University of Cambridge School of Medicine
Neurosciences

Author Of 3 Presentations

Disease Modifying Therapies – Risk Management Oral Presentation

FC02.01 - Safety of Alemtuzumab Over 9 Years in Patients With Non-MS Autoimmunity

Speakers
Presentation Number
FC02.01
Presentation Topic
Disease Modifying Therapies – Risk Management
Lecture Time
13:00 - 13:12

Abstract

Background

Alemtuzumab is an anti-CD52 monoclonal antibody therapy approved for treating RRMS. Although alemtuzumab is associated with non–MS-related secondary autoimmune events, the role pre-existing non-MS autoimmunity plays in secondary autoimmunity is unclear.

Objectives

To assess the impact of 1) pre-existing non-MS autoimmunity and 2) post-alemtuzumab thyroid autoimmunity on subsequent onset of new autoimmunity up to 9 years after initiating alemtuzumab.

Methods

In clinical trials (NCT00050778, NCT00530348, NCT00548405, NCT00930553, NCT02255656), patients were monitored for autoimmune adverse events (AEs). All patient- and investigator-reported AEs were recorded. An autoimmune event was pre-existing if it occurred prior to initiating alemtuzumab or was in the medical history database.

Results

A total of 1216 patients from the alemtuzumab clinical development program who received alemtuzumab 12 mg were included in the analysis. Ninety-six had pre-existing non-MS autoimmunity. Up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) pre-existing autoimmunity; similar percentages of patients with versus without pre-existing autoimmunity had ≥2 new autoimmune events (5.2% vs 8.2%, respectively). Most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab. Treatment-emergent thyroid autoimmunity after alemtuzumab Course 1 was not associated with subsequent nonthyroid autoimmunity after Course 2 (0% of patients with vs 3.0% of patients without thyroid autoimmunity after Course 1). Similarly, thyroid autoimmunity after Course 2 did not predict nonthyroid autoimmunity after Course 3 (1.8% vs 2.0%, respectively). Among 25,292 patients treated with alemtuzumab in the postmarketing setting as of 31 March 2019, additional events (occurring 18–36 months post treatment) included autoimmune hepatitis (10.7 in 10,000) and hemophagocytic lymphohistiocytosis (2.7 in 10,000).

Conclusions

Over 9 years after alemtuzumab initiation, pre-existing non-MS autoimmunity was not associated with subsequent new autoimmune disease. Emergence of thyroid autoimmunity after Courses 1 and 2 does not appear to predict subsequent serious autoimmune disease.

STUDY SUPPORT: Sanofi and Bayer HealthCare Pharmaceuticals.

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Clinical Trials Late Breaking Abstracts

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.

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COVID-19 Late Breaking Abstracts

SS02.01 - COVID-19 in people with MS: A large community-based study of the UK MS Register

Speakers
Presentation Number
SS02.01
Presentation Topic
COVID-19
Lecture Time
10:45 - 10:57

Abstract

Background

The Coronavirus Disease 2019 (COVID-19) pandemic has introduced uncertainties into the multiple sclerosis (MS) community and the focus so far has been the severity of infection among people with MS (pwMS) who have COVID-19. This approach has left questions about the risk of contracting disease in pwMS unanswered which has implications as society gradually returns to normal.

Objectives

To evaluate the trend of COVID-19 incidence in pwMS, their behaviour in response to the outbreak, and the effect of their demographic and clinical characteristics on the likelihood of contracting COVID-19.

Methods

The United Kingdom MS Register (UKMSR) has been collecting demographic and MS related data since 2011 from pwMS all over the UK. On 17 March 2020, existing participants of the UKMSR were asked to join the COVID-19 study. The study was also advertised through social media. In this on-going study, pwMS answer a COVID-19 related survey at participation and a different follow-up survey every two weeks depending on whether they report COVID-19.

Results

We estimate the nationwide overall incidence of COVID-19 in pwMS as 10% (n=522) among 5237 participants until 24 June 2020. The weekly incidence peaked during the 2nd week after lockdown started on 23 March 2020 (13.2%) and remained high until it dropped to 3.5% in the 10th week. The mean (standard deviation) age of the study population was 52.4 (11.9), 76.1% (n=3985) were female, and 95.7% (n=5012) were of white ethnicity. PwMS with a higher web-based Expanded Disability Status Scale (EDSS) score are more likely to self-isolate (odds ratio [OR] 1.389, 95%CI [confidence interval] 1.333−1.447). PwMS who are taking disease modifying therapies (DMTs) and those with progressive MS tend to self-isolate more (OR 1.259, 95%CI 1.059−1.497 and OR 1.245, 95% CI 1.013−1.531, respectively). Older age, progressive MS, and white ethnicity were associated with a lower likelihood of having COVID-19 (OR 0.969, 95%CI 0.957−0.982 and OR 0.595, 95% 0.422−0.838 and OR 0.495, 95%CI 0.347−0.705, respectively). Gender, EDSS, MS Impact Scale version 29 scores and DMTs did not alter the likelihood of contracting COVID-19.

Conclusions

To our knowledge, this is the largest community-based study of COVID-19 in pwMS worldwide. The trend of COVID-19 in pwMS is comparable to that of the UK general population. During a period with strict physical distancing measures, pwMS are not at an increased risk of contracting COVID-19.

