Tuesday, 21 March 2017

Don't write off a write-off: a reassessment of Teriflunomide

Mult Scler. 2017 Mar 1:1352458517695468. doi: 10.1177/1352458517695468. [Epub ahead of print]

The efficacy of teriflunomide in patients who received prior disease-modifying treatments: Subgroup analyses of the teriflunomide phase 3 TEMSO and TOWER studies.

Freedman MS, Wolinsky JS, Comi G, Kappos L, Olsson TP, Miller AE, Thangavelu K, Benamor M, Truffinet P, O'Connor PW; TEMSO and TOWER Study Groups.

Abstract

Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting multiple sclerosis (MS). The objective of this post hoc analysis of the phase 3, pooled TEMSO (NCT00134563) and TOWER (NCT00751881) dataset is to evaluate the effect of teriflunomide treatment on annualised relapse rate and disability worsening across patient subgroups defined according to prior disease-modifying therapy exposure. This analysis provides further supportive evidence for a consistent effect of teriflunomide across a broad range of patients with relapsing MS, including patients who have used and discontinued other disease-modifying therapies.

Figure:   (a) ARR by prior treatment; (b) Disability worsening by prior treatment. Teriflunomide shows a trend towards improvement, including those who have received prior DMT, but the effect is not statistically significant.

Teriflunomide (Aubagio), a first-line oral MS therapy has an Achilles heel, and that is its side-effects; particularly irksome are liver problems (requiring frequent blood tests), diarrhoea, and hair thinning/loss. They occur often enough that they overshadow it's selling point as an alternative to dimethyl fumerate (Tecfidera), which has the PML risk. Teriflunomide blocks rapidly dividing cells and this includes activated T cells by inhibiting pyrimidine (building blocks of genes) synthesis.

Here the TEMSO and TOWER study groups (these were the two of the clinical trials performed prior to licensing of teriflunomide) reanalyse the pooled data by dividing those into ones who received disease-modifying therapies (DMT) before and those who had not, i.e. DMT naïve. Most included in the analysis were DMT naïve with ~30% having used one or more DMT (so this is a 2:1 analysis so to speak). The most frequently used other DMT was interferon beta (IFNβ). Overall, there is a numerical reduction in relapse rate and risk of disability progression with teriflunomide 14mg compared to all the subgroups analysed (see Figure above). The differences, however, are not significant and should be born in mind. The authors point out that this may be due to the small size of the groups analysed but I feel the numbers were sufficient even if it's a post-hoc analysis. Interestingly, they also noted that those who had prior DMTs also had greater MRI activity with more enhancing lesions and relapse rates compared to the treatment-naïve group, which is concerning (those who participated had to be off their DMTs for 3-6 months prior to inclusion) and implies rebound after coming off treatment. The latter is a practical lesson to learn for clinicians swapping treatments.

Overall, despite the less than impressive data, teriflunomide in my books will remain a first-line contender by simply not following the paths trodden by others. It does not pretend to achieve the excellence of the second generation DMTs, nor does it imitate those who are most excellent, and as such, will remain a prudent man's/woman's choice.

10 comments:

  1. NDG surely in this day an age a trend is meaningless, when It is not signficantly significant surely means it does not work?

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    1. Yes in majority of cases, but you also need to look at the raw data. If you look at those >2 DMTs the effect is visible to the eye even accounting for the error bars (there's something going on there, even if it is better compliance to an oral drug vs injectables). The authors have downplayed this but warrents a second look. On of my science phd supervisors used to tell me that you only need statistics if you couldn't see it with your wee eyes (he was Scottish!).

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  2. Being is a hot bed area of MS I've attended quite a few functions.

    I've met quite a few people who are taking Aubagio and had really good results where others have failed with their MS.

    While it does not appear to as often be suggested as a first line therapy locally here.

    I would probably have went this way myself had it not been for Genzyme not saying, "Its ok to take with LDN." (at the time). So, I went with Dimethyl Fumarate.

    In similar mindset however, many many neuro's here do not advise towards a therapy, its more, "Here they are... do research, let us know which you are considering."

    Over the past year through some connection with another medical entity I've learned much as well as the difference between a comprehensive MS Center and that which is more prominent, clinics. Its night and day.

    A clinician should be explaining given a persons MS what choices are best pursued, why and potential side effect in compare to others. Unfortunately at least local to me, doesnt tend happen.

    As it was put to me, "Why have a neurologist at all if they are not pursuing my MS in a personal fashion towards my best outcomes."

    That said, my fiance's neighbor across the road from him has had MS for in excess of 20 years. First on Interferon (avonex), then to Copaxone with both she still had flare-ups. Aubagio was never even offered to her. We were at a function where a rather well known Neuro (who recently passed) wife was speaking. Afterwards I was speaking with her and Jeanie came over to listen in.

    She relayed her experience and the neuro's wife (an MS Nurse) suggested she look at Aubagio given her description of her MS (in detail!). Jeanie did so, she is now NEDA.

