Phase III trials in NMOSD
Cladribine and time to SPMS
Hypogammaglobulinemia
Cannabis and cognition
Concussion and MS
Clinical Tip of the day

Phase III trials in NMOSD
Eculizumab is a complement inhibitor that received FDA approval in June 2019 for the treatment of neuromyelitis optica spectrum disorder (NMOSD) based on the results of the PREVENT trial. The study randomized aquaporin-4 IgG-positive NMOSD patients to placebo or eculizumab 1200 mg/2 weeks with or without concomitant immunosuppressants (Kim et al. ECTRIMS 2019; abstract P604). The proportion of patients who relapsed was 3% with eculizumab versus 42.6% with placebo (Pittock et al. ECTRIMS 2019; abstract P605). The FDA label includes a black-box warning about the risk of meningococcal infections. Eculizumab is currently approved in Canada for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. When initially approved, the drug earned some notoriety as the most expensive drug in the world.

A second study reported the results of the Sakura Star trial of satralizumab, a monoclonal antibody that binds to the interleukin-6 receptor (Traboulsee A. ECTRIMS 2019; abstract P603). A total of 95 NMOSD patients were randomized to placebo or satralizumab 120 mg SC given in weeks 0, 2 and 4 and monthly thereafter. Relapse risk was reduced 55% with active treatment. The proportion relapse-free at week 96 was 72.1% with satralizumab versus 51.2% with placebo.
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Cladribine and time to SPMS
A post-hoc analysis of the CLARITY trial found that the proportion of patients who progressed to SPMS was 54% lower with cladribine 3.5 mg compared to placebo (6.7% vs. 13.5%) (Vermersch P. ECTRIMS 2019; abstract P385). A proxy definition of SPMS was used since SPMS was not recorded in the trial. The risk of SPMS was similarly reduced in patients with baseline EDSS score >3.5 (12.2% vs 22.4%, 45% reduction) and < 3.0 (3.5% vs 7.7%, 54% reduction). The proportion of patients with at least one EDSS score ≥6.0 during the study was 6.4% with cladribine compared to 14.5% with placebo.
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Hypogammaglobulinemia
Antibody deficiency secondary to treatment with an anti-CD20 therapy is emerging as a potential safety concern due to the increased risk of serious infection (Tallantyre et al. J Neurol 2018;265:1115-1122). A retrospective study (n=327) reported that IgG deficiency is common in MS patients: 7.9-8.6% of untreated MS patients and 14.9-15.5% for the full cohort of treated and untreated patients (Zoehner G. ECTRIMS 2019; abstract P407). IgG levels were lower in MS patients treated with rituximab, IV steroids, natalizumab and fingolimod compared to untreated patients. A separate study reported an incidence of hypogammaglobulinemia of 6.0% during long-term (mean 29.1 months) treatment with rituximab (Hallberg et al. ECTRIMS 2019; abstract 64). An analysis of phase III extension data for ocrelizumab reported that Ig levels dropped below the lower limit of normal in 5.7% (IgG), 5.4% (IgA) and 29.2% (IgM) at week 264 (Derfuss et al. ECTRIMS 2019; abstract 65). The incidence of serious infections was three-fold higher (6.5/100 patient-years) with low IgG, and two-fold higher with low IgM (3.66/100 PY). All infections resolved with standard care. It should be noted that low Ig levels may contribute to a false-negative result on JC or varicella zoster virus testing (Zoehner 2019).
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Cannabis and cognition
A University of Toronto study reported that long-term cannabis users can improve their cognitive test results (processing speed, memory, executive function) if they stop taking cannabis at least 28 days beforehand (Feinstein A. ECTRIMS 2019; abstract P542).
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Concussion and MS
A retrospective analysis of Ontario databases found that head trauma during adolescence was not associated with a higher risk of a subsequent MS diagnosis (Pavolo CA. ECTRIMS 2019; abstract P396). However, over the longer term (>15 years), concussion was associated with a significantly increased risk of MS (hazard ratio 1.85). In the sensitivity analysis, there was an increased MS risk (HR 1.37) post-concussion after 8 years of follow-up. Previous studies have reported conflicting results. Database analyses in Sweden reported an increased risk of developing MS in adolescents after one (odds ratio 1.22) and two (OR 2.33) concussions during adolescence (Montgomery et al. Ann Neurol 2017;82:554-561). A Danish study found no association between head trauma during adolescence and the development of MS (Pfleger et al. Mult Scler 2009;15:294-298).
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Clinical Tip of the day
An accelerated vaccination schedule for hepatitis B will substantially reduce vaccine effectiveness (Wundes A. ECTRIMS 2019; abstract P671). The standard schedule for Engerix-B is three injections over a 6-month period (months 0, 1 and 6), which will delay starting a higher-efficacy DMT. An accelerated schedule (months 0, 1 and 2 with a booster at month 12) can be used to enable earlier DMT start. In the current study, only 10 of 39 patients (26%) mounted a protective anti-Hep B titre with the accelerated protocol and 16/39 (41%) failed to mount a response. The usual seroresponse rate with Engerix-B is >90%.
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