A number of new studies have provided data on the long-term safety and efficacy of high-efficacy disease-modifying therapies in MS. The data were presented at the American Academy of Neurology (AAN) annual meeting, held April 2-7 in Seattle, Washington. The following is a summary of key studies.
Ocrelizumab: An earlier switch from interferon-beta to ocrelizumab reduces brain volume loss but does not result in a significantly lower number of new T2 or Gd+ lesions, according to six-year data from OPERA I/II (Arnold et al. AAN 2022; P6.002). At 6 years, continuous ocrelizumab was associated with a significant reduction in tissue loss in cortical grey matter, thalamus and cerebellum, but not in whole-brain atrophy or T1 lesion volume versus an interferon/ocrelizumab switch. There was no difference between the two groups in new/enlarging T2 or Gd+ T1 lesion count.
A retrospective chart review reported that infection risk in MS and NMO patients (n=291) increased after two years of continuous ocrelizumab or rituximab (Peters et al. AAN 2022; P13.011). Mean time on treatment was 46 months. During therapy, 43% of patients required antibiotics and 10% were hospitalized for infection. Infection rates increased after two years of treatment. Duration of therapy was the only factor associated with an increased risk of infection-related hospitalization.
Ofatumumab: Two long-term analyses were presented by Hauser et al. (AAN 2022; P5.004 and S14.004). Efficacy was evaluated in patients completing the phase III ASCLEPIOS I/II trials and who enrolled in the ALITHIOS long-term extension (n=1367). In the group on continuous ofatumumab there was sustained efficacy on all endpoints at four years. Annualized relapse rate (ARR) remained low (0.05); the estimated proportion with 6-month confirmed disability progression was 14.8% at 48 months. The mean number of Gd+ lesions was 0.01/scan; the mean number of new T2 lesions was 0.07. There were substantial reductions in ARR and lesion counts in the group that switched from teriflunomide to ofatumumab; results were similar to those seen with continuous ofatumumab. However, the estimated proportion with 6-month confirmed disability progression remained higher (18.3%) in the switch group at month 48.
A safety analysis was performed of patients exposed to ofatumumab in the ASCLEPIOS I/II, APLIOS and APOLITOS studies (N=1969). Mean age was 38.7 years; mean time from MS diagnosis was 6.37 years; and mean EDSS score at baseline was 2.87. The median duration of drug exposure was 28.1 months. The most common adverse events were infections, such as nasopharyngitis (17.5%), upper respiratory tract infections (11.1%), urinary tract infections (10.9%), and COVID 19 (10.6%). The rate of serious infections was 4.01% (adjusted incidence 1.53/100 patient-years). One serious opportunistic infection (Pneumocystis jirovecii pneumonia) was recorded. As reported previously, mean serum IgG levels remained stable and above the lower limit of normal; IgM levels declined but remained above the LLN (see also Ofatumumab safety update: modest effect on Ig, NeuroSens, March 25, 2022). The malignancy rate was 0.86% (adjusted incidence 0.33/100 PY). There were six deaths, including two from COVID-19. The COVID-19 infection rate was 1.5% for fully-vaccinated patients and 2.0% for partially-vaccinated patients.
A separate safety analysis reported that 25.6% of patients on continuous ofatumumab experienced systemic injection-related reactions; 99.5% of reactions were mild-to-moderate in severity (Kramer et al. AAN 2022; S7.011). The most common systemic symptoms were fever, headache, chills and fatigue. Six reactions were considered serious (weakness requiring hospitalization, hypersensitivity reactions). No life-threatening injection reactions were seen.
Tolebrutinib: This Bruton’s tyrosine kinase (BTK) inhibitor is currently in development. In the phase II dose-finding study, subjects received one of four doses of tolebrutinib (5, 15, 30 or 60 mg/day) for 12 weeks (Reich et al. Lancet Neurol 2021;20:729-738). After a treatment gap of up to 21 weeks, patients could enroll in the extension phase at the same dose, then were switched to the 60-mg dose for the open-label phase III study. At 18 months, the most common adverse events were headache (12.8%), COVID-19 (12.8%), nasopharyngitis (10.4%), upper respiratory tract infection (8.0%) and arthralgia (5.6%) (Oh et al. AAN 2022; S14.003). No new safety signals were seen after switching to the higher dose.
MRI outcomes were also reported (Arnold et al. AAN 2022). In the group on continuous tolebrutinib 60 mg, the number of Gd+ lesions was low (0.47), the number of new/enlarging T2 lesions increased slightly from week 24 to weeks 48 and 72. Median volume of slowly-expanding lesions was substantially lower in the 60/60-mg group compared to the 30/60-mg group (283.5 vs. 675 mm3).