A false sense of security?

A

Just catching up with my reading. Whilst I was away on holiday the ASCLEPIOS I and II trials was published in the New England Journal of Medicine. 

There is little doubt that ofatumumab is superior to teriflunomide when it comes to suppressing focal inflammation, i.e. relapses, MRI activity and peripheral blood neurofilament levels. However, ofatumumab’s effectiveness against teriflunomide on the real MS (delaying disability progression and reducing the relative loss of brain volume) is less impressive. Is this just another example of a dissociation between the anti-inflammatory effects of an anti-CD20 therapy and its impact on the end-organ as measured using brain volume loss or is it telling us something about teriflunomide and the cause of MS? 

Image from supplementary material N Engl J Med 2020; 383:546-557.

It is clear, at least to me, that MS the disease is not due to focal inflammation. Based on the Prentice criteria for disease surrogates, both relapse and focal MRI activity don’t predict disability outcomes in natural history studies and placebo arms of clinical trials. If focal inflammation was MS then relapses and focal MRI activity would predict outcome whether or not you are on a DMT. The point I making here may be a philosophical one, but it a critically important one. In comparison, sustained or confirmed disability progression has to be MS and is based on the pathological correlates that define MS (demyelination, neuroaxonal loss and gliosis). 

So why does ofatumumab do so poorly on these metrics relative to teriflunomide, when you would expect it do better? I think teriflunomide is the outlier and this opinion is based on several observations.

Teriflunomide has effects on disability progression that are way and above what you expect from its impact on relapses and focal MRI activity; i.e. both teriflunomide phase 3 placebo-controlled trials were positive on disability progression, despite a moderate reduction in relapse rate (~33% vs. placebo). 

Teriflunomide also has a significant and unexpected effect on brain volume loss compared to placebo, which again is out of proportion to its anti-inflammatory effects.

Teriflunomide is more effective when used 2nd and 3rd line. Teri is the only DMT to show the latter and this observation was seen in both phase 3 studies, which makes it likely to be a real, and a very important, finding.

Finally, teriflunomide is a broad-spectrum antiviral agent, which may be part of its mode of action in MS. Could teriflunomide be targeting the viral cause of MS independent of its effects on the immune system’s response to that virus? Could it be an anti-EBV agent? Although teriflunomide’s antiviral mode of action needs more study, I suspect this is the reason why teriflunomide is the outlier that disproves the dogma. 

Despite these observations, I suspect the MS community is going to propel ofatumumab to blockbuster status within the first 12 months of its launch. However, I want to reiterate that I think anti-CD20 therapies are lulling us into a false sense of security, i.e. because anti-CD20 therapies are so good at suppressing relapses and focal MRI activity we think we have sorted out the treatment of MS. However, when you look carefully at the end-organ of pwMS on anti-CD20 it is clear that their brains are still being shredded by smouldering MS. It is clear to me that we need to go way and beyond ofatumumab and anti-CD20 therapies to target whatever is causing smouldering MS. This is why we need to think combination therapies and find an add-on therapy, possibly an antiviral, that normalises brain volume loss in people with MS who are rendered free of focal inflammatory activity. 

Hauser et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med 2020; 383:546-557.

BACKGROUND: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known. 

METHODS: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.

RESULTS: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, −0.11; 95% confidence interval [CI], −0.16 to −0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, −0.15; 95% CI, −0.20 to −0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P=0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P=0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P=0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups. 

CONCLUSIONS: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231).

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

40 comments

    • I suspect yes. I would love to do an alemtuzumab induction trial in combination with teriflunomide to prevent secondary autoimmunity and to prevent any recurrent disease activity in SPMS.

  • Prof G,

    “There is little doubt that ofatumumab is superior to teriflunomide when it comes to suppressing focal inflammation, i.e. relapses, MRI activity and peripheral blood neurofilament levels.” Does the latter mean that you don’t think that testing NfL is of use, or is it just blood NfL levels?

    Any thoughts on whether this anti-viral trial is likely to be positive:

    https://www.nationalmssociety.org/About-the-Society/News/MS-Trial-Alert-Testing-ATA188-in-Progressive-MS?feed=AllNationalNews

    I’ve had two doses of Lemtrada, Vit D supplementation + time in the sun, ideal weight (following Keto), ideal blood pressure, plenty of exercise. Is there anything else I could be doing until an anti-viral which addresses the real MS comes to market?

    Thanks.

    • Peripheral blood NFL is, in my opinion, a marker of focal inflammation in MS. It may be a marker of smouldering MS, but the signal for this will be very low, i.e. the loss of axons and neurons in smouldering MS is very slow and at a level that may not show up in the peripheral blood.

