Teriflunomide long-term effects…You can’t have it both ways

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Characterizing lymphocyte counts and infection rates with long-term teriflunomide treatment: Pooled analysis of clinical trials. Comi G, Miller AE, Benamor M, Truffinet P, Poole EM, Freedman MS. Mult Scler. 2019 Jun 7:1352458519851981. doi: 10.1177/1352458519851981. [Epub ahead of print]

BACKGROUND:In Phase 3 studies, teriflunomide reduced relapse rates and disability progression compared with placebo; however, decreases in lymphocyte counts were also observed.

OBJECTIVE:To describe the effect of long-term teriflunomide treatment on lymphocyte counts and infection rates among patients in pooled analyses of Phase 3 core and extension studies.

METHODS:Four randomized trials (TEMSO, TOWER, TENERE, and TOPIC) compared teriflunomide 7 mg or 14 mg treatment with either placebo and/or subcutaneous interferon (IFN) β-1a 44 µg in patients with relapsing forms of multiple sclerosis (MS) (or first clinical episode suggestive of MS in TOPIC).

RESULTS:In 1895, patients ever exposed to teriflunomide, mean (standard deviation) absolute lymphocyte counts declined from Week 0 (1.89 (0.59)) to Week 24 (1.67 (0.52)) and then remained stable thereafter. In the core plus extension studies (up to 10.7 years), 7.3% and 2.2% experienced Grade 1 and Grade 2 lymphopenia, respectively. Infections were reported in 56.9% of patients without lymphopenia, 60.9% with Grade 1 lymphopenia, and 54.8% with Grade 2 lymphopenia. Serious infections occurred in 3.7%, 4.3%, and 7.1%, respectively.

CONCLUSION: Long-term risk of lymphopenia and infections in patients who continue to receive teriflunomide is low, demonstrating a limited impact on adaptive and innate immunity.

Therefore teriflunomide will be a low(er)-efficacy treatment…You can’t have it both ways.

You should not expect to dissociate benefit from the side effect when you are using a sledgehammer to crack a nut, when the sledgehammer has no idea which nut is good or bad. The immune system is the bad guy in MS and the good guy when dealing with infection. How any drug works….it is all based on biology.

At a recent meeting we were talking about how MS drugs work and my fave MS treatment came up yes you know the one:-). The EMA website says it works by “targeting the mechanisms thought to be important in MS”, the audience laughed when I said that….so no wonder it gets a new mechanism of action every few months. However, I then said that “it must do all of these things badly”….why? Because it is not that effective in MS. You can’t have it both ways.

That is why trying to work out how lower efficacy agents work is difficult.

So now we have teriflunomide.

ProfG keeps saying to me it is anti-viral. We know terifluomide is anti-proliferative…this is why it has some of the side effects it has…it is simple biology. Now I accept that teriflunomide could be anti-viral as viruses use the host cell machinery to replicate and most assays involve measuring viral reproduction. Is it anti-viral, if the virus is not replicating?

ProfG says it that teriflunomide could be anti-EBV…so I think OK it must do this badly why…because teri is in that first-order low efficacy range.

So it it is strongly anti-viral and getting rid of virus is the solution then teri should work brilliantly….But it doesn’t… so this says the viral idea is wrong…You can’t have it both ways Alternatively it says that the anti-viral effect must be weak if the idea is right you can’t have it both ways.

OK EBV is latent in most cell, so it is not replicating, most immune cells are not replicating but they do need to be replaced. So what happens in the long-term. There is a small drop in white blood cells.

Infection rate was about 50% was this lower than not being on drug because if it were anti-viral then this should drop shoudn’t it?

But

Neurology, 2014; 82 (10 Supplement) Teriflunomide Treatment Is Not Associated With Increased Risk of Infections: Pooled Data From the Teriflunomide Development Program (P2.194) Barry Singer, Giancarlo Comi, Aaron Miller, Mark Freedman, Myriam Benamor, Philippe Truffinet

“In placebo-controlled studies, duration of treatment exposure and frequency of patients with infections was similar across groups (14mg=1517 patient-years [PYs], 53.4%; 7mg=1561 PYs, 52.9%; placebo=1508 PYs, 52.7%). Rate of infections over time was similar across treatment groups. Serious infections occurred infrequently, with similar incidence across groups (14mg=2.7%; 7mg=2.2%; placebo=2.2%)”. 

So infections rates are not increased, which is good but is that because it is not that an effective immunomodulator and is this why it is in the first-group of MS drugs about as effective as the other CRAB (Copaxone, Rebif, Avonex, Betaferon) drugs.

Now I have suggested that potent MS drugs potently get rid of memory B cells. So it would predict that teriflunomide is not that great at depleting memory B cells…Why…Because you can’t have it both ways.

What happens if you complare the percentage of memory B cells in the CD19 B cell population before and after teriflunomide it is the same.

So you say “Ha-Ha” you are wrong on the memory B cell front as they don’t drop…. and I say “Ho-Ho” because if you look at the number of CD19 B cells they drop so the absolute number of memory B cells must drop but not that much.. So maybe it is anti EBV as it gets rid of memory B cells…but does this badly.

Now the other thought of ProfG was that teriflunomide works better as a second line drug than an first line treatment. I asked where is the evidence for this? He sends me a paper and I remeber looking at some posters from ECTRIMS where I remember thinking teriflunomide seems to do better than I would have thought for a low(er)-efficacy treatment

So then I think what happens to the memory B cells because there should be a difference in effect first line verses second line. I have only seen one paper looking at memory B cells and many of the people in that study had teriflunomide and it was a bit better than I would have predicted

I did find a paper in rheumatoid arthritis, which surprisingly did show that if leflunomide was used second line it tended to deplete memory B cells better than when used first line. Leflunomide breaks down and produces teriflunomide as the active ingredient of leflunomide.

We do not use enough teriflunomide to answer the question and did contact the manufactures. Not sure they have the data. Most people have sent all their time looking at T cells, T cells, Teclls to have the data.

We also wrote to someone in Germany who uses teriflunomide and would have B memory cell data and the answer (graphs) came back that teriflunomide depletes memory cells not very well….yes we knew that that was already published by someone else…… but the answer about first and second line use was not answered despite asking….Why not? I have no idea…..Maybe it is now their idea and we have been cut from the equation.

Yes we do give away ideas on the blog. So anyone with enough people using teriflunomide, it can be your idea. See if there is a difference in memory B cell depletion when used first or second line in MS. The supporting references are out there if you look…come-on I can’t give you everything on a plate…you have to do some work…I will look forward to seeing the results in ECTRIMS.

Coi multiple

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