Which is Best..I don’t know, they are much of a muchness

You asked which is best based on brain volume.

The immune reconstitution agents (some people call this induction therapy..but it is a confusing terminology as it is used to describe the initial dosing schedule of oreclizumab) agents). These are alemtuzumab (Cohen et al. 2012, Coles et al. 2012) and cladribine (Giovannoni et al. 2010, Comi et al. 2013, de Stefano et al. 2018)) and possibly ocrelizumab (Baker et al. 2017) although it is used as a continuous immunosuppressive (Hauser et al. 2017).

Which is best?

ProfG says the influence on the changes of brain volume by an agent from Cambridge makes it looks good.

However, I have an issue

What’s the data for Cladribine, I missed it in Giovannoni et al. 2010 and Comi et al 2013 and we had to wait until de Stano et al. 2018 to get the result.

On face value it looks like alemtuzumab is good and we know that with time the atrophy rate goes down to the rate found in normal aging. This is good

However, I don’t think it is important in this context, as we can’t compare the data. 

The influences on relapse rate looks similar across the board. This doesn’t surprise me as they are all good memory B cell depleters. 

However, the annualized relapse rate for natalizumab is 0.23 (0.62-0.87) in the AFFIRM trial as the trial was done many years before the others.

Is that bad compared to 0.14 (0.12-0.17) for cladribine, but the placebo in the natalizumab trial was 0.73 (0.62-0.87)  verses 0.33 (0.29-0.38) in the cladribine study.

Next up we have problems as brain atrophy is a tainted outcome measure that is not fit for purpose. 

It is subject to too many artifacts and if the agents are anygood as anti-inflammatory agents they make the brain shrink as the brain swelling due to inflammation is reduced. You have to wait for years for the effects to become clearer and may require rebaselining. With time this will be done. However, again I dont think that is  the main problem. 

If you look at the duration of disease before treatment in the different trials. I think you can’t compare the  2 years for alemtuzumab and the 9 year for Cladribine. 

How much brain reserve would be lost in 7 years? 
Answer is Lots

Therefore to know what’s best you have to do a head to head study or do trials under comparable conditions.


 Trial                                         CARE-MS I      CARE-MS II        OPERA I       OPERA II      CLARITY


Time from Onset (years)          2.1 +1.4        4.7 + 2.86            6.74 + 6.37      6.72 + 6.10          8.97 + 7.4

Annualized Relapse Rate           0.18                  0.26                     0.16                0.16                     0.14  
                                        (95% CI 0.13-0.23)  (0.21-0.33)           (0.12-0.20)     (0.12-0.20)           (0.12-0.17)

                                                  Parenchymal Fraction                      Brain Volume                    Brain Volume
Brain Volume                            -0.867%          -0.615%            -0.57%            -0.64%               -0.56% + 0.68 
                              (95% -1.47 to -0.254) (-1.299-0.006)       (-0.66–0.49)     (-0.73-0.54)

COI. Multiple but not relevant.

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  • Thanks MD. Great post. But I think you are grudgingly saying Alemtuzumab is the best but… However let me make the same point again. If MS was a B mediated disease Ocrelizumab should win hands down regardless the duration of the disease. It suppresses new inflammatory lessions by 99 percent. It should stop brain atrophy in its tracks. But doesn't ! Time to eat your hat?

    • Alem is a very good drug if we could mitigate the risks it would be even better but the manufacturer needs to be less slippery with the data. No lesions should equate to effect on relapses. I have never said that B cells are all that are involved in neurodegeneration which is in part measured by atrophy the iñnate immune response is centre stage.ocrelizumab will not deal with bain inflammation and starting treatment 4 years later will be a key difference. HSCT will be the winner for efficacy.

    • The attack is the match the fuse is your smoldering nerves lighting fuses for six years in bound to be different to two years worth.

    • Even if it proves to be slightly less effective, surely it makes sense to favour Cladribine due to its much better safety profile as well as its ease of use/much less monitoring?

  • Brain volume loss, as I understand, is based solely on MRI measurements which vary from radiologist to radiologist and also correlate poorly with patient outcomes/disability.

    Which one of these medications do best treating the actual patient clinical outcomes (ie. halting their progression) and not treating just the inaccurate MRI brain volume loss?

    • "Which one of these medications do best treating the actual patient clinical outcomes (ie. halting their progression)"

      Think maybe this is kinda like asking what treatment will preserve my muscles in my ALS or save my memory in my ALZ.

  • Thanks Dr. G for a great post.

    Here's what I can't wrap my head around.

    When you look at the CARE MS II extension data presented at ECTRIMS this year from years 3-8, BVL is 0.19% and to your point in line with healthy controls.

    However, look at the NEDA-3 rates from years 3-8. 15%

    So despite 'normalization' of brain atrophy, the continuous NEDA rate is quite bad despite a supposed immune system reboot.

    I suspect this is driven by new T2 lesion formation, which per yearly epoch was experienced by nearly 30% of patients per year.

    What do you think?

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