIMS 2019; P152). The authors have further speculated that the primary mode of action of siponimod, a sphingosine-1 phosphate receptor 1,5 modulator, is to ameliorate neurodegeneration in the CNS, which then reduces peripheral immune cell recruitment and the formation of inflammatory white-matter lesions (Behrangi 2019). In support of this is the finding of reduced EAE clinical scores when siponimod was administered by intracerebroventricular infusion (Gentile et al. J Neuroinflammation 2016;13:207). When infused into the brain, siponimod attenuated astrocyte and microglia activation and reduced lymphocyte infiltration into the CNS without significantly altering peripheral lymphocyte counts. A recent publication also reported reduced lymphocyte infiltration into the CNS with siponimod in EAE (Hundehege et al. Neural Regen Res 2019;14:1950-1960).

Clinical data in SPMS

The EXPAND trial reported a 26% reduction in six-month confirmed disability progression with siponimod compared to placebo (Kappos et al. Lancet 2018;391:1263-1273). Perhaps more significant was the finding of a lower rate of brain atrophy with siponimod over months 12-24 (mean -0.50% vs. -0.65%, a 23% reduction). A subsequent analysis of MRI data from EXPAND reported an 88% reduction in cortical grey-matter loss and a 47% reduction in thalamic volume loss at month 12 with siponimod compared to placebo (Arnold et al. ECTRIMS 2019; abstract P382). This effect was maintained at month 24: a 43% reduction versus placebo in cortical GM volume loss, and a 31% reduction in thalamic volume loss. Interestingly, a recent imaging study found less of an effect on cortical GM volume and thalamic volume loss with fingolimod (Gaetano et al. Neurology 2018;90:e1324-e1332). While the two studies are not directly comparable, the differing effects of siponimod and fingolimod on GM atrophy may partially explain the failure of the INFORMS PPMS trial. What was especially noteworthy in that study was the minimal effect on brain atrophy with fingolimod for reasons that have not been fully explained (Lublin et al. Lancet 2016;387:1075-1084).

An analysis of EXPAND presented at ECTRIMS examined the effect of treatment in the subgroup of 779 patients with active SPMS (Gold et al. ECTRIMS 2019; abstract P750). The active subgroup was more likely to have >1 relapse in the two years before screening (75.8% vs. 36.0%) and Gd+ lesions at baseline (44.9% vs. 21.3%) compared to the full cohort. Six-month CDP was reduced 37% in the active group versus placebo compared to 26% for the full cohort. This suggests that the reduction in peripheral immune activation is an important contributor to the therapeutic effect. However, an interesting finding was that brain atrophy at month 24 was less in the full cohort (active and inactive patients) receiving siponimod (PBVC -0.71%) compared to those with active disease (-0.86%). While this suggests that inflammatory activity is an important contributor to brain atrophy, it may also indicate that progressive tissue loss is not entirely dependent on inflammation and may respond to therapy. Moreover, a separate analysis found that a significant treatment effect on the EDSS Motor Integration subscale (cerebellar/pyramidal function, ambulation) was seen earlier with siponimod in patients without baseline Gd+ lesions (month 9) compared to those with baseline Gd+ lesions (month 12) (Cutter et al. ECTRIMS 2019; abstract P435). On the Collateral subscale (bowel/bladder, brainstem, cerebral, sensory and visual functions), a significant treatment effect was seen at month 27 in patients without Gd+ lesions, which may reflect a therapeutic lag phenomenon previously described with fingolimod and other DMTs (Roos et al. ECTRIMS 2019; abstract P1053; Sormani et al. ECTRIMS 2016; abstract 215).

A separate analysis of EXPAND found that siponimod delayed the time to requiring a wheelchair (EDSS >7) in the subgroup of patients with severe disability at entry (EDSS 6.5) (Vermersch et al. ECTRIMS 2019; abstract 158). The proportion who progressed to EDSS >7 was 19.8% with siponimod compared to 26.1% with placebo, a 36% risk reduction. This translated to a delay of 4.3 years in requiring a wheelchair (12.0 vs. 16.3 years). These results suggest that treatment may still benefit progressive MS patients with extensive neuroaxonal loss and accumulated disability.

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