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.