Ofatumumab showed a consistent and long-term reduction in relapse rates and MRI lesion activity in patients with recently diagnosed, treatment-naïve relapsing multiple sclerosis.
In new data from the phase 3 ASCLEPIOS I and II (NCT02792218; NCT02792231) and ALITHIOS open-label extension studies (NCT03650114), ofatumumab (Kesimpta; Novartis) displayed sustained efficacy over 6 years in patients with recently diagnosed, treatment-naïve (RDTN) relapsing multiple sclerosis (RMS). These findings support the long-term use of ofatumumab, a fully human anti-CD20 monoclonal antibody with a 20 mg subcutaneous monthly dosing regimen, in the disease course.1
Presented at the
"The field of MS is actively trying to answer the treatment conundrum of starting with an escalation therapy or, instead, using highly effective disease-modifying therapies (DMTs) early in the disease process," Pardo, founding director of the Multiple Sclerosis Center of Excellence at Oklahoma Medical Research Foundation, told NeurologyLive®. "This study adds to the mounting evidence favoring the latter by showing the sustained benefit in markers of active inflammatory activity, both clinical and by MRI, up to 6 years, and by identifying that although a later switch to ofatumumab from teriflunomide resulted in improvement of those outcomes, there was no catching up for accumulated disability measures."
The RDTN subgroup comprised of patients in the continuous/switch groups (mean age at baseline, 36.8/35.7 years; women, 69.1%/65.8%; mean EDSS, 2.30/2.28). These analyses included cumulative data from the RDTN subgroups randomized to ofatumumab in the core (continuous group) and those originally randomized to teriflunomide who then switched to ofatumumab in ALITHIOS (switch group).
In the analysis, low annualized relapse rate (ARR) among RDTN patients with RMS on continuous ofatumumab in the core phase 3 trials were reduced further in the ALITHIOS, from 0.104 to 0.050 (52.0%), which corresponded to an adjusted ARR of 1 relapse per 20 years. Notably, rates of 3- and 6-month progression independent of relapse activity (PIRA) with first-line ofatumumab were also lower compared with the switch group. In addition, investigators observed a significant increase in the number of patients with no evidence of disease activity (NEDA-3) on continuous first-line ofatumumab treatment maintained up to 6 years.
In RDTN patients with RMS initially treated with teriflunomide, investigators observed significant reductions in ARR (71.3%) and in MRI lesion activity (Gd+ T1, 98.5%; neT2, 93%), and a significant increase in rates of NEDA-3. Despite this, the rates of 3- and 6-month CDW events remained higher compared with patients who received continuous ofatumumab. These findings indicated that the efficacy benefit of first-line ofatumumab on delaying disability worsening was not fully achieved in the switch group. Across both treatment groups, 9 out of 10 patients achieved NEDA-3 over 6 years.
"The use of highly effective DMTs such as ofatumumab in RDTN individuals resulted in very good control of relapses and a profound suppression of new, enlarging, or enhancing brain MRI lesions, and results in lesser disability worsening that cannot be recovered if its use is delayed," Pardo said. "There is great value in having long-term results, 6 years for this study, as this has practical implications in clinical practice where we help these patients manage their disease for a lifetime. Continued collection of data for longer periods will further guide optimal MS care."
In the prior analyses, the RDTN continuous subgroup (n = 314) sustained a low ARR over years 1–5 (0.1–0.01). Notably, investigators observed marked reductions in ARR among the patients in the switch subgroup (n = 314) from year 2–3 (0.1–0.053) and were sustained through years 3–5 (0.053–0.037). Overall, T2 lesion activity was suppressed in the continuous group for up to 5 years, and from years 3–5 (annualized number of new/enlarging T2 lesions, 1.29–0.043) in the switch group. Additionally, the odds of achieving no evidence of disease activity increased from 89% at year 2 to 96% at year 5 in the continuous group, and from 36% to 58% at year 2–3, reaching 90% at year 5 in the switch group.
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At AAN 2023, long-term data from ASCLEPIOS I and II and ALITHIOS open-label extension studies suggested that better outcomes in patients with MS are achieved with ofatumumab and favor earlier initiation with the therapy.2 Among those treated with the therapy for up to 4 years in the clinical programs, PIRA was the predominately occurring disease progression.
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“In the ASCLEPIOS I/II core studies, ofatumumab [showed] 3- and 6-month CDW [rates of] 10.90% and 8.15%, [respectively], delay[ing] disability accrual compared with teriflunomide, [which showed] 3- and 6-month CDW [rates of] 14.98% and 11.95%. PIRA was the main contributor to overall 3- and 6-month CDW,” Cohen and colleagues wrote.
During the core studies, the majority of patients were free from 3-month and 6-month CDW (ofatumumab, 85.0%; teriflunomide, 80.7%). At the 4-year time point and data cutoff of September 25, 2021, the percentage of patients with 6-month CDW was 12.6% (119 of 946) in the continuous group and 15.8% (148 of 936) in the switch group.
In the continuous group, the 6-month PIRA Kaplan-Meier cumulative event rate (KM-CER) remained low at 11.0%. The 6-month PIRA rate accounted for the majority of patients (72.3%; n = 86)—the core studies’ rate was 65.9%, and extension study rate was 92.9%. The 6-month relapse-associated worsening KM-CER was also low at 3.5%, accounting for only 25.2% of patients (30 of 119)—the core studies’ rate was 30.8%, and extension study rate was 7.1%.
Up to the 4-year mark, the overall mean percent brain volume change remained low, at –1.42% and –1.62% for the continuous and switch groups, respectively. Annual brain volume change for the continuous ofatumumab group remained low in the core (–0.34% per year) and extension studies (–0.28% per year). Among those in the switch group, the rate of change was –0.42% per year (core study) and –0.29% per year (extension study).
