Primary-progressive MS: studies ongoing
One of the great disappointments of multiple sclerosis research is a lack of effective treatments for people with progressive forms of the disease. But attention is slowly focusing on this neglected area and some advances may be made soon.
“Progressive” refers either to people who develop disability from the beginning and have few or no relapses (primary-progressive MS, or PPMS), or who start to show a progressive deterioration in their physical functioning after living for years with relapsing and remitting symptoms (SPMS). Most people with relapsing-remitting MS (RRMS) eventually develop SPMS. Once SPMS develops, it proceeds along the same path of physical decline and at the same rate as PPMS.
People who are taking an interferon for their RRMS can continue taking it even after they’ve transitioned to SPMS. This is because of a handful of studies looking at interferons in SPMS. For example, one trial called SPECTRIMS showed that Rebif had an effect on relapses, but unfortunately it had no impact on disability (SPECTRIMS Study Group. Neurology 2001;56:1496-1504). A subsequent analysis of five SPMS trials concluded the same thing: interferons are not effective once disability has started to progress (La Mantia and colleagues. Cochrane Database Syst Rev 2012 Jan 18;1:CD005181).
The reason is that MS is a two-stage disease (Leray and colleagues. Brain 2010;133[Pt 7]:1900-13). In the first stage, what matters is inflammation, which manifests as relapses and flare-ups on an MRI. This inflammation may set the stage for the second, neurodegenerative phase, in which widespread damage to the nerve cells and fibres occurs. How closely these two phases are linked is the subject of much debate in the research community. Some believe that inflammation has to happen first before there is neurodegeneration – it is the match that lights the fire. Others believe that inflammation and neurodegeneration are somewhat separate processes – that neurodegeneration starts to occur early on in MS even if there’s little or no inflammation.
What this means is that treatments that primarily target inflammation – which includes all of the current MS therapies – can be expected to have little or no direct impact on neurodegeneration. In the earlier stages of SPMS or PPMS, there may be some inflammation going on, and so interferons and other therapies will be able to control that to some degree. But as disability progresses, this inflammation wanes and neurodegenerative processes start to predominate.
Few studies have looked at whether MS therapies work in PPMS. One trial of Betaseron found that there was some impact on brain health, but the effect was very modest (Tur and colleagues. Arch Neurol 2011;68:1421-1427). The PROMISE study also found that Copaxone had no effect in PPMS (Wolinsky and colleagues. Ann Neurol 2007;61:14-24). The CUPID trial of a marijuana formulation (dronabinol, a form of THC) found there was no impact on disability (Zajicek and colleagues. Lancet Neurol 2013;12:857-865).
There is some evidence to suggest that potent immunosuppression – either with drugs such as Novantrone (mitoxantrone) or procedures such as bone-marrow transplantation (BMT) – can slow disability, at least for a time (Hartung and colleagues. Lancet 2002;360:2018-2025; Saccardi and colleagues. Blood 2005;105:2601-2607). However, Novantrone can only be used for a couple of years because it has toxic effects on the heart that accumulate over time. BMT is effective in “rebooting” the immune system, but as the immune system rebuilds itself, it’s likely that progression will begin again.
The next phase of research may be more promising. One approach is to use MS drugs that are more potent. A preliminary trial of Tysabri found that treatment appears to reduce some of the damage, but the study didn’t look at an actual effect on progression (Romme Christensen et al. Neurology 2014;82:1499-1507). For that we’ll have to wait for the results of the phase III ASCEND trial, which is studying Tysabri in PPMS. However, since the drug doesn’t enter the brain to a significant degree, it may be that this treatment will have little impact on neurodegeneration.
Later this year, we should also see some results from the INFORMS trial of Gilenya. This medication does have direct effects on specialized cells in the brain that have been implicated in neurodegeneration (Groves and colleagues. J Neurol Sci 2013;328:9-18), so expectations are high. The trial design poses a few problems, however, such as a short duration of treatment (so there may not be time for an effect to be seen), and a very broad range of people. So we’ll probably have to look at subgroups (e.g. people with early vs. late PPMS) and specific indicators (called biomarkers) of a treatment effect.
More experimental therapies include Rituxan, which was shown to slow disability progression in younger people with PPMS (Hawker and colleagues. Ann Neurol 2009;66:460-471). This drug won’t be approved for MS, but similar medications (such as ocrelizumab and ofatumumab) are in development for MS. A trial of ocrelizumab in PPMS is now recruiting people and preliminary results are expected in the next two or three years. We can also expect to see more work on BMT in progressive MS. A novel therapy called masitinib showed some benefit in SPMS and PPMS (Vermersch and colleagues. BMC Neurol 2012;12:36), and is also being investigated. So the hope is that this research activity will start to unravel some of the mysteries of neurodegeneration and provide some solutions for people living with progressive MS.
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