Last week I wrote a post about how pharma may report on the next Cladrimod (cladribine or ozanimod/posenimod) study in “Dr Dooley will be happy that their uncited work from 2016 has been repeated….MS drugs affect memory B cells!”. In that post I made a prediction on how the lymphocyte subset data would be reported from the next MS drug so that the potential for memory B cell depletion would be lost in a sea of T cell stuff. Little did I realise that this was to surface so quickly. So was I disappointed?
In my prediction…..No, in the result…..Yep absolutely
The next study it turns out is with ozanimod. This is a sphingosine-1 phosphate modulator that is similar to siponimod and a bit like fingolimod where we know what happens to the the lymphocyte subsets. It reduces the numbers of central memory and naive T cells and has more of a limited effect on the effector memory T cell populations. This later population is usually the dominant cells in the CNS of MS. There is a marked inhibition of memory B cells…but this has not registed and so what happened with ozanimod?
There is a depletion of T cells and B cells notably with the higher dose
Then the subsets and central memory CD4 and CD8 T cells drop and effector memory T cells drop abit in the CD4 compartment and not in the CD8 compartment…But remember this is the major subset of T cells in the CNS during MS
Next T regulatory cells, which we are told control the autoimmune reactions and what happens yep you guessed it….they do down in number not up. However TH17s drop, so it this the key?
Then what’s next? The B cells subsets? Whats’ done….Nothing!!!!…It’s behind you!!!!, So do we have any idea how ozanimod may really work?…It’s a decrease in Th17 …should we say Yawn?. Now the study apparently was started in 2016 and maybe the authors hadn’t heard of memory B cells, but I will bet that they are depleted. This is an opportunity missed. We will just have to wait…so an easy explanation goes begging I suspect.
I can see the T cell marketing video already…..an orange juice moment
Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS.Harris S, Tran JQ, Southworth H, Spencer CM, Cree BAC, Zamvil SS.Neurol Neuroimmunol Neuroinflamm. 2020 Jul 31;7(5):e839. doi: 10.1212/NXI.0000000000000839. Print 2020 Sep.PMID: 32737072OBJECTIVE: To better understand ozanimod’s mechanism of action (MOA), we conducted exploratory analyses from a phase 1 study to characterize ozanimod’s effect on circulating leukocyte subsets in patients with relapsing multiplesclerosis. …
Objective: To better understand ozanimod’s mechanism of action (MOA), we conducted exploratory analyses from a phase 1 study to characterize ozanimod’s effect on circulating leukocyte subsets in patients with relapsing multiple sclerosis.
Methods: An open-label pharmacodynamic study randomized patients to oral ozanimod hydrochloride (HCl) 0.5 (n = 13) or 1 mg/d (n = 11) for ∼12 weeks (including 7-day dose escalation). Circulating leukocyte subsets were quantified using flow cytometry (days 28, 56, and 85) and epigenetic cell counting (days 2, 5, 28, 56, and 85) and compared with baseline (day 1) using descriptive statistics.
Results: Ozanimod caused dose-dependent reductions in absolute lymphocyte counts. Observed by both methodologies, circulating CD19+ B- and CD3+ T-cell counts were reduced by >50% with ozanimod HCl 0.5 mg and >75% with 1 mg at day 85. Based on flow cytometry, ozanimod HCl 1 mg showed greater decreases in CD4+ than CD8+ T cells, greater decreases in both CD4+ and CD8+ central memory vs effector memory T cells, and reductions in mean CD4+ and CD8+ naive T cells by ≥90% at day 85. In the flow cytometry analysis, changes in monocytes, natural killer, and natural killer T cells were minimal. Using epigenetic cell counting, greater reductions for Th17 than T regulatory cells were determined.
Conclusion: Ozanimod induced dose-dependent reductions in circulating B- and T-cell counts and differential effects on naive and memory CD4+ and CD8+ T cells and CD19+ B cells. Data characterized with both a novel epigenetic cell-counting method and flow cytometry support ozanimod’s MOA.
COI: No relevant