Author Of 3 Presentations
LB1151 - Clinical outcomes in patients with COVID-19 infection during phase IV studies of cladribine tablets for treatment of multiple sclerosis (ID 947)
Abstract
Background
The COVID-19 pandemic has become a significant concern for patients (pts) with multiple sclerosis (MS) and their healthcare providers, prompting various guidelines on the appropriate use of disease-modifying drugs (DMDs) such as cladribine tablets.
Objectives
We report on clinical outcomes in pts who developed COVID-19 infection during two ongoing Phase IV studies of cladribine tablets (CLARIFY-MS [NCT03369665] and MAGNIFY-MS [NCT03364036]). Post-approval cases of COVID-19 infection are reported elsewhere.
Methods
CLARIFY-MS is investigating the impact of cladribine tablets on health-related quality of life in pts with highly active relapsing MS, while MAGNIFY-MS aims to determine the onset of action of cladribine tablets in such pts. Both studies utilize an open-label, single-arm, multicenter design, in which pts are treated with cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years). Some 680 pts are continuing in both studies. Cases of suspected COVID-19 infection were identified from adverse event reports and reviewed in terms of patient baseline characteristics, comorbidity, disease/treatment history (including most recent Extended Disability Status Scale [EDSS] score before COVID-19), and timing of cladribine tablets dosing/lymphocyte counts in relation to COVID-19 severity and outcomes.
Results
Three cases of suspected COVID-19 infection were identified (CLARIFY-MS, n=2; MAGNIFY-MS, n=1). Patient #1 (21-year history of MS; most recent EDSS score, 4.5; concomitant cardiovascular disease/asthma; prior DMD use) developed severe COVID-19 infection (confirmed) necessitating hospitalization but recovered and was discharged with residual cough/fatigue. Patient #2 (2-year history of MS; most recent EDSS score, 2; previous deep vein thrombosis during pregnancy; no prior DMDs) was also hospitalized for severe COVID-19 symptoms (not confirmed) but self-discharged and was recovering with chest tightness, fatigue, and neuropathic pain under self-isolation. The remaining patient (7-year history of MS; most recent EDSS score, 1; prior use of interferon β-1a) experienced mild symptoms of COVID-19 infection (confirmed); hospitalization was not required and the patient recovered under self-isolation. None of the pts required mechanical ventilation or died.
Conclusions
All 3 pts who developed COVID-19 infection during two ongoing Phase IV studies of cladribine tablets recovered or were recovering, and none required mechanical ventilation.
P0032 - Baseline serum Neurofilament light chain levels predict conversion to McDonald 2005 MS within 2 yrs of a first clinical demyelinating event in REFLEX (ID 1096)
Abstract
Background
Serum Neurofilament light chain (sNfL) is a biomarker of neuronal damage, reflecting disease activity, drug response, and is predictive of future disability in established multiple sclerosis (MS).
Objectives
Post hoc analysis to assess whether baseline (Month [M] 0) sNfL concentration can predict conversion to McDonald (McD) 2005 MS in patients (pts) with a first clinical demyelinating event (FCDE) receiving subcutaneous interferon β-1a (scIFNβ-1a) once (qw) or three (tiw) times weekly, or placebo (PBO) in the phase 3 trial REFLEX.
Methods
Pts randomized to scIFNβ-1a tiw (n=171) or qw (n=175), or PBO (n=171) were followed-up over 2 yrs; converters to 'clinically definite MS' switched to open label scIFNβ-1a tiw. High and low M0 sNfL subgroups were defined by median sNfL concentration (26.1 pg/ml at M0). Median (95% confidence intervals [CI]) time to McD MS (days) by treatment group and M0 sNfL subgroup was calculated by Kaplan Meier. Hazard ratios (HR; 95% CI) to determine factors influencing risk of conversion to McD MS were calculated using a univariate Cox’s proportional hazard model. A stepwise multivariate Cox’s proportional hazard model was performed using factors selected from the univariate model (threshold P<0.15). For both models, variable selection was based on a two-sided Wald test.
Results
High sNfL levels at baseline correlated with the likelihood for conversion to McD MS (low vs high M0 sNfL, HR [95% CI]: 0.58 [0.47; 0.72], P<0.001). Other baseline factors that reduced the risk of conversion to McD MS (univariate model) included: classification of FCDE (mono- vs multifocal: 0.68 [0.55; 0.83], P<0.001) and low numbers of MRI lesions (number of T2 lesions: 1.02 [1.02; 1.03], P<0.001; number of T1 gadolinium-enhancing [Gd+] lesions: 1.14 [1.11; 1.17], P<0.001; number of T1 hypointense lesions: 1.04 [1.02; 1.05]; P<0.001). Furthermore, treatment with scIFNβ-1a tiw (vs PBO: 0.53 [0.41; 0.69], P<0.001) or qw (0.71 [0.56; 0.91], P=0.006) reduced the risk of conversion to McD MS. These findings were confirmed by multivariate models for baseline sNfL subgroup (P=0.024), classification of FCDE (P<0.001), most baseline imaging findings (number of T2 lesions, number of T1 Gd+ lesions; (P≤0.001), and on-study treatment (both P<0.001).
Conclusions
Among other factors, baseline sNfL concentration was identified as a predictor of conversion to McD MS in patients with a FCDE.
