American Academy of Neurology annual meeting – 13-18 April 2024

The following summarizes some of the highlights from Day 2 of AAN 2024.

April 18 Edition
April 17 Edition
April 15 Edition

Anti-CD20 agents: long-term data
Anti-CD40L – updated efficacy results
MAb exposure during breastfeeding – safety data
Inadequate long-term follow-up of post-traumatic epilepsy

CONGRESS HIGHLIGHTS – TUESDAY EDITION

Anti-CD20 agents: long-term data
Two new studies have reported on the long-term efficacy and safety of ofatumumab 20 mg SC over a six-year period. A total of 1643 RMS patients from the ASCLEPIOS I/II, APLIOS and APOLITOS studies entered the ALITHIOS open-label extension (Wiendl et al. AAN 2024;P9.010). At year 6, 91.9% of patients on continuous ofatumumab had no evidence of disease activity (NEDA). The mean adjusted annualized relapse rate (ARR) was 0.054. In the continuous ofatumumab group, the mean number of Gd+ lesions was 0.01; the mean number of new/enlarging T2 lesions was 0.072. The proportion of patients with six-month confirmed disability progression (CDP) was 21.1% at six years. The exposure-adjusted incidence rate of serious adverse effects was 4.40/100 patient-years. The incidence of infections was 38.86/100 PY; the most common infections were COVID-19 (34.3%), nasopharyngitis (20.6%), upper respiratory tract infection (14.9%), and urinary tract infection (14.4%). The incidence of malignancies was 0.34/100 PY and remained stable during the six years of observation. The level of immunoglobulins remained above the lower limit of normal both for IgG (97.2%) and IgM (65.9%). There was no association seen between low IgG/IgM levels and the risk of serious infections.

A separate analysis examined the six-year efficacy and safety of ofatumumab in the subgroup of previously untreated patients from ASCLEPIOS I/II (n=465) (Pardo et al. AAN 2024;S31.003). In the continuous ofatumumab group, mean age at baseline was 36.8 years, mean time since diagnosis was 0.58 years and mean EDSS was 2.30. Mean ARR during the open-label extension was 0.05. The mean number of Gd+ lesions/scan was 0.001; the mean annualized rate of new/enlarging T2 lesions was 0.07. Patients randomized to the teriflunomide group experienced a 96.4% reduction in Gd+ lesions and an 82.7% reduction in new/enlarging T2 lesions after switching to ofatumumab. With respect to progression independent of relapse activity (PIRA), the rate of 6-month PIRA events was substantially higher in the switch group (16.8% vs. 11.1%). This higher rate of early damage was associated with a significantly higher rate of 6-month CDP in the teriflunomide/ofatumumab switch vs. continuous ofatumumab group (23.7% vs. 16.6%). The authors concluded that the benefits of first-line ofatumumab cannot be recovered in newly-diagnosed patients who later switch from teriflunomide to ofatumumab.

Ten-year data for ocrelizumab from the OPERA I/II and ORATORIO trials were also reported (Hauser et al. AAN 2024;S31.005). In the RMS group from the OPERA trials (N=1656), the proportion of patients with no 48-week confirmed EDSS events was 76.6%; 92.1% were EDSS <6.0. Earlier treatment with ocrelizumab was associated with a lower risk of EDSS progression (hazard ratio 0.61); first-line vs. delayed ocrelizumab prolonged the time between progression events by 9.5 years. In the PPMS group in ORATORIO (N=732), 36.4% had no 48-week confirmed EDSS events and 80.4% were EDSS <7.0. Earlier treatment was also associated with a lower risk of EDSS progression (HR0.74) in this group; the time to progression events was delayed 1.6 years with earlier treatment. The incidence of serious adverse events was 6.3/100 PY in the OPERA studies and 12.6/100 PY in ORATORIO at 10 years. The rate of serious infections (excluding COVID-19) was 1.8/100 PY and 4.4/100 PY, respectively. The incidence of malignancies in the OPERA I/II extension was 0.4/100 PY.

Anti-CD40L – updated efficacy results
Frexalimab is a monoclonal antibody that targets the CD40 ligand, which is involved in B cell activation and release of pro-inflammatory cytokines. Results from the 12-week open-label extension of the original 12-week phase II trial were presented at ECTRIMS 2023 (Novel treatments: targeting CD40 ligand, NeuroSens, November 1, 2023). Overall, 96% of frexalimab-treated patients were free of Gd+ lesions and 91% had no new T2 lesions at week 24. Results at 48 weeks are now available (Giovannoni et al. AAN 2024;S31.007). The number of Gd+ lesions was low in patients in the higher-dose (0.0) and lower-dose (0.2) groups, and in the placebo groups that switched to the higher (0.2) and lower dose (0.1) groups. The most common adverse events were nasopharyngitis, headache, and COVID-19. A separate study reported a significant reduction in least-squares mean physical impact scores on the MSIS-29 with higher-dose frexalimab (Vermersch et al. AAN 2024;P10.001). No significant improvement was seen in psychological impact score. No significant improvements were seen in the lower-dose group versus placebo. Significant improvement with both doses was seen in fatigue scores as evaluated by the novel Patient-Reported Outcomes Measurement Information System Short Form-Fatigue-Multiple Sclerosis 8a (PROMIS-Fatigue-MS-8a) tool.

MAb exposure during breastfeeding – safety data
Animal studies have detected the secretion of monoclonal antibodies in breast milk and patients are generally advised not to receive MAb therapy during breastfeeding. An analysis of the German MS and Pregnancy Registry identified 183 cases in which a patient with MS or NMOSD was exposed to a MAb while breastfeeding (Witt et al. AAN 2024;S7.003). MAbs used were natalizumab (68% of cases), ocrelizumab (19%), rituximab (6%) and ofatumumab (5%). The median time to MAb exposure postpartum was day 19; median duration of drug exposure during breastfeeding was 172 days. MAb exposure was not associated with an increase in hospitalizations or systemic antibiotic use, nor was there an association with developmental delay or weight in the child during follow-up visits.

Inadequate long-term follow-up of post-traumatic epilepsy
There is inadequate follow-up of the estimated 375,000 new cases per year of post-traumatic epilepsy (PTE) in the U.S., according to a retrospective chart review over a five-year period (Kotas et al. AAN 2024;P6.006). Overall, 1,886 cases of traumatic brain injury were identified, of which 178 (9.44%) were categorized as PTE. The main risk factor for PTE was the occurrence of severe brain injury (odds ratio 2.95). While most patients (63.9%) received a neurology consult at some point, few patients (10.7%) saw a neurologist >6 months after the traumatic brain injury.

April 18 Edition
April 17 Edition
April 15 Edition