Teriflunomide is not a high efficacy agent…predicted by B cells

We have been suggesting that the activity of drugs relate to their capacity to deplete memory B cells. 

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K.
Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017;16:41-50.

A student looking at table 1, said what happened to teriflunomide?

I don’t know why I missed it.

If we look to the arthritis data, where leflunomide is a licenced drug we can see that memory B cells are depleted

McComish J, Mundy J, Sullivan T, Proudman SM, Hissaria P.
Changes in peripheral blood B cell subsets at diagnosis and after treatment with disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis: correlation with clinical and laboratory parameters. Int J Rheum Dis. 2015;18(4):421-32.
“In patients requiring leflunomide, total memory B cells, IgM memory B cells, non-switched memory B cells and absolute numbers of switched memory B cells were reduced”

Teriflunomide is the active metabolite of leflunomide, so teriflunomide must delete memory B cells

so what about teriflunomide in MS?

Gandoglia I, Ivaldi F, Laroni A, Benvenuto F, Solaro C, Mancardi G, Kerlero de Rosbo N, Uccelli A. Teriflunomide treatment reduces B cells in patients with MS.Neurol Neuroimmunol Neuroinflamm. 2017; 4(6):e403.

Ha Ha you say there is no difference in memory B cell (B Mem) numbers, so our idea is shot down in flames?

However I say…Ho Ho because we need to look at the absolute numbers of cells not the percentage of cells within the B cell pool and whilst there is no change in the proportions of memory B cells after teriflunomide treatment, there is a decrease (40-50%) in the absolute number of B cells

Therefore the absolute numbers of  memory B cells drop by 40-50%.

Phew a narrow squiek, but the drop in B cells is not in the same league as cladribine and alemtuzumab (80-90%) , so this would suggest teriflunomide would be a low efficacy drug.

However we know this already, but it is good to have the idea of hierachical efficacy of drugs relating to depletion capacity confirmed.

Demonstrating this with cladribine was another excellent example 

Ceronie B, Jacobs BM, Baker D, Dubuisson N, Mao Z, Ammoscato F, Lock H, Longhurst HJ, Giovannoni G, Schmierer K. Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells. J Neurol. 2018; 265:1199-1209.

So what happenes when you switch from a CRAB to teri or dimethyl fumarate?

Ontaneda D, Nicholas J, Carraro M, Zhou J, Hou Q, Babb J, Riester K, Mendoza JP, Livingston T, Jhaveri M. Comparative effectiveness of dimethyl fumarate versus fingolimod and teriflunomide among MS patients switching from first-generation platform therapies in the US. Mult Scler Relat Disord. 2018 Oct 10;27:101-111. doi: 10.1016/j.msard.2018.09.038. [Epub ahead of print

BACKGROUND: Previous real-world comparative research of MS disease modifying therapies (DMTs) in the overall population has suggested dimethyl fumarate (DMF) to be comparable to fingolimod (FTY) and more efficacious than teriflunomide (TERI) in reducing relapses. However, there is limited comparative evidence in patients switching from platform DMTs in the US. The objective of the study was to compare the annualized relapse rate (ARR) and risk of relapse in MS patients who have switched from a platform therapy to DMF, FTY, or TERI.
METHODS: MS patients (18-65 years old) initiating an oral DMT from June 2013 to March 2015 were identified from the Truven MarketScan®Commercial Claims Database. The index date was the date of first oral DMT fill. Patients were required to have: continuous enrollment in the database for 12 months pre-index date and ≥3 months post-index date; ≥1 MS diagnosis over the pre-index period; discontinuation of a platform DMT with no evidence of oral or infusion DMTs over the pre-index period; and adherence to the index drug for ≥90 days. DMF patients were propensity-score matched (PSM) 3:1 to FTY and to TERI based on age, gender, region, a claims-based MS severity measure, ARR, and number of hospitalizations over the pre-index period. Patients were censored when they dropped out of the database or at the end of the study period (March 31, 2016). Post-index relapses were annualized.
RESULTS: The database included 20,311 oral DMT users. After applying the study criteria, the PSM yielded 1602:534 switch patients for the DMF-FTY matched cohort. DMF-FTY patients were well-matched on all covariates: age (mean = 44 for both), gender (28% vs. 26% male, respectively), MS severity measure (0.99 vs. 1.08), and baseline ARR (0.40 vs. 0.44). PSM yielded 833:279 switch patients for the DMF-TERI match. DMF-TERI patients were well-matched on all covariates: age (mean = 50), gender (24% vs. 25% male), MS severity measure (0.86 vs. 0.99), and baseline ARR (0.23 vs. 0.30). The standardized differences confirmed balance across all covariates for matched cohorts. 
Now the Result
The matched DMF-FTY cohorts had comparable post-index ARR (Rate Ratio [RR] = 1.07 [95% Cl: 0.861, 1.328]) and risk of relapse (Hazard Ratio [HR ]= 0.996 [95% CI: 0.803, 1.236]). 
So switch to dimethyl fumarate and fingolimod and the risk of future relapse was the same, so they have comparative efficacy in the real world escalation
Post-index ARR was significantly lower with DMF in comparison to TERI (RR = 0.667 [0.486, 0.914]). The risk of relapse was also significantly lower when switching to DMF than TERI (HR = 0.679 [0.503, 0.917]).
So if you switch t teriflunomide after a CRAB your chances of a relapse are about 30% higher than if you switch to dimethyl fumarate (or fingolimod)
CONCLUSION:In this analysis, the effectiveness profiles for those oral DMT users specifically switching from platform therapies are consistent with findings from previous research conducted among all oral DMT users, regardless of prior therapy.

So teriflunomide isn’t that great even if it is not used first line, time is brain, why waste it.

CoI: Multiple but not relevant

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  • That's a really good post. I love the narrative that develops when you bring several papers together.

    What does Vitamin D do to memory b cells? Do the other lifestyle factors e.g. exercise, fasting, alcohol influence their numbers?

  • B cell infuence seems to be a secondary effect of teriflunomide. Terif. is an immunomodulatory drug with antiviral properties and the fact that it works well on older patietns where the immunosuppressants don't work well (see also "elephant" post) proves the opposite of your point.

  • Does this mean that fingo users could switch to DMF with a view to having Cladribine or another PIRT a bit down the road? I think you have suggested that fingo stops the PIRTs from working properly. Or am I mistaken about that?

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