Allan G Kermode

Objectives
To characterize the use of ofatumumab (OFA), a fully human self-administered anti-CD20 monoclonal antibody, in a real-world setting in Australia by assessing the profile of relapsing multiple sclerosis (RMS) patients initiating OFA through an evaluation of patient demographics, background MS disease characteristics and prior therapy history as recorded in MSBase.

Methods
This is a retrospective secondary use of MSBase Registry data study, describing the baseline characteristics of RMS patients in Australia initiated on OFA treatment, including demographics, disease duration, expanded disability status scale (EDSS), treatment history with disease-modifying therapies (DMTs) prior to commencing OFA and proportion of naïve patients initiating ofatumumab relative to patients having received a prior DMT.

Results
As of 1st January 2024, MSBase has included 320 eligible patients initiated on OFA, with 22.2% treatment naïve, 30.9% switching from ocrelizumab, 14.7% switching from natalizumab, 3.1% from alemtuzumab and 27.7% from oral DMTs. The reasons for switching DMT to OFA included scheduled stop (13.1%), evidence of disease activity (9.1%), convenience (6.9%), side effects/intolerance (6.2%), JCV antibody positive (2.8%), pregnancy planned/confirmed (2.5%) and not reported (37.2%). The median age of patients initiating OFA was 42.67 [36.65, 51.98] years, with a median disease duration of 9.19 [3.61, 17.11] years and median EDSS of 2 [1.5, 3.5].

Conclusion
The real-world data from this secondary use of data MSBase registry analysis provides a valuable snapshot of the Australian experience of relapsing MS patients initiated on OFA, with 22% of patients treated as first line therapy.

Background
COVID-19 vaccination-induced Spike antibodies are attenuated in people living with multiple sclerosis (pwMS) on high-efficacy disease-modifying therapies (DMTs). It is currently unknown whether vaccine boosters will elicit a greater protective antibody cross-reactivity against emerging variants of concern, such as XBB.1 and BQ.1.1.

Objective
We aimed to determine the breadth of Spike antibody immunoreactivity in pwMS after COVID-19 vaccination.

Methods Spike antibodies to Wuhan, XBB.1, and BQ1.1 SARS-CoV-2 were assessed in paired sera from pwMS (1-month post-second and -third doses, n=37) and general community controls (n=10). Demographic and treatment information was available in all patients.

Results
At 1-month post-third dose, pwMS who did not seroconvert (n=12) were treated with ocrelizumab (11/21) and fingolimod (1/3). Natalizumab, fingolimod, ocrelizumab, dimethyl fumarate, and ofatumumab were associated with decreased titers of Spike antibody compared to controls, whereas alemtuzumab, cladribine, and IFNs were associated to titers comparable to controls. When serial Wuhan Spike antibody titers were compared at 1-month post-second and -third doses, most DMTs (alemtuzumab, fingolimod, cladribine, dimethyl fumarate, interferon-beta, natalizumab, ocrelizumab, and ofatumumab) were able to increase or maintain their Spike antibody titers. Spike antibody titers against XBB.1 and BQ1.1 was reduced by 80% compared to the Wuhan titers in all groups. The third dose increased median titres compared to the second dose in most DMTs including the CD20-depleting DMTs but to a much lesser extent (ocrelizumab n=10; ofatumumab n=2).

Conclusion
Some SARS-CoV-2 variants and some DMTs reduce Spike antibody titres or prevent seroconversion even after a third dose of vaccine.

Objective:
Using global MSBase registry, this study establishes 6-month confirmed disability progression events as indicators of long-term disability worsening suitable for use in randomized clinical trials in multiple sclerosis (MS).

Background:
Randomized clinical trials evaluate short-term treatment effect on disability in the form of 3–6-month confirmed disability progression, but whether these translate into long-term disability outcomes is unknown.

Design/Methods:
A Cox proportional hazards model identified associations between patients’ demographic and clinical characteristics and the probability of recovery from disability progression events. The coefficients from this model were used to calculate a sustained progression score, which was evaluated in a validation cohort and applied to a trial cohort.

Results:
902 patients (development cohort), patient characteristics at the time of progression associated with lower probability of subsequent improvement were age (hazard ratio (HR)=0.98), primary progressive (HR=0.37) and progressive-relapsing (HR=0.36) MS, expanded disability status scale score >=6 (HR=0.71) and its change from baseline (HR=0.67), number of affected functional system scores (HR=0.92) and pyramidal (HR=0.79) functional system score (p<0.05). The strength of the association with pyramidal score decreased with time (HR=1.01). A relapse within previous month (HR=1.46) and worsening in sensory functional system score (HR=1.17) were associated with higher probability of improvement after progression. The sustained progression score (range 0.39–4.79) in the validation cohort with 1,271 progression events, estimated a 53% lower chance of improvement for each unit increase in the score (HR=0.47). The proportions of progression events sustained at 5 years stratified by the score were 1: 68%, 2: 79%, 3: 94%, 4: 100%. The progression scores were then applied to the CLARITY trial data.

Conclusions:
Estimate of the probability of disability progression events being sustained over the long term will enable future trials to establish the effect of therapy not only on the short-term but also on long-term disability accrual.