Natalizumab in progressive MS: Phase II results


A number of preliminary studies have investigated the possible effects of natalizumab in progressive MS. The latest is the open-label phase IIb NAPMS trial that examined the effect of treatment on osteopontin, an inflammatory marker, and CSF neurofilament (NfL) light chain, a marker of axonal damage  (Romme Christensen et al. Neurology 2014;82:1499-1507).

A total of 17 of 24 patients (71%) completed the 60-week study. CSF osteopontin decreased by 65 ng/mL. Decreases in NfL were correlated with increases in cortical grey matter and normal-appearing white matter on magnetization transfer ratio (MTR) imaging. The researchers concluded that natalizumab reduces inflammation and tissue damage in progressive MS.

A separate study has also reported that NfL antibody levels are elevated in RRMS and in SPMS to a lesser degree compared to healthy controls; antibody levels decreased significantly after 24 months of treatment with natalizumab (Amor et al. Mult Scler 2014;20:1355-1362). Early studies suggested that NfL antibodies in CSF were a marker of cerebral atrophy and lesion load (Eikelenboom et al. Neurology 2003;60:219-223).

There are conflicting data on the relevance of osteopontin and NfL as biomarkers of disease progression in MS. Osteopontin, as the name implies, has been described as a bridge between bone and blood (Haylock & Nilsson. Br J Haematol 2006;134:467-474). It is a cytokine that was first discovered in bone and regulates bone mineralization. Once referred to as early T-cell lymphocyte activatation-1 (ETA-1), osteopontin is also secreted by activated T cells, stimulating IL-12 release from macrophages and dendritic cells (Weber et al. Science 1996;271:509-512; Ashkar et al. Science 2000;287:860-864).

Consistent with this pro-inflammatory effect, a number of studies have reported elevated CSF osteopontin levels in patients with CIS, RRMS and PPMS (Braitch et al. Arch Neurol 2008;65:633-635; Bornsen et al. Mult Scler 2011;17:32-42). Higher osteopontin levels have also been reported in patients with other inflammatory neurological and non-neurological disorders (Chowdhury et al. Arch Neurol 2008;65:232-235); thus it appears to be a biomarker of inflammation rather than a specific marker of MS.

In the study by Bornsen et al., higher osteopontin levels in CSF were associated with higher degrees of disability, however, osteopontin decreased significantly following treatment both with methylprednisolone or placebo. In the study by Chowdhury et al., high CSF osteopontin levels were seen in RRMS patients with active disease but were not correlated with disability status.

Serum levels of osteopontin have also been analysed in a study of 492 consecutive patients. Levels were higher in RRMS and SPMS compared to healthy controls, but were lower in patients treated with natalizumab or glatiramer acetate (Kivisakk et al. Mult Scler 2014;20:438-444). There was no association between osteopontin levels and clinical or radiological measures of disease activity.

Osteopontin levels have been reported to be correlated with NfL. In the short term, NfL levels appear to increase in progressive MS, but may decline with age (Romme Christensen et al. Mult Scler 2013;19:87-874; Khademi et al. PLoS One 2013;8:e63172).

A retrospective analysis found that natalizumab improved ambulation in patients with SPMS, but the study population included RRMS patients from AFFIRM and SENTINEL, as well as relapsing MS patients in the phase I DELIVER study that used different routes of administration for natalizumab (Cadavid et al. PLoS One 2013;8:e53297).

The phase III ASCEND trial (A Study to Characterize the Efficacy of Natalizumab on Disability) is currently evaluating natalizumab in SPMS; the trial is ongoing and no results have been published.

Dr. Fran
çois Grand’Maison: At present there are no reliable markers for disease activity and axonal degeneration in MS. This is most unfortunate because the neurological exam, as measured by the EDSS, and MRI metrics are only mildly correlated with each other and with disease activity. At this time, the best indicator of a treatment response for axonal degeneration would be slowing of EDSS progression in the absence of relapses in patients with primary- or secondary-progressive MS. This is what the ongoing ASCEND trial (natalizumab vs placebo) will attempt to measure in SPMS.

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