OBJECTIVE:To evaluate the safety and efficacy of cladribine tablets in patients still experiencing active relapsing MS despite interferon (IFN)-β treatment.
METHODS: A 96-week phase II study, randomizing patients treated with IFN-β to cladribine tablets 3.5 mg/kg/IFN-β or placebo/IFN-β. Patients were to receive cladribine tablets 3.5 mg/kg/IFN-β or placebo/IFN-β in a 2:1 ratio (n = 172) with safety and exploratory efficacy outcomes being assessed.
RESULTS: Adverse events (AEs) and serious AEs were similar across treatment groups, except lymphopenia. Fifty of 124 (40.3%) cladribine/IFN-β recipients vs 0% of placebo/IFN-β recipients reported lymphopenia as an AE, with grade 3/4 lymphopenia (laboratory lymphocyte count < 500 cells/mm3) experienced by 79/124 (63.7%) vs 1 (2.1%), respectively. Patients treated with cladribine tablets 3.5 mg/kg/IFN-β were 63% less likely to have a qualifying relapse than placebo/IFN-β recipients, and cladribine tablets 3.5 mg/kg/IFN-β reduced most MRI measures of disease activity.
CONCLUSIONS: In patients with active relapsing MS despite IFN-β treatment, cladribine tablets 3.5 mg/kg/IFN-β reduced relapses and MRI lesion activity over 96 weeks compared with placebo/IFN-β but led to an increased incidence of lymphopenia.
CLASSIFICATION OF EVIDENCE:This study provides Class I evidence that for patients with active relapsing MS despite IFN-β treatment, cladribine tablets added to IFN-β reduced relapses and MRI lesion activity over 96 weeks and increased the incidence of lymphopenia.
Cladribine inhibts MS, as was shown in the CLARITY trials, but it was also indicated in other trials.
The ORACLE trial was at the first demyelinating event, and the ONWARD trial was comparing cladribine with interferon beta.
These trials were terminated when the manufacturers decided to can the development of oral cladribine.
Guess what the ONWARD trial showed?
Montalban X, Leist TP, Cohen BA, Moses H, Campbell J, Hicking C, Dangond F. Cladribine tablets added to IFN-β in active relapsing MS: The ONWARD study. Neurol Neuroimmunol Neuroinflamm. 2018 Jul 11;5(5):e477.
This study perhaps shows why cladribine has such a hard time getting approved. Cladribine had some serious adverse effects. The one still mentioned by the European Medicines Agency in the approval documentation was lymphopenia.
Which “numbnut” allowed this to be even considered as a adverse event?
It is not a “side-effect” but an “effect” and the mechanism of action of the drug.
Severe lymphopenia (grade 3/4) occurred in about 85% of our cohort of people treated with alemtuzumab, verses 1.5% treated with generic cladribine in our does-adjusted study and 6% in the first year of the oral cladribine CLARITY study. Even after the first year of treatmet cladribine only occurred in about 25% of people after 3.5mg/kg.
In this study there was 88.2% of people who had grade 3/4 (<500 cells/microlitre) lymphopenia following 5mg/kg cladrine and beta interferon), this dose was discontinued but about 65% of people got severe lymphopenia following delivery of 3.5mg/kg cladribine and beta interferon, so much more than with cladribine alone.
The annualised relapse rate was 0.12 on cladribine/beta interferon verses 0.32 with beta interferon alone. So the cladribine relapse rate was similar to that observed in the CLARITY study.
There were no malignancies reported in the patients, so supporting our idea that the cancer reported in the CLARITY study was, in part, a statistical fluke.
COI: Have received consultancy from Merck.