  • Good day. Are you saying there is a benefit to starting on ocrevus but then switching to teriflunomide? I am RRMS but since starting ocrevus, I feel like slow progression is still occurring absent of new lesions or clinical relapses. I am meeting with neurologist to discuss switching to tysabri or lemtrada but never even considered teriflunomide. Thank you.

    • All I am putting forward are hypotheses to explain an outlier (teriflunomide) and the ofatumumab and other anti-CD20 data. What we need are trials to test these hypotheses. I think the iTeri trial is interesting because it could potentially derisk the long-term infectious complications of CD20 therapy; you don’t develop hypogammaglobulinaemia on teriflunomide.

  • Hear hear!
    I was on rituximab for two years, no relapses or mri changes yet had elevated CSF NFL. Now 5 days short of 1 year post HSCT.

    If I had known this a few years ago I would have pushed for HSCT or alemtuzumab then!

  • Thank you, prof G.

    Even if what you wrote here is really not comfortable for me because I would have preferred to be able to say to myself ‘I will be totally fine with my anti-CD-20’ (I am on ocrelizumab first-line – small person & low BMI – no spine lesion – EDSS 0 – no cognitive problem), I will follow your advice and don’t let me go to a potentially false sense of security.

    So, what would be your advice for pwMS in the same situation that me (on anti-CD20) but who cannot have Alem?

    • Anti-CD20 therapies are high efficacy DMTs and are very effective DMTs. But they are not a cure for MS and I doubt they will stop smouldering MS even if used early in the disease.

    • Hi Bob, like you I used Ocrevus as first line. My MS was a bit more active than yours, initial EDSS 5, lesion load evident in spine and brain. I am also small and low BMI, under 40yrs. Unfortunately, my infusion related reactions got progressively worse with each subsequent infusion. So by my fourth cycle, I had developed too many anti-drug antibodies and became “allergic” to Ocrevus and most likely all anti-CD20 meds. I had to stop Ocrevus, plus while I was mostly NEDA, I continued to progress.

      I am adverse to PML risk, so tysabri is out. I cannot use anti-CD20 to de-risk lemtrada, so that is out. And HSTC is too risky for me and not approved in the US anyways.

      I am 8 months post my last infusion and remain b-cell depleted (I monitor lymphocytes monthly). In consultation with my MS neuro, we decided to try teriflunomide, given its safety profile, performance in BVL, and anti viral aspects (EVB). The hope is Teri will stop the bad b-cells from developing. I am a regular reader of this blog and post comments often, so I will keep everyone updated on my progress, success, and possible failures. Good luck! But the fact that you reading this blog suggests you are on the right track. I am not an expert, just a well informed pwms.

      • Hi Tom. Thank you for your personal remarks. Very interesting to me (I was diagnosed at 28 with the classic optic neuritis).

        Some questions :
        – How do you know you are progressing? I mean, I have absolutely no symptom so I don’t know what ‘progress’ would mean in my case.
        – Did your infusion reaction problems come out of the blue or did they begin at your first infusion? (I did my two first half-dose without any side effect).
        – please keep us updated about your Teri ‘experiment’!

        Best,
        Bob.

        • Bob, I should preface my statement by saying I was happy with my choice to use Ocrevus as a first line treatment. It stopped my active inflammation EARLY, which I believe is the only decision….early and aggressive. Unfortunately I was no longer able to continue with that treatment, so I had to switch.

          There is very little data/research on DMT use after Ocrevus (still relatively new drug). So once again I am handed over 10-12 different possible DMT brochures. I appreciate your support, by no means is it an experiment…..days of research, difficult debates with my doctors, and the determination to advocate for the most appropriate and risk mitigated treatment approach is what lead me (and majority of my care team) to Teri.

          I suspect my progression is smoldering MS. I started Ocrevus 2 months after my first major flair up, and it helped with the most debilitating symptoms. It also stopped the development of lesions, which were very active at the time. However, my less extreme symptoms continue to progress. So in my experience, you will know if your are progressing slowly, it sucks! No new lesions, no major flair ups, just a slow and painful slide. Nevertheless, I stay positive and focus on what I have, not on what I lost or may loose. If you say you have no symptoms, I would be happy with that.

          And, yes, my infusion related reactions happened the first time, and progressively got worse each subsequent time. Despite the pre-infusion protocol, around mid-drip, my eyes and throat would swell, itchy everywhere (mostly ears and throat), and increased heart rate. They would stop the drip, administer more IV antihistamine, wait about an hour and restart the dip. On the fourth cycle (third full dose) the infusion reaction almost resulted in intensive care. My reaction is very rare, yet should be more widely publicized and researched by the drug company, but that is not good for business. So I am left to work within the confines of the system.

