Author Of 1 Presentation
LB01.02 - Phase 2 clinical trial evidence that a retinoid-X receptor agonist promotes remyelination in people with relapsing-remitting multiple sclerosis
Abstract
Background
Retinoid acid X receptor [RXR] gamma agonists promote oligodendrocyte progenitor cell differentiation and remyelination following experimental demyelination.
Objectives
To assess the safety and efficacy of bexarotene, a non-specific RXR agonist licensed for cutaneous T-cell lymphoma, as a remyelinating therapy in people with relapsing remitting multiple sclerosis.
Methods
In a double-blind, placebo-controlled, phase 2a trial (Cambridge Centre for Myelin Repair: CCMR-One), participants aged 18-50 years with relapsing remitting multiple sclerosis, stable on dimethyl fumarate for at least 6 months, were randomised to bexarotene 300mg/m2 or placebo for 6 months. The primary efficacy outcome was change in mean lesional magnetisation transfer ratio (MTR) for lesions whose baseline MTR was below the median lesional MTR for that patient. The secondary efficacy outcome was change in full-field visual evoked potential (VEP) latency in eyes with electrophysiological evidence of optic neuropathy (baseline latency >118ms). We analysed by intention to treat.
Results
52 patients were randomised 1:1 to receive six months of bexarotene or placebo. Two placebo patients withdrew before receiving study drug and one bexarotene patient withdrew consent during the trial. All bexarotene patients experienced adverse effects, notably central hypothyroidism (26 [100%]) and hypertriglyceridaemia (24 [92%, mean maximum of 6.79 mmol/L ,SD 4.4]; as well as rash (13 [50%]) and neutropenia (10 [38%]). Two discontinued placebo because of adverse events and five discontinued bexarotene because of rash [2], neutropenia, triglyceridaemia and mood disturbance. The primary efficacy outcome was negative (mean submedian lesion MTR change was 0.25pu in the bexarotene group versus 0.09pu in the placebo group, p=0.54), but in an exploratory, lesion-level analysis, though treatment difference in submedian lesions was too small to achieve significance, it was statistically significantly greater than in supermedian lesions (p=0·007). This suggests that bexarotene has a biological effect on MTR and that this effect is dependent on baseline lesional MTR. This interpretation is supported by the finding that bexarotene treatment reduced full field visual evoked potential latency compared to placebo in the 52 eyes with delayed VEPS at baseline, by 4·66 ms/eye (95% CI -8·38 -0·93; p=0·014) and in all eyes, by a per-protocol analysis, by 4.02ms/eye (P=0.015).
Conclusions
Despite a negative primary efficacy outcome, evidence from both magnetisation transfer ratio imaging and visual evoked potentials suggest that a retinoic X receptor agonist, bexarotene, promotes remyelination in people with multiple sclerosis. We have also a heterogeneous response of MS lesions to a drug promoting remyelination. Although bexarotene’s safety profile precludes its widespread use, these data support efforts to develop a selective RXR-gamma agonist.
Author Of 1 Presentation
P0850 - Cladribine personalised dosing to treat multiple sclerosis: observations in 208 patients (ID 1521)
Abstract
Background
Oral cladribine (Mavenclad®) was approved as a disease-modifying treatment (DMT) for highly active relapsing multiple sclerosis (RMS) in August 2017. We have treated a large cohort of people with MS (pwMS) using a personalised dosing schedule of subcutaneous cladribine (Litak®) (CPD) since 2014.
Objectives
To report safety and efficacy of cladribine personalised dosing (CPD) as an immunotherapy in people with multiple sclerosis.
Methods
CPD was offered to pwMS irrespective of their disease course, provided they had MRI-detectable inflammatory activity (gadolinium-enhancing T1 and/or more T2 lesions over past ≤2 years) or an elevated neurofilament light chain (NfL) level in their cerebrospinal fluid (CSF). Litak® 10 mg was given on three consecutive days (four in pwMS >90kg) during week 1. Based on total lymphocyte count at week 4, patients were given another 0-3 doses at week 5. A second cycle of CPD was administered 11 months later. Follow-up included recording of adverse events and relapses, annual EDSS, 9-hole-peg, Timed-25-foot-walking, Symbol-Digit-Modalities tests, and full blood counts. Proportions of pwMS with no evidence of disease activity (NEDA), and of progression or active disease (NEPAD), were calculated where complete clinical datasets were available.
Results
208 pwMS (100 relapsing, 108 progressive) underwent CPD. 192/208 received a second treatment cycle. Baseline age 44 (17-72) years, EDSS 0-8.5. Tolerability was very good. One myocardial infarction and one breast cancer occurred. Two severely disabled pwMS died (one influenza, one encephalitis). 12/208 had transient skin reactions. Lymphopenia ≥ grade 3 was detected in <3%. At 2 years, 66% (95% CI 49%, 80%) of pwRMS (total n=38) had NEDA and 62% (95% CI 32%, 86%) of pwPMS (total n=13) NEPAD. Of 23 pwMS with elevated baseline CSF-NfL, 22 had normal levels at follow-up. Median CSF-NfL levels were 652 pg/mL (IQR 458-1063) and 344 pg/mL (IQR 186-505) at baseline and follow-up, respectively.
Conclusions
CPD is a promising and well-tolerated alternative for pwMS not eligible for licensed DMTs. Efficacy in pwRMS was similar to controlled trial data. NEPAD rates in the proportion of pwPMS with full datasets was promising, underpinning the rationale of multi-centre, placebo-controlled trial ChariotMS (Oral cladribine to halt deterioration in people with advanced MS; n=200), starting recruitment of pwMS with EDSS 6.5-8.5 from January 2021.