P0382 - Reduction in CUA MRI lesions in the first 6 months of cladribine tablets treatment for highly active relapsing multiple sclerosis: MAGNIFY-MS study (ID 982)
Abstract
Background
The MAGNIFY-MS study (NCT03364036) aims to determine the onset of action of cladribine tablets 3.5 mg/kg over 2 years (CT3.5) in patients with relapsing multiple sclerosis (RMS). Efficacy data from the pivotal trial CLARITY showed that outcomes in CT3.5-treated patients were superior to placebo with regard to number and relative reduction of standardized combined unique active (CUA) lesions over the 96-week trial. Carrying out early and frequent magnetic resonance imaging (MRI) will provide valuable insights into the onset of action of CT3.5.
Objectives
To report on the onset of action of CT3.5 by observing changes in counts of CUA MRI lesions during the first 6 months of the MAGNIFY-MS study.
Methods
MRI scans were performed at screening, baseline, and at months 1, 2, 3 and 6 following CT3.5 treatment on patients with highly active RMS. Differences in CUA lesions between post-baseline periods (period 1, months 1–6, period 2, months 2–6, and period 3, months 3–6) were compared to the baseline period. CUA lesion count was standardized to period length and number of MRIs in a period. A mixed effects linear model was used to account for within pooled centre correlation and adjusted for CUA lesion count during the baseline period, age, and baseline expanded disability status scale (EDSS; >3, ≤3). Type-I-error inflation due to multiple testing was controlled by a gatekeeping procedure.
Results
The full analysis set considered for primary analysis included 270 patients. Reductions in mean CUA count were observed from month 1 onwards compared to baseline; by -1.193 in period 1, -1.500 in period 2 and -1.692 in period 3 (all p<0.0001). In particular, the mean T1 Gd+ lesion counts were decreased from month 2 onwards compared to baseline; by -0.857 at month 2, -1.355 at month 3 and -1.449 at month 6 (all p<0.0001). Sensitivity analysis using negative binomial distribution showed that the treatment effect increased with time measured as lack of CUA in subsequent periods; by 61% in period 1, 77% in period 2, and 87% in period 3 (all p<0.0001). The proportion of patients without any CUA lesions increased in the first 6 months; by 52% in period 1 (p=0.0241), 66% in period 2 (p<0.001), and 81% in period 3 (p<0.001).
Conclusions
MRI was used to assess disease activity in a group of highly active RMS on CT3.5 treatment from one month onwards. Data show an early onset of action on CUA lesions that was significant from month 1 versus baseline, with a treatment effect that increased over the first 6 months.
Presenter Of 1 Presentation
P0032 - Baseline serum Neurofilament light chain levels predict conversion to McDonald 2005 MS within 2 yrs of a first clinical demyelinating event in REFLEX (ID 1096)
Abstract
Background
Serum Neurofilament light chain (sNfL) is a biomarker of neuronal damage, reflecting disease activity, drug response, and is predictive of future disability in established multiple sclerosis (MS).
Objectives
Post hoc analysis to assess whether baseline (Month [M] 0) sNfL concentration can predict conversion to McDonald (McD) 2005 MS in patients (pts) with a first clinical demyelinating event (FCDE) receiving subcutaneous interferon β-1a (scIFNβ-1a) once (qw) or three (tiw) times weekly, or placebo (PBO) in the phase 3 trial REFLEX.
Methods
Pts randomized to scIFNβ-1a tiw (n=171) or qw (n=175), or PBO (n=171) were followed-up over 2 yrs; converters to 'clinically definite MS' switched to open label scIFNβ-1a tiw. High and low M0 sNfL subgroups were defined by median sNfL concentration (26.1 pg/ml at M0). Median (95% confidence intervals [CI]) time to McD MS (days) by treatment group and M0 sNfL subgroup was calculated by Kaplan Meier. Hazard ratios (HR; 95% CI) to determine factors influencing risk of conversion to McD MS were calculated using a univariate Cox’s proportional hazard model. A stepwise multivariate Cox’s proportional hazard model was performed using factors selected from the univariate model (threshold P<0.15). For both models, variable selection was based on a two-sided Wald test.
Results
High sNfL levels at baseline correlated with the likelihood for conversion to McD MS (low vs high M0 sNfL, HR [95% CI]: 0.58 [0.47; 0.72], P<0.001). Other baseline factors that reduced the risk of conversion to McD MS (univariate model) included: classification of FCDE (mono- vs multifocal: 0.68 [0.55; 0.83], P<0.001) and low numbers of MRI lesions (number of T2 lesions: 1.02 [1.02; 1.03], P<0.001; number of T1 gadolinium-enhancing [Gd+] lesions: 1.14 [1.11; 1.17], P<0.001; number of T1 hypointense lesions: 1.04 [1.02; 1.05]; P<0.001). Furthermore, treatment with scIFNβ-1a tiw (vs PBO: 0.53 [0.41; 0.69], P<0.001) or qw (0.71 [0.56; 0.91], P=0.006) reduced the risk of conversion to McD MS. These findings were confirmed by multivariate models for baseline sNfL subgroup (P=0.024), classification of FCDE (P<0.001), most baseline imaging findings (number of T2 lesions, number of T1 Gd+ lesions; (P≤0.001), and on-study treatment (both P<0.001).
Conclusions
Among other factors, baseline sNfL concentration was identified as a predictor of conversion to McD MS in patients with a FCDE.