Cladribine Tablets in the Treatment of Patients with Multiple Sclerosis: An Integrated Analysis of Safety from the Multiple Sclerosis Clinical Development Program

Background: Treatment with cladribine tablets in the CLARITY, CLARITY Extension, and ORACLE-MS studies demonstrated efficacy vs placebo across a spectrum of patients with both early and relapsing multiple sclerosis (RMS). The adverse event (AE) profiles from these individual studies have been presented elsewhere. Pooling safety data for integrated analyses is an established route to a comprehensive characterization of the safety profile of a therapy.

Objectives: To report the emergent overall adverse event (AE) profile from an integrated pool of safety data collected in trials which evaluated cladribine tablets as monotherapy, in patients with early or RMS. 

Methods: The monotherapy oral cohort (patients who received cladribine tablets only) was derived from CLARITY, CLARITY Extension, ORACLE-MS, and the PREMIERE registry, and included 923 patients who received cladribine tablets 3.5 mg/kg: 3432.65 patient years exposure for this dose. 641 patients received placebo in this cohort (2025.97 patient years). Adjusted adverse events incidences per 100 patient years (Adj-AE per 100PY) were calculated for the integrated analyses. 

Results: The mean study period for patients was 194 weeks in the monotherapy oral 3.5 mg/kg cohort and 165 weeks in the placebo cohort; age (36.5 years), proportion of females (66.3%) and prior disease modifying drug experience were balanced among groups. Adj-AE per 100PY rates for cladribine 3.5 mg/kg and placebo were: treatment emergent AE (TEAE): 103.3 and 94.3; TEAEs leading to discontinuation: 2.1 and 1.1; serious AEs: 4.0 and 3.6; serious AEs leading to death: 0.26 and 0.25. With regard to the known, expected events with cladribine treatment, Adj-AE per 100PY for lymphopenia (preferred term) were 7.94 (3.5 mg/kg) and 1.06 (placebo), and for system organ class of infection and infestations, 24.93 (3.5 mg/kg) and 27.05 (placebo); herpes zoster (preferred term), 0.83 (3.5 mg/kg) and 0.20 (placebo). Adj-AE per 100PY for the system organ class of neoplasms, benign, malignant, and unspecified were 1.14 and 1.01, for cladribine and placebo, respectively. 

Conclusions: The AE profile for cladribine tablets 3.5 mg/kg as a monotherapy has been well-characterized in a pooled population of patients with early and active MS. Lymphopenia was expected from the mode of action of cladribine tablets, but with no evidence for an overall increased risk of infections, or neoplasms.