    In similar tone, I met a lady late last year who's been on Avonex for over 25 years and its worked for her, two exacerbations in 20+ years after the initial incidents.

    The problems with statistics in trials is they are a generalized figure, just like the EDSS scale is rather askew. MS patients lifestyle's differ, multi-center trials are dispersed, lesion loads differ. Since few drivers of MS have been qualified as defacto and even Pharma tends state, "We dont know" on WHY our med EXACTLY has results statistics I see like NASCAR points.

    Much revolves in statistics and marketing, they walk hand in hand in meds from DMT's to cold and sinus meds.

    I agree with you Dr. Gnanapaven, Aubagio is an important asset of choice for pwRRMS, its oral, its different and I've met numerous people where it has been a game changer in their lives and MS progression.

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  3. In my experience Teriflunomide is under-rated and patients who get to year 3 and beyond are doing exceptionally well. There is more to this drug than meets the eye.

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    1. What about those that don't get to three years which is surely most people.

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  4. NeuroDoc Gnanapavan there is a lot to the mode of action Teriflunomide that we don't know about. Although we all say its anti-proliferative this is not borne out by its clinical profile. It is not associated with persistent lymphopaenia, there is no opportunistic infection signal, vaccines responses are maintained and we don't have a secondary malignancy signal. I therefore don't feel that it is working as an anti-T-cell therapy. There is also an extensive literature that it has quite potent antiviral effects. Could its main mode of action be antiviral? Teriflunomide is also an inhibitor or the aryl hydrocarbon receptor; the latter is how laquinimod is working. Could Teriflunomide be the tortoise of the DMT world that wins the race?

    Prof Gold and myself have more than a passing interest in Teriflunomide's mode of action. What is clear we need to do more work on its mode of action.

    In addition, Leflunomide, a pro-drug of Teriflunomide, is one of the drugs on our essential off-label DMTs. Leflunomide may just be what pwMS in resource poor environments can afford.

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    1. ProfG. If it is anti-proliferative it would not remove many cells except B cells which proliferate more and lymphocyte numbers do drop

      http://www.neurology.org/content/86/16_Supplement/P5.282.short

      However, if its main mode is anti-viral, then it must be telling us that relapsing MS has little to do with viruses. Becuase it is not really blocking relapses. Likewise Laquinimod was pretty poor at inhibiting relapses too.

      Surely two wrongs don't make a right.

      You can't have it both ways or can you?

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    2. "there is a lot to the mode of action Teriflunomide that we don't know about".

      Them maybe the pharma companies should be more open and publish the data so we will know.

      It appears to me that there is alot of data that never makes it into papers. There are loads of abstracts (ECTRIMS/AAN) that never become papers, why not? In this day and age we have got so many journals desperate for content. The authors of the abstracts should hold their heads in shame, if it is good enough for an abstract it is surely good enough for a paper, the data has been analysed and written it should only take a few hours/days to write the paper. The authors on the abstract need to take responsibility to get this stuff out and not simply use them as a justification for a trip to the meeting.

      ECTRIMS in past years has restricted the number of abstracts presented and maybe rejects 25%. I was tolld that the rules are changing and pharma can't help people attend the meeting unless they are presenting. So will the number of abstracts increase this year as ECTRIMS won.t want to lose revenue from lack of neuros attending.

      Anyway back to the rant.

      If you are in the inner circle of pharma land you may get sent these abstracts, so you know what others don't, so you have another world view that others dont understand...maybe this is why we have T cell world vision, when pharma are after b cells.

      Problem is the information flow is controlled.

      What do I mean.

      For example we have been sold a story that fingolimod works by trapping cells in lymph glands. Is this really true?

      Do lymph nodes blow up because they are packed full of cells, so you have to walk like a lizard or John Wayne?, because your lmyph glands in the groin are so big. I think the answer is no

      It is clear to me that it is deleting cells, but this idea doesn't get entertained. Are we being served a partial cureve ball.

      Where are the killer experiments...

      Maybe Novartis reps can provide a list (on or offline to ProfG)...e.g. the efflux of lymph glands of sheep treated with FTY720 because maybe it is time for a student project and a new literature review.

      This is because we can find loads of evidence where cells are being killed. What's not right about those papers?

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    3. "Teriflunomide is also an inhibitor or the aryl hydrocarbon receptor; the latter is how laquinimod is working. "

      Aha!

      Ahrs were frequently dysregulated in inflammatory contexts one way or another when I was doing microarrays of sick hearts in grad school. Little did I know at the time that AHRs control part of the ILC1/3 axis. This could go some ways into explaining the diarrheal effects and maybe even some of the effect of diet on MS if someone puts the story together.

      Could be similar to the blockade of NLRP3 by type 1 IFN signalling.

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  5. GG my last paragraph was intended at those in the know who'd be able to contradict my audacity for reporting negatively; even as anonymous comments. So if anyone has the answers please come out of the closet...

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