ProfG has got his way and a double dose of ocrelizumab is going to be trialled. He has wondered whether the dose of oral cladribine is optimum. In the phase III clarity trial 3.5mg/kg and 5.25mg/kg were tested and were pretty similar, but the higher dose had more adverse events…but one of those that caught the regulators eye was lymphopenia, which is a mechanism of action. The dose was adjusted to avoid lymphopenia. Therefore, one wondered if one was diluting the effect away. It seems that it can deplete B cells as well as alemtuzumab and ocrelizumab and depletes T cells better than ocrelizumab but natalizumab is continuously given and will target T, B and monocytes. In this study supported by the makers of cladribine, they tried to do a virtual head to head studies and it argues that it is similar to fingolimod better and not as good as natalizumab.
Signori A, Saccà F, Lanzillo R, et al. Cladribine vs other drugs in MS: Merging randomized trial with real-life data. Neurol Neuroimmunol Neuroinflamm. 2020;7(6):e878. doi:10.1212/NXI.0000000000000878
Objective: Cladribine tablets were tested against placebo in randomized controlled trials (RCTs). In this study, the effectiveness of cladribine vs other approved drugs in patients with relapsing-remitting MS (RRMS) was compared by matching RCT to observational data.
Methods: Data from the pivotal trial assessing cladribine tablets vs placebo (CLARITY) were propensity score matched to data from the Italian multicenter database i-MuST. This database included 3,150 patients diagnosed between 2010 and 2018 at 24 Italian MS centers who started a disease-modifying drug. The annualized relapse rate (ARR) over 2 years from treatment start and the 24-week confirmed disability progression were compared between patients treated with cladribine and other approved drugs (interferon, glatiramer acetate, fingolimod, natalizumab, and dimethyl fumarate), with comparisons with placebo as a reference. Treatment effects were estimated by the inverse probability weighting negative binomial regression model for ARR and Cox model for disability progression. The treatment effect has also been evaluated according to baseline disease activity.
Results: All weighted baseline characteristics were well balanced between groups. All drugs tested had an effect vs placebo close to that detected in the RCT. Patients treated with cladribine had a significantly lower ARR compared with interferon (relapse ratio [RR] = 0.48; p < 0.001), glatiramer acetate (RR = 0.49; p < 0.001), and dimethyl fumarate (RR = 0.6; p = 0.001); a similar ARR to that with fingolimod (RR = 0.74; p = 0.24); and a significantly higher ARR than natalizumab (RR = 2.13; p = 0.014), confirming results obtained by indirect treatment comparisons from RCTs (network meta-analyses). The relative effect of cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years) was higher in patients with high disease activity vs all treatments except fingolimod and natalizumab. Effects on disability progression were largely nonsignificant, probably due to lack of power for such analysis.
Conclusion: In patients with RRMS, cladribine tablets showed lower ARR compared with matched patients who started interferon, glatiramer acetate, or dimethyl fumarate; was similar to fingolimod; and was higher than natalizumab. The beneficial effect of cladribine tablets was generally amplified in the subgroup of patients with high disease activity.
Will we ever get real head to heads. This will be the way