Queen Mary University London
The Blizard Institute, Centre for Neuroscience, Surgery & Trauma

Author Of 2 Presentations

Clinical Trials Poster Presentation

P0196 - Cladribine to halt deterioration in people with advanced multiple sclerosis (ChariotMS) (ID 585)

Abstract

Background

Whilst the introduction of disease modifying treatments (DMTs) has transformed the management of people with early/relapsing MS (pwRMS), the use of DMTs in people with MS who are largely or completely wheel chair-dependent (EDSS>6.5) remains controversial. Evidence suggests that slowing or stopping disease deterioration is possible even past this arbitrary (loss of ambulatory function) threshold. Pathology and anecdotal clinical data support the hypothesis that even at an advanced stage of MS (AMS) inflammatory activity is a key driver of functional decline and that effective immunotherapy may halt this process. Cladribine tablets are a highly effective and central nervous system (CNS) penetrant DMT for people with highly-active RMS. It effectively depletes B cells, particularly memory B cells, a likely key mechanism of disease control in MS. Evidence, suggesting that (i) a significantly higher number of CNS axons supply upper compared to lower limb functions and (ii) longer axons are more vulnerable to the effects of focal inflammatory demyelination than shorter ones, corroborate our hypothesis that upper limb function can be protected even beyond EDSS=6.5.

Objectives

Primary Objective: To investigate whether cladribine tablets over 24 months is an effective DMT in people with AMS (pwAMS; EDSS=6.5-8.5) as measured using the 9-hole peg test (9HPT) peg speed.

Secondary Objectives: To establish whether there is a difference in pwAMS between treatment with cladribine tablets or placebo in (i) blood/serum biomarkers of inflammation (lymphocyte subsets) and/or neurodegeneration (neurofilament light chain), (ii) MRI loss of brain volume and spinal cord cross sectional area, (iii) T2 lesion burden, (iv) hypo-intense lesions on T1 weighted scans, (v) quality of life, and (vi) whether cladribine is a cost-effective treatment for pwAMS.

Methods

Randomised, double-blind, placebo-controlled phase IIb trial. To detect a 15% treatment effect in 9HPT peg speed with 90% power at 5% significance and 20% drop-out over 104 weeks n=200 pwAMS will be recruited across 20 UK MS centres.

Results

Protocol and ancillary documents have been submitted for ethics approval. So far 17 centres have agreed to recruit pwAMS for ChariotMS. Due to the COVID-19 pandemic start of recruitment has been deferred to 04 Jan 2021.

Conclusions

ChariotMS will be the first DMT-trial focussing on pwAMS. If successful, ChariotMS would expand the DMT landscape to include pwAMS and provide a platform for add-on therapies.

Collapse
Disease Modifying Therapies – Risk Management Poster Presentation

P0285 - Alemtuzumab depletion failure and neutralizing anti-drug antibodies: a case report and call for monitoring (ID 912)

Speakers
Presentation Number
P0285
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab is a monoclonal antibody that targets CD52 positive T-cells and B-cells, and is used to treat relapsing remitting multiple sclerosis. However, despite humanization and depletion of peripheral T and B cells, alemtuzumab generates the highest frequency of binding and neutralizing antibodies of all humanized antibodies currently in clinical use. In some individuals, antibody neutralization appears to be sufficiently severe to allow disease-breakthrough.

Objectives

The objective of this report is to highlight a need to re-evaluate how we approach and monitor anti-drug antibodies to alemtuzumab during treatment of patients with multiple sclerosis.

Methods

This is a presentation of a case report of a 40 year old woman with a history of MS who was started on alemtuzumab in June 2015.

Results

She had breakthrough disease activity in September 2018, so received her third cycle of alemtuzumab in December 2018. In July 2019 she developed right eye blurry vision and bilateral lower extremity weakness. MRIs demonstrated longitudinally extensive right optic neuritis, 17 enhancing lesions throughout the cerebral hemispheres, corpus callosum, and brainstem, five enhancing cervical cord lesions, and two enhancing thoracic cord lesions. Review of her records revealed that her lymphocytes did not deplete following the third cycle of alemtuzumab. A novel serum assay was performed which demonstrated a very high titer of binding and neutralizing alemtuzumab anti-drug antibodies (>7.7 x 105 Lux) compared to an untreated serum sample (1.22 x 104 Lux).

Conclusions

We concluded that her new lesions were secondary to her multiple sclerosis, unchecked as a result of alemtuzumab depletion failure. We are additionally concerned that depletion failure was secondary to the presence of alemtuzumab neutralizing antibodies. We propose that following lymphocyte counts in the months following treatment should be routine if not imperative, with the goal of monitoring for treatment failure. More pro-actively, it may be appropriate to evaluate for neutralizing antibodies before considering administration of third or fourth cycles of treatment.

Collapse