      • Hi Tom,

        I am an Ocrevus user and your post caught my eye. I didn’t even know that it was possible to become ‘allergic’ but can I ask what sort of infusion reactions you experienced? I have just completed my first two half doses and after each one have become more n more symptomatic. There is very little on the various Ocrevus groups to suggest this is a common experience

        Thanks

        • Annon 7:21pm, hopefully my comments above provide you with some insights into my experience with Ocrevus. I use the word “allergic” sarcastically. I suspect my infusion related reactions were an anti-drug antibody response that manifested as symptoms similar to an allergic reaction. However, since no one in the US will test for anti-drug antibodies, I will never know. The drug worked and depleted my B-cells. The clinical trail data suggests my experience happens in <1% of treated patients, so apparently very rare.

          I should have known something was not right when I felt like I got run over by a truck for a weak after each infusion. I would read these stories and watch pwms blogs with people saying how good they felt after the infusion and how much their symptoms improved after starting the drug. As I stated above, my most severe flair-up symptoms improved, yet I still felt pretty horrible. I would get two maybe three months of stable symptoms in-between infusions, then I would hit the "crap gap" (the 4-6 weeks before your next infusion). These drugs do not appear to cure or fix MS, they just slow the progression, hence you still progress just at a slower pace. Good luck, it can be scary, but you found a great resource…..this blog!

      • Re spironolactone— A lot of women take it for treatment of acne. Polycyclic ovarian syndrome as well. It blocks androgen, so can cause some feminization in men. I think that it is used as a part of the drug protocol before or during male to female sex change surgery. So it probably would not be considered for research because the majority of men would not be willing to be part of a study that involved taking a medication that could cause the development of feminine characteristics and make them start growing breasts, etc lol.
        I never thought that I would wanna have acne again lol. I had it before I was diagnosed with MS and before it started being used much for acne. A dermatologist treated my acne with retin a, which took care of that problem. I don’t have polycyclic ovaries either. I’m 38 and do still use retin a though.
        Hmmm, maybe I’ll start trying to have acne again and get my dermatologist to prescribe spiritual for that. For science purposes 😂 🤷🏻‍♀️ I’d definitely rather have horrible skin than worsening of MS anyway.

  • Prof G,

    Forgive my bluntness. Are you out on a limb with your hypothesis (about the real / smouldering MS) or are there other MSologists who are likeminded? I’m convinced, but to get trials to test the hypothesis some more big guns will need to support you to get the required traction. You’re also not going to be overly popular with pharma who have invested heavily in anti CD 20 therapies. My advice – don’t go jogging down dark alleys and check your sock draw for scorpions / tarantulas etc

    • Hugh the companies that have anti-CD20 therapies are all working on follow-on and add-on compounds. They know as well as I do that anti-CD20 therapies are not the final solution to MS. Let’s say anti-CD20 is the new 1st-line platform therapy on which we can build a treatment pyramid 😉

    • I didn’t say it had no effect. It does reduce end-organ damage and there appears to be a dose-effect, which is why I have been pushing for a double-dose (DoDo) study.

      • Prof G, how do trials like this get funded and off the ground? Do you have to approach the drug companies (you mentioned “no takers” in an earlier post) or does it come from the government or other funding bodies or charities?

      • Hmm…DoDo study, maybe consider a different name. We all know the fate of the dodo. Does not have a good juju for a successful study.🙁

  • At this point I wouldn’t be surprised if one single b-cell depletion with a following 3g/d valaciclovir (or some other antiviral) lifelong maintenance phase would be enough to stop MS from progressing.

    • Are there any pwMS taking spironolactone for heart failure or other condition and their MS has stabilised?
      It is 50 year old kidney drug and a drug used for CFS, plus other conditions.

  • This is great and sold Teri to me. I tested positivive for the JC virus so if I have to switch from Tysabri, I will ask to go on this one.

  • Even if Teriflunomide as an add-on does what you suggest, it is not what PWMS want

    For some people the side effects are bad enough that they must stop taking the drug. For others, the side effects may not be very serious, but who wants to feel sick or have diarrhoea every day

    Plus, the price of MS drugs being what it is, funding a daily drug can be a problem. It can certainly become a problem at some time in the future.

    A lifelong add-on drug should be inexpensive and the side-effects should be easily tolerable

    (Of course we are spoiled now. In the past there was no choice except to inject yourself and suffer regular flu-like symptoms)

    • Teri is about to come off-patent and the prices will drop by well over 90%. In addition, leflunomide is a teriflunomide prodrug and it is already cheap. Not all people get adverse events. In fact, a minority do. As always it is horse for courses.

      • Whats the chance that the patent is extended?…they seem to have done it with other drugs like fingolimod and cladribine

By Prof G

Translate

Categories

Recent Posts

Recent Comments

Archives