Cladribine, is cladribine, is cladribine

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News from the European Academy of Neurology 2019. Our data is reproducible and oral cladribine does what we said it does.

EPO1241 Changes in Lymphocyte subpopulations in Highly Active Multiple Sclerosis patients during Cladribine treatment.M. Ruggieri, C. Gargano, A. Iaffaldano, A. Manni, P. Iaffaldano, D. Paolicelli, M. Trojano; Bari/IT

Background and aims: Background: Cladribine tablets 3.5mg/kg is the first short-course oral disease-modifying drug approved for Highly Active Relapsing Multiple Sclerosis (HA-RMS). Immunophenotyping studies show that Cladribine depletes lymphocyte subsets (LS) in vivo with a predilection for B cells, but these effects are not fully understood.

Aim: We investigated in vivo Cladribine effects on memory B cells (Bmem), regulatory B cells (Bregs) and regulatory T cells (Tregs) in blood-samples.

Methods: Nine HA-RMS patients started Cladribine (Early Sales Program) from July 2018. Blood samples were collected at the beginning of treatment (W0) and after 8 (W8), 24, 48 weeks and were analysed by flow cytometry. Wilcoxon signed-rank test was used to comparison continuous variables between W0 and W8.Results:

Results: Six of the nine patients in the study (mean age: 37.3±9.1; disease duration: 8.4 (6.2-29.7) years) had complete data at W8. After 2 months we observed a statistically significant decrease of 79% in Bmem CD19+CD27+ (W0:3.29±0.77 vs W8:0.69±0.3, p=0.028), 56.9% in Bregs CD19+CD38+ (W0:3.94±1.9 vs W8:1.7±2.03, p=0.028) and 74.9% in Bregs CD19+CD25+ (W0:1.99±0.74 vs W8:0.5±0.56, p=0.028). Furthermore, we observed an increasing of 16% in Tregs CD4+CD25+ at W8 (p=0.075).Conclusion:

Conclusions: Our results supported the hypothesis that the main effect of Cladribine seems to be the selective depletion of B lymphocytes especially Bmem. Moreover, Cladribine could help to restore immunotolerance by increasing Tregs in the early phase of treatment. Further studies with longer follow-up will be necessary to confirm these findings and to define the role of LS as biomarkers of treatment efficacy and safety.

The active ingredient of oral cladribine is cladribine and we have shown that subcutaneous cladribine depletes B cell subsets and that depletion of memory B cells persist. Here B regulatory cells are CD19+, CD38+. However this subset includes immmature and mature B cells. They are called B regulatory cells because they produce interleukin 10. However, I say again interleukin 10 is a B cell growth and differentiation factor . Also whilst T regulatory cells are CD25+ (interleuki 2+), the dominant CD25+ expressing cells are memory B cells. They observed no efffect on T regulatory cells..yes p=0.075 is no statistically significant difference. We know from data already studied, there is an actual decrease in the absoluret number of regulatory cells, but this is when you work on absolute numbers

It seems the T cellers are so desparate the show that cladribine increases T regs. However, I would point out there was data published over 2 years ago that this happens to a T reg subset…The authors of that work seem to have been too busy swaning around on the company coat-tails, presenting corporate posters, to publish this. Snooze and you loose..once the first paper comes out…the story is old ha,t no matter if you show the same answer using bigger groups.

Wonder what Merck has found?

After all they seem to be doing a phenotyping study in 300 people according to stuff they published over a year ago at the British Neurology Association 2018.

The magnify-ms study: mavenclad® tablets in active rms N de Stefano,  A Achiron, F Barkhof, A Chan, T Derfuss,  S Hodgkinson, L Leocani, X Montalban, A Prat, K Schmierer, F Sellebjerg, P Vermersch, H Wiendl, B Keller, S Roy 

Background Cladribine tablets (CT) improve clinical and MRI outcomes in patients with active RMS, with significant differences versus placebo after 24 weeks.

Objective Describe the design of a study to assess the onset of CT’s clinical and MRI effects in patients with active RMS.

Methods MAGNIFY-MS is a 2 year prospective Phase IV trial (including approximately 100 centres in Europe). Eligible patients will receive two years treatment with CT 3.5 mg/kg cumulative dose. Frequent MRI assessments (including lesion count, lesion volume, brain volume and MTR) will be performed at screening, baseline and 1, 2, 3, 6, 12, 15, 18 and 24 months. Various T- and B-cell subtype counts and functional profiling (eg cytokine production) will be assessed. Clinical outcomes will include changes in cognition (SDMT), disability (EDSS/KFS, 9HPT, T25FW), relapses, NEDA, NEDAP and safety at timepoints up to 24 months.

Results Aim recruit 300 patients. Primary endpoint: change in the count of combined unique active lesions at end of 6 months versus baseline. Final outcomes expected in 2021.

Conclusions MAGNIFY-MS will provide important information on the effects of CT, including early MRI changes, insights into effects on a range of disability and cognition markers, and detailed characterization of immune cell reconstitution.

Maybe they will wait until the trial ends in 2021 and the B memory story has been published umpteen times by then…Must ask to find out. But remember Snooze you lose

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