Efficacy and safety of four-year ofatumumab treatment in relapsing multiple sclerosis: The ALITHIOS open-label extension

Figure 1.. Analysis sets and time periods. *The “newly switched ofatumumab group” comprised patients randomized to teriflunomide in ASCLEPIOS I/II (those who completed treatment were eligible to enter ALITHIOS and be switched to ofatumumab); the “continuous ofatumumab group” comprised patients randomized to ofatumumab in ASCLEPIOS I/II (those who completed treatment were eligible to enter ALITHIOS). All patients who completed study treatment in the core period were eligible to enter ALITHIOS but could withdraw prior to treatment. The efficacy analysis set comprised all patients randomized to ofatumumab or teriflunomide in ASCLEPIOS I/II, regardless of whether they completed/discontinued study treatment. The safety analysis set comprised patients who received ≥1 dose of ofatumumab in ASCLEPIOS I/II, APLIOS, APOLITOS, or ALITHIOS. Percentages based on the number of randomized patients. The open-label extension period was defined as following the first dose of ofatumumab in ALITHIOS (below the dashed line); the core period is prior to the open-label extension (above the dashed line). Reasons for the discontinuation of study treatment are presented in Supplementary Table 1.

Figure 2.. Relapse data: (a) within-group comparison of ARR during the core and open-label extension periods; (b) between-group comparison of total confirmed relapses up to 4 years in the newly switched ofatumumab group and continuous ofatumumab group (efficacy analysis set). Data from the efficacy analysis set. Adjusted ARR presented as ARR (95% CI). aConfirmed relapses are those accompanied by a clinically relevant change in the EDSS. Comparisons obtained from fitting a piecewise negative binomial model for the core period and open-label extension time periods with log-link, adjusted for treatment and region as factors, number of relapses in previous year, baseline EDSS score, baseline number of Gd+ lesions and the patient’s age at baseline as covariates. The natural log of the time-in-study (in years) by time period is used as offset to annualize the relapse rate in each time period. Baseline variables are from the core period baseline. P values in panel A are nominal P values; P value in panel B is from a Wilcoxon Rank Sum test. ARR: annualized relapse rate; CI: confidence interval; EDSS, Expanded Disability Status Scale; Gd+, gadolinium-enhancing; RR: rate ratio.

Figure 3.. Kaplan–Meier estimates of cumulative event rates (% patients) for confirmed disability worsening (left-hand panel) and cumulative number of confirmed disability worsening events (right-hand panel): (a) 3mCDW and (b) 6mCDW (efficacy analysis set). Data from the efficacy analysis set. Superior efficacy of ofatumumab in the core period was established previously versus teriflunomide (for more information, refer to Hauser, et al. 4 ). Cut-off for core and open-label extension periods based on the first dose of ofatumumab in the open-label extension period. “Difference” refers to the difference in KM estimates (newly-switched ofatumumab group minus continuous ofatumumab group). aP value is a Log-Rank test. 3mCDW: 3-month confirmed disability worsening; 6mCDW: 6-month confirmed disability worsening; CI: confidence interval; HR, hazard ratio; KM: Kaplan–Meier.

Figure 4.. Lesion activity on MRI in the core and extension periods: (a) within-group comparison, mean number of Gd+ T1 lesions/scan; (b) between-group comparison, mean number of Gd+ T1 lesions; (c) within-group comparison, mean annualized rate of neT2 lesions; and (d) between-group comparison, mean number of neT2 lesions (efficacy analysis set). Data from the efficacy analysis set. Panels A and C: data are presented as mean (95% CI). Data were estimated from fitting a piecewise negative binomial model for the core and open-label extension time periods with log-link, adjusted for treatment and region as factors for panels A and B, and treatment for panels C and D. For panels A and B, baseline number of T1 Gd+ lesions and patient’s age at baseline were covariates; the natural log of the number of scans with evaluable Gd+ lesion counts by period is used as offset to obtain the lesion rate per scan in each period. For panels C and D, baseline volume of T2 lesions and patient’s age at baseline were covariates; the natural log of the time-in-study (in years) by period is used as offset to annualize the lesion rate in each period. Baseline variables are from the core period baseline. P values in…

Figure 5.. No evidence of disease activity (NEDA-3): (a) core period, open-label extension period and overall; (b) during the first year of treatment and after first year of treatment, by study period (efficacy analysis set). Data from the modified efficacy analysis set for NEDA-3. All P values are nominal. The statistical model used logistic regression to adjust for treatment and region as factors, and for age, baseline EDSS score, number of Gd+ lesions at baseline as covariates. N=total patients in each treatment group. aRe-baseline was performed at entry to the extension period. CI: confidence interval; EDSS, Expanded Disablity Status Scale; Gd+, gadolinium-enhancing; M: month; NEDA-3: three-parameter no evidence of disease activity; OR: odds ratio.