The American Academy of Neurology (AAN) annual meeting, scheduled for April 25-May 1, 2020, was cancelled due to the COVID-19 pandemic. The following summarizes some of the new research that would have been presented at AAN 2020.
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CONGRESS HIGHLIGHTS – WEDNESDAY EDITION
Multiple sclerosis
DMF long-term data
Ocrelizumab – B cell repopulation
How common are zoster infections?
Ponesimod – new trial data
MRI lesions underreported
Narcolepsy
Pitolisant – real-world data
Multiple sclerosis
DMF long-term data: Most patients treated with dimethyl fumarate had no confirmed disability progression over a 10-year follow-up, according to a pooled analysis of data from DEFINE/CONFIRM and ENDORSE (Gold et al. AAN 2020; abstract P6.012). Of the 410 originally randomized to DMF 240 mg BID, 192 patients received continuous DMF for 10 years. The relapse-free rate was 51%; the median time to relapse was 518 weeks. ARR in years 0-10 was 0.107. At 10 years, EDSS remained <3.5 in 89%, and 64% had no confirmed disability progression. QoL measures remained stable.
Ocrelizumab – B cell repopulation: Ocrelizumab produces a rapid, profound depletion of B cells, but its impact on different B cell subsets is not uniform (Shinoda et al. AAN 2020; abstract P5.019). At 3 months after initiation, plasmablasts and CD11c+ B cells showed less depletion. At 6 months, a subset of memory B cells and CD10+ transitional B cells repopulated more quickly; the ratio of B cells producing IL6/IL10 was diminished. CD11c+ B cells are a pro-inflammatory memory B cell subset that has been implicated in a number of autoimmune diseases. CD11c+ cells overexpress genes involved in B cell activation and antigen presentation and differentiate into antibody-secreting cells (Golinsky et al. Front Immunol 2020;11:32).
How common are zoster infections?: An analysis of the FDA’s adverse events database (FAERS) found that reports of herpes zoster infections were 4.7-fold more common in women than men (Carlisle et al. AAN 2020; abstract P17.015). Annual report rates were highest for natalizumab, fingolimod, DMF and ocrelizumab, less frequent for alemtuzumab and interferon-beta, and lowest for teriflunomide and glatiramer acetate. Zoster infection was more common in older individuals but about 25% of reports were in patients younger than 40 years.
Ponesimod – new trial data: OPTIMUM is the phase III trial comparing ponesimod, a sphingosine-1 receptor modulator in development, with teriflunomide in RMS for 108 weeks (n=1131). Ponesimod was administered over a 14-day titration period to minimize the need for first-dose observation. Annualized relapse rates (ARR) were 0.20 with ponesimod versus 0.29 with teriflunomide (Fox et al. AAN 2020; abstract S40.010). Time to 24-week confirmed disability accumulation was reduced 8.1% with ponesimod and 9.9% with teriflunomide, a nonsignificant 16% reduction. Mean number of combined unique active lesions per scan was 1.405 and 3.164, respectively. The rate of no evidence of disease activity (NEDA) was 25% with ponesimod and 16.4% with teriflunomide. The most common adverse events with ponesimod included elevated liver enzymes (19.5% vs. 9.4% with teriflunomide), headache (11.5% vs. 12.7%) and upper respiratory tract infections (10.6% vs. 10.4%) (Sprenger et al. AAN 2020; abstract P5.021). Events of special interest with ponesimod were hepatobiliary/liver enzyme abnormalities (22.7% vs. 12.7% with teriflunomide), hypertension (10.1% vs. 9.0%) and pulmonary events (8.0% vs. 2.7%). In the long-term extension of the phase IIb study, ARR was 0.154 and 6-month confirmed disability accumulation was 20.4% with ponesimod 20 mg at 8 years (Freedman et al. AAN 2020; abstract P9.003).
MRI lesions underreported: New/enlarging lesions reported in clinical trials typically use human readers but this appears to underestimate the true lesion number (White et al. AAN 2020; abstract S45.002). A study obtained MRIs from the phase II SPRINT-MS trial of ibudilast in progressive MS. New/enlarging T2 lesions were identified on 19% of scans using a semi-automated analysis compared to 5% using a human reader. For scans with >1 lesion, the median number of lesions/scan was 2 with the semi-automated method and 0 with a radiologist reader.
Narcolepsy
Pitolisant – real-world data: Pitolisant (Wakix) is an H3 receptor antagonist/inverse agonist that received FDA approval in August 2019 for the treatment of excessive daytime sleepiness in patients with narcolepsy. Results are available for 623 patients enrolled in the expanded access program (Davis et al. AAN 2020; abstract P3.002). About 98% were previously treated. Patients were titrated to the highest tolerable dose (maximum 35.6 mg/day) over a three-week period and 70% continued to take other narcolepsy medications (e.g. stimulants, sodium oxybate, modafinil, antidepressants). One-third of patients discontinued pitolisant, primarily due to adverse events or lack of effect. The most common adverse events were headache (10.8%), nausea (7.2%), anxiety (5.9%) and insomnia (5.4%). A separate study of 15 narcolepsy patients treated at a sleep medicine clinic reported no significant changes in sleep architecture or sleep quality in patients treated with pitolisant (Triller et al. AAN 2020; abstract P3.001).
Clinical tip of the day: Most patients will experience significant blood pressure elevations during alemtuzumab infusions. A Canadian retrospective study at the London MS clinic looked at BP changes in 31 patients receiving alemtuzumab (Shosha et al. AAN 2020; abstract P7.003). Mean age was 35 years; mean duration of MS was 9.2 years. None had a history of hypertension or vascular events. Systolic BP increased by a mean of 19.2 mmHg during cycle 1, with an average increase of 16% over the first five doses. Diastolic BP increased by 6.2 mmHg during cycle 1 doses. Similar increases were seen in cycle 2 (SBP 16.9 mmHg, DBP 5.4 mmHg) and cycle 3 (SBP 8.9 mmHg, DBP 4.2 mmHg). Overall, 54.8% had >20% increase above baseline BP during their infusions.
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