Natalizumab in progressive MS: Results of an open-label, phase 2A, proof-of-concept trial

TY - JOUR

T1 - Natalizumab in progressive MS

T2 - Results of an open-label, phase 2A, proof-of-concept trial

AU - Romme Christensen, Jeppe

AU - Ratzer, Rikke

AU - Börnsen, Lars

AU - Lyksborg, Mark

AU - Garde, Ellen

AU - Dyrby, Tim B

AU - Siebner, Hartwig R

AU - Sorensen, Per S

AU - Sellebjerg, Finn

PY - 2014/4/29

Y1 - 2014/4/29

N2 - Objective: Natalizumab inhibits the migration of systemic immune cells to the CNS and may be beneficial in progressive multiple sclerosis (MS). The objective of the study was to examine the effects of natalizumab in progressive MS. Methods: In an open-label phase 2A study, 24 patients with progressive MS were included to receive natalizumab treatment for 60 weeks. Response to natalizumab was assessed in CSF and MRI studies. The primary endpoint was change in CSF osteopontin, a biomarker of intrathecal inflammation, from baseline to week 60. Results: Seventeen patients completed the study. No new safety issues were encountered. CSF osteopontin decreased by 65 ng/mL (95% confidence interval 34-96 ng/mL; ρ = 0.0004) from baseline to week 60 in conjunction with decreases in other CSF biomarkers of inflammation, axonal damage, and demyelination. Magnetization transfer ratio increased in both cortical gray and normal-appearing white matter and correlated with decreases in CSF neurofilament light chain. Conclusions: Natalizumab treatment of progressive MS reduces intrathecal inflammation and tissue damage, supporting a beneficial effect of natalizumab treatment in progressive MS and suggesting that systemic inflammation contributes to the pathogenesis. Moreover, the study establishes the feasibility of using CSF biomarkers in proof-of-concept trials, allowing a low number of participants and short study duration. Classification of evidence: This study provides Class IV evidence that in patients with progressive MS, natalizumab reduces biomarkers of intrathecal inflammation.

AB - Objective: Natalizumab inhibits the migration of systemic immune cells to the CNS and may be beneficial in progressive multiple sclerosis (MS). The objective of the study was to examine the effects of natalizumab in progressive MS. Methods: In an open-label phase 2A study, 24 patients with progressive MS were included to receive natalizumab treatment for 60 weeks. Response to natalizumab was assessed in CSF and MRI studies. The primary endpoint was change in CSF osteopontin, a biomarker of intrathecal inflammation, from baseline to week 60. Results: Seventeen patients completed the study. No new safety issues were encountered. CSF osteopontin decreased by 65 ng/mL (95% confidence interval 34-96 ng/mL; ρ = 0.0004) from baseline to week 60 in conjunction with decreases in other CSF biomarkers of inflammation, axonal damage, and demyelination. Magnetization transfer ratio increased in both cortical gray and normal-appearing white matter and correlated with decreases in CSF neurofilament light chain. Conclusions: Natalizumab treatment of progressive MS reduces intrathecal inflammation and tissue damage, supporting a beneficial effect of natalizumab treatment in progressive MS and suggesting that systemic inflammation contributes to the pathogenesis. Moreover, the study establishes the feasibility of using CSF biomarkers in proof-of-concept trials, allowing a low number of participants and short study duration. Classification of evidence: This study provides Class IV evidence that in patients with progressive MS, natalizumab reduces biomarkers of intrathecal inflammation.

KW - Adult

KW - Antibodies, Monoclonal, Humanized

KW - Cerebral Cortex

KW - Chemokine CXCL13

KW - Disability Evaluation

KW - Drug Administration Schedule

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Immunologic Factors

KW - Magnetic Resonance Imaging

KW - Male

KW - Matrix Metalloproteinase 9

KW - Middle Aged

KW - Multiple Sclerosis, Chronic Progressive

KW - Myelin Basic Protein

KW - Neurofilament Proteins

KW - Osteopontin

KW - Secondary Prevention

KW - Treatment Outcome

U2 - 10.1212/wnl.0000000000000361

DO - 10.1212/wnl.0000000000000361

M3 - Journal article

C2 - 24682973

SN - 0028-3878

VL - 82

SP - 1499

EP - 1507

JO - Neurology

JF - Neurology

IS - 17

ER -