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.

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.

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.