Long-term Ofatumumab Treatment Shows Freedom From Disease Progression, Favors Earlier Initiation

Article

The data, from the phase 3 ASCLEPIOS I and II trials and ALITHIOS open-label extension, suggest that most patients remained free from disease progression, with most progression being independent of relapse activity.

Jeffrey A. Cohen, MD, a neurologist in the Mellen Center for Multiple Sclerosis Treatment and Research at Cleveland Clinic

Jeffrey A. Cohen, MD

Long-term data from the phase 3 ASCLEPIOS I and II (NCT02792218; NCT02792231) and ongoing ALITHIOS open-label extension studies (NCT03650114) suggest that better outcomes in patients with multiple sclerosis (MS) are achieved with ofatumumab (Kesimpta; Novartis) favor earlier treatment initiation with the therapy.1

All told, among those treated with the disease-modifying therapy (DMT) for up to 4 years in the clinical programs, progression independent of relapse activity (PIRA) was the predominately occurring disease progression, though the study authors noted that low rates of confirmed disability worsening (CDW) and PIRA “indicated that most patients remained free from disease progression.” Additionally, the annual rate of brain volume change remained low over the course of the study.

The results were presented at the 2023 American Academy of Neurology (AAN) Annual Meeting, April 22-27, in Boston, Massachusetts, by Jeffrey A. Cohen, MD, a neurologist in the Mellen Center for Multiple Sclerosis Treatment and Research at Cleveland Clinic, in Ohio. The goal of the study, Cohen et al wrote, was to assess the aforementioned outcomes—as well as relapse-associated worsening—in patients with relapsing MS for up to 5 years.

“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.

The ASCLEPIOS I/II trials included 1882 patients who were randomly assigned to either ofatumumab (n = 946) or teriflunomide (Aubagio; Sanofi) (n = 936), of whom 1367 entered the long-term ALITHIOS extension study (continuous ofatumumab, n = 690; switch to ofatumumab, n = 677). 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.

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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 (week 240), 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).

These data add to the existing supporting data for ofatumumab compared with teriflunomide, such as the analyses published in Multiple Sclerosis in September 2022 by Ludwig Kappos, MD, professor of neurology, University of Basel, et al.2 In those data, annualized relapse rate (ARR) and CDW rate were superior for ofatumumab among patients with recently diagnosed, treatment naïve (RDTN) MS.

Of the 1882 participants randomly assigned to treatment in the original ASLCEPIOS trials, 615 (32.7%) were RDTN (ofatumumab, n = 314; teriflunomide, n = 301), with a range of 0.1 to 2.9 years from diagnosis for both groups. As the authors anticipated, RDTN participants in both groups were younger, with lower disability scores and lower T2 lesion volume at the time of the analysis compared with the overall ASCLEPIOS population. All told, 90% of participants were treated with either drug for at least 1 year, and 25% had received treatment for more than 2 years.

All told, those treated with the B-cell targeting agent had an ARR of 0.09, representing a 50% greater reduction than those on teriflunomide (rate ratio [RR], 0.50; 95% CI, 0.33-0.74; P <.001). Additionally, ofatumumab reduced the risk of 3-month CDW numerically by 38% (HR, 0.62; 95% CI, 0.37-1.03; P = .065) and of 6-month CDW by 46% (HR, 0.54; 95% CI, 0.30-0.98; P = .044) relative to teriflunomide.2

Kappos and colleagues concluded that “these findings are consistent with those observed in the overall ASCLEPIOS population and show that ofatumumab can delay disability worsening in early MS.” They added that these data continue to support the use of ofatumumab as a first-line treatment for this patient population.

Last fall, at the 2022 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, held October 26-28, in Amsterdam, Netherlands, Cohen presented a late breaker presentation on the comparison of clinical and MRI outcomes in patients who initiated ofatumumab in the ASCLEPIOS trial versus those who switched from teriflunomide in the ALITHIOS open label extension study (NCT03650114).3 He spoke with NeurologyLive® shortly thereafter, noting that, “there was very consistent benefit of ofatumumab as compared to teriflunomide in all the various subgroups: people that had varying numbers of prior DMTs—irrespective of which DMT they were on before the trial—and younger and older participants. And that benefit was maintained in the participants who had originally been on ofatumumab in the core trial and then continued on it in the extension.”

Check out the video below to hear more from Cohen on the data presented at ECTRIMS 2022.

Click here for more coverage of AAN 2023.

REFERENCES
1. Cohen J, Hauser S, Zielman R, et al. Effect of Longer-term Ofatumumab Treatment on Disability Progression and Brain Volume Change. Presented at: AAN Annual Meeting; April 22-27, 2023; Boston, MA and Virtual. Neurology. doi:10.1212/WNL.0000000000202543
2. Gartner J, Hauser SL, Bar-Or A, et al. Efficacy and safety of ofatumumab in recently diagnosed, treatment-naïve patients with multiple sclerosis: results from ASCLEPIOS I and II. Mult Scler. 2022;28(10)L1562-1575. doi:10.1177/13524585221078825
3. Cohen J, Gold R, de Sèze et al. Efficacy of Early Ofatumumab versus Late-Switch from Teriflunomide: Subgroup Analysis of the ALITHIOS Open-Label Extension Study by Prior Disease Modifying Therapy Exposure and Age. Presented at: 2022 ECTRIMS Congress; October 26-28; Amsterdam, Netherlands. Abstract 1210
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