Early cladribine treatment prevents MS

Barts-MS rose-tinted-odometer: ★★★★★★ (6-star bull’s blood red #8a0303)

Yesterday’s post on using cladribine to prevent CIS from converting to MS and whether this is MS prevention or an MS cure generated a robust debate. Good, this was the purpose of the post; i.e. to get you thinking. 

As you are aware that as the diagnostic criteria for MS evolve many people diagnosed with CIS in the past actually have MS when the new diagnostic criteria are applied retrospectively. This then allows you to see how well cladribine works in preventing conversion to MS in the small subgroup of subjects who have ‘CIS’ and not MS when they were treated with cladribine. 

The subjects who were still CIS after applying the newer McDonald diagnostic criteria showed that cladribine’s treatment effect improved with a reduction in risk of conversion to clinically definite MS by 63% on low-dose cladribine and by 75% on high-dose cladribine compared to placebo. I am not sure the MS community has clocked how effective cladribine really is when used early. 

This post-hoc analysis also suggests that people with CIS treated with lower doses of cladribine actually do better than those on higher doses. The dose-effect is pretty clear when you look at the time to next attack or three-month confirmed disability worsening. Have we optimised the dose of cladribine? When you are trying to prevent/cure MS maybe not!

Any predictions? I predict that a proportion of patients with CIS treated early with cladribine may never go on to have a second attack or disability progression and hence are prevented from developing MS or cured of their MS, depending on how you define MS. Anyone taking bets? 

Freedman et al. The efficacy of cladribine tablets in CIS patients retrospectively assigned the diagnosis of MS using modern criteria: Results from the ORACLE-MS study. Mult Scler J Exp Transl Clin. 2017 Oct 9;3(4):2055217317732802.

Background: Multiple sclerosis (MS) diagnostic criteria have changed since the ORACLE-MS study was conducted; 223 of 616 patients (36.2%) would have met the diagnosis of MS vs clinically isolated syndrome (CIS) using the newer criteria.

Objective: The objective of this paper is to assess the effect of cladribine tablets in patients with a first clinical demyelinating attack fulfilling newer criteria (McDonald 2010) for MS vs CIS.

Methods: A post hoc analysis for subgroups of patients retrospectively classified as fulfilling or not fulfilling newer criteria at the first clinical demyelinating attack was conducted.

Results: Cladribine tablets 3.5 mg/kg (n = 68) reduced the risk of next attack or three-month confirmed Expanded Disability Status Scale (EDSS) worsening by 74% vs placebo (n = 72); p = 0.0009 in patients meeting newer criteria for MS at baseline. Cladribine tablets 5.25 mg/kg (n = 83) reduced the risk of next attack or three-month confirmed EDSS worsening by 37%, but nominal significance was not reached (p = 0.14). In patients who were still CIS after applying newer criteria, cladribine tablets 3.5 mg/kg (n = 138) reduced the risk of conversion to clinically definite multiple sclerosis (CDMS) by 63% vs placebo (n = 134); p = 0.0003. Cladribine tablets 5.25 mg/kg (n = 121) reduced the risk of conversion by 75% vs placebo (n = 134); p < 0.0001.

Conclusions: Regardless of the criteria used to define CIS or MS, 3.5 mg/kg cladribine tablets are effective in patients with a first clinical demyelinating attack. ClinicalTrials.gov registration: The ORACLE-MS study (NCT00725985).

Conflicts of Interest

Preventive Neurology




General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

22 thoughts on “Early cladribine treatment prevents MS”

  1. Does it really merit the 6* rating when it isn’t available to uk patients even as a first line …. Will obviously never be available for CIS

  2. Early cladrabine followed by and anti – cd20 surly would be a good strategy. But the most effective drugs arnt really accessible early on in the UK as the person above states. Times have to change.


    Please amend as follows:


    [Prof G – you’re a scientist not Mystic Meg]

    Where’s MD1? Probably on a deckchair on Skegness beach with a can of John Smiths. Can someone make sure he’s okay. His post on why am I called MD had a tinge of sadness about it.

    1. Another commenter complained the blog was too downbeat and depressing, hey ho, I suspect the balance is about right.
      It’s a hypothesis Sid, it’s there to be disproved, that’s how science (should) work. Hopefully there’s a good chance it won’t be.
      As for MD, your constant snarking has had its desired effect and he’s given up.
      Well done.

  4. How accessible is cladribine to the private patient? People are paying £50-85,000 to take out their whole immune system, mainly in a foreign land. What cost cladribine to the informed CIS patients?

  5. It sounds as though cladribine should be made available as a treatment – how is it possible to access it

    Does any campaigning need to happen here in the UK to make it accessible or bring it to the attention of the wider MS community?

    1. Yes neuros or company need to fill in a form and make the case that cladribine should be available for active rather than highly active MS….as Malcolm QALY (NHS england) doesn’t seem to be able to read the literature (we (royal we) did write to him. Thre is a blog post on it) ….It was a big mistake by the manufacturers to accept the highly active label, I uess they were told to do this, it could have been the perfect COVID-19 drug (can be home-dosed, minimal monitoring, long term treatment effect, effective, disappears quickly, allows vaccine response etc etc (COI multiple), yet to many the SH1 has stuck and it is tarnished. The ABN said “Schtop” and is not even on people’s radar.

      One reason is people do not understand how it works and when been fed the T cell guff that was originally rolled out, or it is a complex mix of regulation approach, it does not make sense and confuses people…Give them the B cell story…reassuringly simple (COI Multiple). The penny is dropping, but it should have dropped in 2017/2018/2019. The benefit of anti-CD20 and more but without the COVID-19-related CD20 problems (COI multiple).

  6. Although I appreciate the message, I am a bit provoked that it is now being stated that high dose cladribine DOES make a difference, while not long ago it was stated that there was no significant benefit from the high doses.

    Was this data really not available or clear when Merck decided on the bodyweight dosing regime for Mavenclad?!?!

      1. Do you know if the CLASSIC-MS study will differ between the low and high dose paramteres when reporting on their outcome measures?

  7. Why is the lower 3.5 mg/kg dose more effective than the higher 5.25 mg/kg dose? I think this is also the case in RRMS RCT.

      1. It would be great if you could elaborate on that, if only a little, considering that both your post and the graphs indicate differently? This is confusing.

      2. It is about statistics; there really is no difference between the doses except that which occurs by chance.

  8. I’m not convinced by this data, would appreciate longer-term data, even only up to 5 years would be much much better. I suspect the IR effect of Clad pretty much lasts for 2 years, and after 2yrs we will see the curve moving again.

    I also have a question on dosing, in a perfect world (doctors can prescribe however they want), how would you dose Clad following CD20. Would you reduce the dose, at 6 months after previous CD20 infusion? Or would you prefer to wait for a certain amount of B-cells to reappear before administrating Clad?

    1. As the Dude said “That’s just like your opinion, man”.
      Let’s try for a bit of optimism once in a while (and I say that as a dyed in the wool Welsh cynic) 🙂

  9. I’ll bet that your prediction is right! I’ll wait for more data to support this but my gut feeling tells me you’re right 🙂

    I’ve been using it more frequently during the pandemic and I’ve see excellent results so far.. I’m surprised that it’s not available in the UK to early MS patients while reading the comments above

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