Ocrelizumab: long-term data
Biotin in progressive MS
Increased myocardial infarction risk in MS
No adverse impact with frequent gadolinium exposure
Emerging treatment approaches: targeting Bruton’s tyrosine kinase

Ocrelizumab: long-term data
The open-label extension of the OPERA I/II trials of ocrelizumab reports sustained efficacy for up to 5 years (Hauser et al. ECTRIMS 2018; abstract P590). Following the 96-week double-blind phase, subjects continued on ocrelizumab or were switched from interferon-beta to ocrelizumab. The overall continuation rate for the 3-year extension period was 88.6%. In the subgroup on continuous ocrelizumab, the annualized relapse rate (ARR) declined from 0.11 in year 2 to 0.07 in year 5; the proportion with 6-month confirmed disability progression increased from 7.7% in year 2, to 13.9% in year 4 and 16.1% in year 5. In the group switched from IFN-beta, there was a significant reduction in ARR, from 0.20 prior to switching to 0.10 in the year after switching. ARR reductions were not significant thereafter (ARR 0.07 in year 5). The proportion with 6-month confirmed disability progression was 12.0% in the year prior to switching, increasing to 15.6% in year 1 of ocrelizumab, 18.1% in year 2, and 21.3% in year 3.

In the CHORDS phase III study, the efficacy of ocrelizumab was examined in patients with RRMS (n=608) who had previously had a suboptimal response to a disease-modifying drug (DMD) (Leist et al. ECTRIMS 2018; abstract P635). Mean time from MS diagnosis was 3.9 years. According to the 48-week interim analysis, 92.7% were relapse-free, 96.4% had no Gd+ lesions, 65.3% had no new/enlarging T2 lesions and 96.4% had no 6-month confirmed EDSS progression. ARR was 0.047.
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Biotin in progressive MS
A small 12-month placebo-controlled trial reported that high-dose biotin (MD1003; 100 mg TID) was effective in improving disability (EDSS decrease >1 point or >20% decrease in T25FW) at 9 months (confirmed at 12 months); 12.6% of biotin-treated subjects achieved the endpoint compared to 0% with placebo (Tourbah et al. Mult Scler 2016;22:1719-1731; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC5070917/pdf/nihms802765.pdf). Benefits have been maintained during the 48-month open-label extension (De Seze et al. ECTRIMS 2018; abstract P592). In the group receiving continuous biotin, the proportion with an improvement in disability was 13% at month 18, 8% at month 24, and 13% at months 36 and 42. For the group switched from placebo to biotin, the percentages were 7% at month 18, 5% at month 24, 0% at month 36, and 3% at month 42. Response rates ran in parallel once both groups were on therapy, although a delay in treatment was associated with a poorer outcome. The dropout rate was high (64.7%), primarily due to withdrawal of consent and lack of efficacy.
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Increased myocardial infarction risk in MS
A Canadian epidemiological study reports that the risk of acute myocardial infarction (AMI) is elevated in MS patients compared to the general population (Marrie et al. ECTRIMS 2018; abstract P408). The study used health claims databases in British Columbia and Manitoba and identified 14,565 MS patients and 72,825 matched controls. AMI incidence was 146.2 per 100,000 population in the MS population versus 128.8/100,000 in the matched population (incidence rate ratio 1.18). The hazard ratio was 1.62. The authors concluded that the elevated AMI risk cannot be fully accounted for by traditional cardiovascular risk factors.
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No adverse impact with frequent gadolinium exposure
A Canadian study examined the potential toxicity of gadolinium contrast agent exposure using data from a trial in secondary-progressive MS (Ackermans et al. ECTRIMS 2018; abstract P479). A total of 612 subjects received infrequent (1-4) or frequent (5-11) gadolinium injections over the 104-week study period. There were no significant differences between the two groups with respect to change from baseline to week 104 in EDSS score, MSFC, Timed 25-Foot Walk, 9-Hole Peg Test or PASAT. The risk of progression favoured the cohort with frequent Gd exposure (HR 0.68). The authors concluded that frequent Gd exposure does not result in greater clinical worsening in SPMS over a two-year follow-up period.
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Emerging treatment approaches: targeting Bruton’s tyrosine kinase
A limitation of anti-CD20 B cell therapies is depletion of a range of B cell subsets, including the regulatory B cells required for maintenance of self-tolerance. This has stimulated interest in more highly targeted therapies that inhibit Bruton’s tyrosine kinase (BTK). BTK is a signalling molecule that is upregulated by the B cell receptor, resulting in NF-kappaB activation, anti-apoptotic effects and defective elimination of autoreactive B cells (Kil et al. Blood 2012;119:3744-56). Animal studies indicate that BTK functions as a rheostat (rather than an on-off switch), setting the threshold for B cell activation and for elimination of autoreactive B cells.

To date, one BTK inhibitor, ibrutinib, has been approved for hematologic malignancies, and numerous agents are currently in development for autoimmune disorders. Two new studies have examined the potential role of the BTK inhibitor, evobrutinib, in MS. In EAE, evobrutinib reduced CNS inflammation and demyelination and improved EAE severity over the 2-month observation period (Torke et al. ECTRIMS 2018; abstract P575). Treatment prevented B cell activation and conversion from naïve to antigen-activated B cells. A separate phase I study examined the safety of six doses of evobrutinib in healthy volunteers (Becker et al. ECTRIMS 2018; abstract P551). Adverse events occurred in 25% of subjects after a single dose, and 48% of subjects after multiple dosing. The nature and incidence of adverse effects were similar with evobrutinib and placebo. No prolongation of the QT interval was reported. Phase II study results will be presented at ECTRIMS on Friday, October 12, at 2 pm (Montalban et al. ECTRIMS 2018; abstract 322).
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