Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Abstract

Biogen.

Autoimmune encephalomyelitis in NOD mice is not initially a progressive multiple sclerosis model

“…37,38 However, NOD mice can show comparable susceptibility to other induced autoimmunities when B. pertussis toxin is used as coadjuvant. 39 The immunodominant epitopes associated with the development of EAE in ABH mice are proteolipid protein (PLP [56][57][58][59][60][61][62][63][64][65][66][67][68][69][70] ) and myelin oligodendrocyte glycoprotein (MOG [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] ) peptides. 33,34 However, wild-type NOD mice only exhibited modest susceptibility (n = 9/13) to SCH-induced EAE (Fig 1; Table 1), with disease that had poor consistency in severity (range of maximum severity grade 0.5-4 n = 9) and day of onset (range 14-49. n = 9).…”

“…The results represent the mean maximum group score of the first episode AE SEM; the mean maximum score of animals that developed EAE during the first episode AE SEM and the mean day of onset AE SD. The NOD mice immunized with SCH, MOG [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] or PLP [56][57][58][59][60][61][62][63][64][65][66][67][68][69][70] were from stock based in the United Kingdom. The NOD mice immunized with MOG 35-55 peptide were from different stock based in Australia and #the scoring system used was different.…”

“…Animals (11)(12)(13)(14)(15) week) were injected subcutaneously with 1 mg mouse spinal cord homogenate (SCH), 16 200 lg mouse proteolipid protein residues 56-70 (PLP [56][57][58][59][60][61][62][63][64][65][66][67][68][69][70] ) peptide 33,34 or 200 lg MOG residues 8-22 (MOG [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] ) peptide 34,35 emulsified in Freunds adjuvant supplemented with 60 lg Mycobacteria tuberculosis and M.butyricum on day 0 and 7. 16 Animals were injected intraperitoneally with 200 ng Bordetella pertussis toxin immediately and 24 h after each injection of antigen, as described previously.…”

“…3 This is supported not only by radiological and pathological findings, but most importantly, by the response to therapy. [4][5][6][7] Although progressive MS may also respond to similar immunotherapy provided there is sufficient neurological reserve in the nerve-tracks affected, [8][9][10] other factors such as innate immune responses are thought to be of central importance in progressive neurodegeneration. 11 This concept underpins the perceived treatment-failure of immunotherapy in advanced (progressive) MS, where replacement of peripheral immunity, which stops relapses, does not always halt accumulation of disability.…”

Cladribine: mechanisms and mysteries in multiple sclerosis

“…Although the evidence is best for relapsing disease, the ONWARD trial suggests that the use of cladribine may be useful as an adjunct in ‘secondary progressive’ disease, for people who are still having relapses as well as gradual disability progression 18. Furthermore, we feel that there is sufficient phase I and II trial evidence15 16 to make the case for a phase III trial of cladribine in advanced progressive MS to assess whether cladribine could improve metrics of progression beyond the EDSS, such as upper limb function17 and cognition, as has been successfully demonstrated for natalizumab 29…”