8th Joint Americas Committee and European Committee for Treatment and Research in MS (ACTRIMS-ECTRIMS) meeting, Virtual Congress, 11-13 September 2020.
The following summarizes some of the highlights from Day 3 of ACTRIMS-ECTRIMS 2020.
CONGRESS HIGHLIGHTS – SUNDAY EDITION
Infection in adolescence an MS risk factor
A Swedish database analysis examined infections in childhood and adolescence as a possible risk factor for the development of MS (Smith et al. ECTRIMS 2020; abstract YI02.06). Bacterial and/or viral CNS infections during adolescence (ages 11-20) were significantly associated with an increased risk of MS (hazard ratio 2.80); when encephalomyelitis was excluded, the estimated hazard ratio was 1.85. Infections during childhood were not associated with MS risk.
Novel DMTs in development
Ponesimod: This sphingosine-1-phosphate (S1P) receptor-1 modulator is in development for relapsing MS. Results from the phase III OPTIMUM trial of ponesimod versus teriflunomide were announced at last year’s ECTRIMS but the data have not yet been published. In an update of MRI findings, ponesimod was associated with significant reductions in the number of new/enlarging T2 lesions (rate ratio 0.44), number of Gd+ lesions/scan (rate ratio 0.42) and change from baseline in brain volume versus teriflunomide at week 108 (Kappos et al. ECTRIMS 2020; abstract P0071). The proportion of patients with no evidence of disease activity (NEDA) at week 108 was 28% with ponesimod and 18% with teriflunomide.
Ofatumumab: This fully human anti-CD20 monoclonal antibody is administered by subcutaneous injection at a dose of 20 mg q4weeks (after three 20-mg loading doses on days 1, 7 and 14). Results from the phase III ASCLEPIOS I and II trials were recently published and reported significant reductions with ofatumumab versus teriflunomide in ARR (0.11 vs. 0.22 and 0.10 vs. 0.25 in the two studies) and six-month CDP (pooled 8.1% vs. 12.0%) (Hauser et al. N Engl J Med 2020;383:546-557). In a new subgroup analysis of newly-diagnosed patients, ARR was 0.09 and 0.18 with ofatumumab and teriflunomide, respectively (Gartner et al. ECTRIMS 2020; abstract P0192). Six-month CDP was 5.9% vs. 10.4%. The rate of serious side effects was similar in the two treatment groups (7.0% vs. 5.3%); the rate of serious infections was 1.9% and 0.7%, respectively.
Subjects in the ASCLEPIOS I/II and the phase II APLIOS studies were enrolled in the ALITHIOS study (n=1873) (Cross et al. ECTRIMS 2020; abstract P0234). Cumulative ofatumumab exposure was 2119 patient-years (median 21 months for the continuous treatment subgroup). The rate of infections was 49.3% in the continuously treated group; the rate of serious infections was 1.8%. There have been no cases of opportunistic infection, hepatitis B reactivation or PML, and no deaths.
Evobrutinib: Phase II results for this oral Bruton’s tyrosine kinase (BTK) inhibitor were published last year and reported a significant reduction in Gd+ lesions versus placebo with the 75 mg/day and 75 mg BID doses (Montalban et al. N Engl J Med 2019;380:2406-2417). The proportion of patients who developed grade 1 lymphopenia was similar with evobrutinib 75 mg/day or 75 mg BID and placebo (4% vs. 6% vs. 6%) at 24 weeks. Treated patients continued in their original assignment for a further 24-week blinded phase; the placebo group was switched to evobrutinib 25 mg/day. For the subsequent 48-week open-label extension, patients received evobrutinib 75 mg/day and then were switched to 75 mg BID (Montalban et al. ECTRIMS 2020; abstract P0197). ARR was 0.25 and 0.11 with continuous evobrutinib 75 mg OD and BID, respectively, at week 48, and 0.18 and 0.12 with the two doses at week 108. The estimated time to 20% of patients having a relapse was shorter for patients originally randomized to placebo (281 days) versus those in the evobrutinib 75 mg/day and 75 mg BID groups (530 days and 827 day). A separate analysis reported that CD19+ B cells and mature-naïve B cells gradually declined during treatment; no change in memory B cells was observed (Montalban et al. ECTRIMS 2020; abstract P0070). Mean immunoglobulin levels (IgA, IgM) fluctuated but remained within the normal range.
Virus exposure in PPMS vs. RRMS
A novel analysis of 166 patients found differences in viral antibody titres in PPMS patients compared to RRMS patients (Dominguez-Mozo et al. ECTRIMS 2020; abstract P0964). IgG antibody-positivity against Epstein-Barr virus (EBNA-1) was significantly more common in RRMS versus PPMS patients aged < 45 years (100.0% vs. 84.5%). Conversely, PPMS patients were more likely to have positive titres against human herpesvirus-6 (26.9% vs. 7.7%). IgG titres against cytomegalovirus were also higher in PPMS compared to RRMS patients.
An analysis by the MSBase group compared postpartum relapses for the period 2011-2019 versus two earlier epochs (2005-2010 and pre-2005) (Yeh et al. ECTRIMS 2020; abstract P1131). The annualized relapse rate (ARR) prior to conception declined over the three epochs, from 0.58 (pre-2005) to 0.40 (2005-2010) to 0.29 (2011-2019); in part this may be attributed to the more frequent use of DMTs up to the time of conception (31% pre-2005 vs. 54% in 2011-2019). In all time periods, ARR decreased during pregnancy and increased in the first three months postpartum. An EDSS score >2 before pregnancy was a risk factor for postpartum relapse. The risk of postpartum relapse was reduced 37% with breastfeeding and 83% with early re-initiation of a DMT. A total of 4.5% of patients experienced confirmed disability progression in the year after childbirth.
MOG antibody testing
Recent treatment recommendations have advised against routine testing for MOG antibodies in patients with suspected MS with typical clinical findings (Freedman et al. Can J Neurol Sci 2020;47:437-455). That recommendation is supported by a new study of the prevalence of MOG antibodies in neurological patients treated at a single centre in Germany (Held et al. ECTRIMS 2020; abstract HT07.03). MOG-Abs were detected in 1.33% of samples. High titres were found primarily in NMOSD patients; low titres were detected primarily in patients with non-MS neuroinflammatory diseases and post-stroke. Persistent low titres were found in a range of non-inflammatory neurological diseases. The authors concluded that MOG-Ab testing has limited utility for diagnosis.
Clinical tip of the day
Stabilizing or improving MS symptoms may be the most useful approach to maintain patients’ work productivity. The Australian MS Longitudinal Study found that year-to-year changes in disability and symptom scores had a greater impact on productivity than symptom severity (Bessing et al. ECTRIMS 2020; abstract P0471). The key symptom clusters associated with productivity changes were pain/sensory symptoms, anxiety/depression and fatigue/cognitive symptoms.