Ofatumumab – new data
Biotin – disappointing results
Natalizumab – 10-year data
Dimethyl fumarate – 10-year results
Declining effect of treatment
Stopping treatment: 2 studies
BTK inhibition
Clinical Tip of the day
Ofatumumab – new data
Ofatumumab is a fully humanized anti-CD20 monoclonal antibody administered subcutaneously that is in development for relapsing MS. In the phase II MIRROR trial, the agent was associated with a 65% reduction in cumulative new Gd+ lesions (Bar-Or et al. Neurology 2018; 90:e1805-e1814). In the phase III ASCLEPIOS trials, 1882 patients were randomized to teriflunomide 14 mg/day or ofatumumab administered as a loading dose (20 mg on days 1, 7 and 14) followed by 20 mg s.c. q4wks (Hauser er al. ECTRIMS 2019; abstract 336). About 60% of patients were previously treated. Annualized relapse rates were 0.11 and 0.10 with ofatumumab in the two studies versus 0.22 and 0.25 with teriflunomide, a reduction of 50-58% versus the active control. The pooled rate of 6-month confirmed disability progression was 8.1% with ofatumumab versus 12.0% with teriflunomide, a significant reduction of 32.5%. The proportion with 6-month confirmed disability improvement was 11.0% vs. 8.1%, a 35.2% difference that was not statistically significant. Ofatumumab was also associated with a 93.8-97.5% reduction in Gd+ lesions and an 82.0-84.5% reduction in new/enlarging T2 lesions. Treatment was well tolerated. The infection rate was 2.5% compared to 1.8% with teriflunomide. Injection site reactions were common but 99% were mild to moderate in severity.
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Biotin – disappointing results
The MS-SPI trial has reported that high-dose biotin (MD1003) was effective in progressive MS using the endpoint of 3-month confirmed disability improvement: 12.6% of patients receiving biotin 100 mg TID showed improvement versus 0% with placebo at month 12 (Tourbah et al. Mult Scler 2016;22:1719-1731). A second prospective study has now reported a lesser effect (Wiertlewski S. ECTRIMS 2019; abstract P1002). The study involved 178 patients (mean age 52 years) with progressive MS. The mean EDSS score at entry was 6.1; mean disease duration was 16.9 years. At one year, 3.8% of biotin-treated patients had a slight reduction in EDSS score but change from baseline in EDSS score or T25FW was not significantly improved.
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Natalizumab – 10-year data
The TYSTEN study is a long-term observational study of natalizumab in France. Data were analysed to determine the time to SPMS in 770 patients with severe MS treated with natalizumab (Bigaut et al. ECTRIMS 2019; abstract P1013). At 10 years, the cumulative probability of SPMS or reaching EDSS 6.0 was 27.7% and 18.9%, respectively. Risk factors for SPMS were >1-point increase in EDSS score, new T2/Gd+ T1 lesion or relapse in the first year of treatment. Patients who achieved no evidence of disease activity (NEDA) in the first year of treatment had a 36% reduced risk of developing SPMS over the next 10 years.
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Dimethyl fumarate – 10-year results
An analysis of patients receiving continuous DMF 240 mg BID for 10 years reported that 51% remained relapse-free (Gold et al. ECTRIMS 2019; abstract P1397). The median time to first relapse was 9.7 years. A total of 79% had minimal disability (EDSS score < 3.5) at 10 years, with 64% demonstrating no confirmed disability progression from baseline. The incidence of serious infections was 2% in Year 1 and < 1% every year thereafter.
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Declining effect of treatment
An MSBase analysis reported that DMTs have a significant impact on clinical/MRI outcomes but the magnitude of these effects declines over time and with worsening disease (Kalincik et al. ECTRIMS 2019; abstract P1421). Overall, treatment was associated with a 45% decrease in relapses. However, the impact decreased over time: -1%/year for age, -14% per EDSS step, -20% with recent disability worsening, -55% per on-treatment relapse and -68% with SPMS onset. In addition, treated patients were 39% more likely to show improvement of disability scores, but this effect declined with age (-2%/year), duration of disease (-6%/year) and disability (-8%/EDSS step).
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Stopping treatment: 2 studies
Two new studies have examined whether DMT discontinuation in patients with prolonged, stable disease is associated with detrimental effects. The first study involved a cohort of 49 RRMS patients treated with an injectable DMT who maintained no evidence of disease activity (NEDA) for at least 5 years (Monschein et al. ECTRIMS 2019; abstract P654). After stopping treatment, 26 of 49 patients (53.1%) maintained NEDA for at least 5 years. A total of 23 patients (46.9%) experienced a relapse, EDSS worsening or both. Older age at DMT discontinuation was predictive of ongoing NEDA status. Patients >45 years had a low risk (10%) of recurrent disease compared to patients < 45 years (56%). A second study retrospectively examined DMT discontinuation in RRMS patients aged >60 years who had been stable for >24 months (Ladeira F. ECTRIMS 2019; abstract P703). The mean age at diagnosis was 41.6 years, median duration of DMT use was 8 years. Eighty percent of patients were treated with a first-line injectable DMT. Over a 70-month period, 8 of 35 patients stopped treatment. No differences were seen between continuers and discontinuers. Stopping treatment was not associated with a significantly increased risk of relapses (hazard ratio 1.35) or disability progression (HR 0.75).
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BTK inhibition
Evobrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that modulates B cell signalling without depleting B cell counts. A phase II trial recently reported that evobrutinib significantly reduced the number of Gd+ lesions versus placebo (Montalban et al. N Engl J Med 2019;380:2406-2417). A new analysis of that dataset examined the effect of treatment on immune cell populations and immunoglobulin levels over the 48-week treatment period (Montalban et al. ECTRIMS 2019; abstract P1358). Evobrutinib was not associated with any clinically relevant changes in the total B cell population (total count, memory B or mature naïve B cells), nor did it affect the number of T cells (total count, Th, cytotoxic T) or natural killer cells. There were no changes in IgG, but small increases in IgA levels and slight decreases in IgM over the last 24 weeks of treatment. A separate study in EAE mice reported that evobrutinib reduced B cell signalling, inhibited T cell proliferation and increased the proportion of Tregs, resulting in a reduction in CNS inflammation and clinical improvement (Torke et al. ECTRIMS 2019; abstract P976).
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Clinical Tip of the day
Cervical screening may be advised in women starting a high-efficacy DMT. An Australian study examined data from a vaccination registry for human papillomavirus (HPV) and for cervical screening tests (Van der Walt et al. ECTRIMS 2019; abstract P1404). In the interim analysis of 102 patients, 88% had not received HPV vaccination. No patient included in the analysis had a history of cervical dysplasia. Overall, 19% of patients had an abnormal cervical screening test over a 9-year period after MS onset (incidence 20.6 cases/1000 person-years). The incidence of abnormal cervical tests was 12.6/1000 PY during treatment with a first-line injectable DMT. The incidence was three-fold higher – 38.6/1000 PY – after starting a high-efficacy DMT. Annual HPV screening is currently recommended for women with MS receiving alemtuzumab. There have been case reports of cervical dysplasia and/or HPV-related conditions with natalizumab and fingolimod (Durrieu et al. Fundam Clin Pharmacol 2019;33:125-126. Triplett et al. Mult Scler 2018; epublished November 14, 2019).
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