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Presenter Of 1 Presentation

Disease Modifying Therapies – Risk Management Oral Presentation

FC02.01 - Safety of Alemtuzumab Over 9 Years in Patients With Non-MS Autoimmunity

Speakers
Presentation Number
FC02.01
Presentation Topic
Disease Modifying Therapies – Risk Management
Lecture Time
13:00 - 13:12

Abstract

Background

Alemtuzumab is an anti-CD52 monoclonal antibody therapy approved for treating RRMS. Although alemtuzumab is associated with non–MS-related secondary autoimmune events, the role pre-existing non-MS autoimmunity plays in secondary autoimmunity is unclear.

Objectives

To assess the impact of 1) pre-existing non-MS autoimmunity and 2) post-alemtuzumab thyroid autoimmunity on subsequent onset of new autoimmunity up to 9 years after initiating alemtuzumab.

Methods

In clinical trials (NCT00050778, NCT00530348, NCT00548405, NCT00930553, NCT02255656), patients were monitored for autoimmune adverse events (AEs). All patient- and investigator-reported AEs were recorded. An autoimmune event was pre-existing if it occurred prior to initiating alemtuzumab or was in the medical history database.

Results

A total of 1216 patients from the alemtuzumab clinical development program who received alemtuzumab 12 mg were included in the analysis. Ninety-six had pre-existing non-MS autoimmunity. Up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) pre-existing autoimmunity; similar percentages of patients with versus without pre-existing autoimmunity had ≥2 new autoimmune events (5.2% vs 8.2%, respectively). Most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab. Treatment-emergent thyroid autoimmunity after alemtuzumab Course 1 was not associated with subsequent nonthyroid autoimmunity after Course 2 (0% of patients with vs 3.0% of patients without thyroid autoimmunity after Course 1). Similarly, thyroid autoimmunity after Course 2 did not predict nonthyroid autoimmunity after Course 3 (1.8% vs 2.0%, respectively). Among 25,292 patients treated with alemtuzumab in the postmarketing setting as of 31 March 2019, additional events (occurring 18–36 months post treatment) included autoimmune hepatitis (10.7 in 10,000) and hemophagocytic lymphohistiocytosis (2.7 in 10,000).

Conclusions

Over 9 years after alemtuzumab initiation, pre-existing non-MS autoimmunity was not associated with subsequent new autoimmune disease. Emergence of thyroid autoimmunity after Courses 1 and 2 does not appear to predict subsequent serious autoimmune disease.

STUDY SUPPORT: Sanofi and Bayer HealthCare Pharmaceuticals.

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Author Of 1 Presentation

Patient-Reported Outcomes and Quality of Life Poster Presentation

LB1176 - Anxiety affects the general well-being of people with MS during the COVID-19 pandemic more than the infection itself (ID 1893)

Speakers
Presentation Number
LB1176
Presentation Topic
Patient-Reported Outcomes and Quality of Life

Abstract

Background

Anxiety and depression are more common in people with multiple sclerosis (pwMS) compared to people without MS. The unpredictable nature of the COVID-19 pandemic has caused widespread distress, but it is unknown if it would affect pwMS disproportionately.

Objectives

To evaluate the impact of the COVID-19 pandemic on the mood and well-being of pwMS in the UK and compare it to that of controls.

Methods

The UK MS Register has been collecting Hospital Anxiety and Depression Scale (HADS) data of pwMS since 2011. In the mood and well-being UKMSR COVID-19 study, we asked pwMS (n=5240) and controls (n=376) to answer questions on General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9) for depression and Revised Impact of Event Scale (IES-R) for post-traumatic stress disorder (PTSD) in addition to changes in their lifestyle and well-being during the COVID-19 outbreak.

Results

The HADS score of pwMS (n=2225) during the COVID-19 outbreak had not changed compared to the year before (mean difference 0.004, 95%CI -0.11−0.12, p=0.952 for anxiety and mean difference 0.05, 95%CI -0.05−0.15, p=0.283 for depression). The rate of anxiety (GAD-7>5) in male pwMS (37.2%) was more than controls (24.3%) (p=0.032) but was similar in female pwMS and controls. More male pwMS had moderate to severe depression (PHQ-9>9) compared to controls (28.5.4% vs 12.2%, p=0.003), but again, the rate was similar in females. More pwMS who had COVID-19, experienced anxiety or PTSD (IES-R>32) compared to those without the infection (54% vs 44%, p=0.018; 30.5% vs 22.5%, p=0.024, respectively). The rate of depression was similar in pwMS with or without symptoms of the disease. Anxiety, compared to the actual infection, was more strongly associated with subjective worsening of general health (57.1% vs 37.3%, with anxiety or COVID-19 respectively, p=0.008) or MS symptoms (61% vs 31.3%, p<0.001).

A high proportion of both pwMS and controls did not experience any change in the quality of their relationships. However, more pwMS reported worsening of their relationships compared to controls (21.4% vs 16.7%, p<0.001). The change in loneliness was similar between the two groups with 4 in 10 pwMS and controls feeling lonelier during the outbreak.

Conclusions

Anxiety during the COVID-19 pandemic is having a more profound effect on the general well-being of most patients compared to the infection itself.

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