Safety of cladribine tablets in the treatment of patients with multiple sclerosis: An integrated analysis

Background: Treating patients with relapsing multiple sclerosis (MS) with cladribine tablets (two times 4 or 5 days of treatment each year for 2 years) results in long-lasting efficacy, with continued stability in many patients for 4 or more years. Safety and tolerability outcomes from individual clinical studies with cladribine tablets have been reported previously. Objective: Report safety data from an integrated analysis of clinical trials and follow-up in patients with MS to further characterize the safety profile of cladribine tablets. Methods: Data for patients treated with cladribine tablets 10 mg (MAVENCLAD (R); 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg) as monotherapy (n=923) or placebo (n=641) in Phase III clinical trials (CLARITY, CLARITY Extension and ORACLE-MS) and followed up in the PREMIERE registry were aggregated (Monotherapy Oral cohort). To better characterize rare events, additional data from earlier studies which involved the use of parenteral cladribine in patients with MS, and the ONWARD study, in which patients were given cladribine tablets in addition to interferon (IFN)-beta or placebo plus IFN-beta were included in an All Exposed cohort (cladribine, n=1926; placebo, n=802). Adjusted adverse events incidences per 100 patient-years (Adj-AE per 100 PY) were calculated for the integrated analyses. Results: The incidence rate of treatment-emergent adverse events (TEAEs) in the Monotherapy Oral cohort was 103.29 vs. 94.26 Adj-AEs per 100 PY for placebo. TEAEs that occurred more frequently with cladribine tablets were mainly driven by the TEAEs of lymphopenia (Adj-AE per 100 PY 7.94 vs. 1.06 for placebo) and lymphocyte count decreased (Adj-AE per 100 PY 0.78 vs. 0.10 for placebo) as anticipated due to the mode of action of cladribine. An increase in TEAE incidence rate was also observed in the cladribine tablets 3.5 mg/kg group vs. placebo for herpes zoster (Adj-AE per 100 PY 0.83 vs. 0.20, respectively). There were no cases of systemic, serious disseminated herpes zoster attributed to treatment with cladribine tablets. In general there was no increase in the risk of infections including opportunistic infections with cladribine tablets versus placebo, except for herpes zoster. Periods of severe lymphopenia (< 0.5x10(9) cells/L) were associated with an increased frequency of infections, but the nature of these was not different to that observed in the overall patient group treated with cladribine tablets 3.5 mg/kg. Within the constraints of a limited sample size, malignancy rates in the overall clinical program for cladribine in MS did not show evidence of an increase compared to placebo-treated patients and there was no increase in the incidence of malignancies over time in cladribine-treated patients. Conclusion: The AE profile for cladribine tablets 3.5 mg/kg as a monotherapy has been well-characterized in a pooled population of patients from early to more advanced relapsing MS. There was no increased risk for infections in general except for a higher incidence of herpes zoster. Lymphopenia was amongst the most frequently observed TEAEs that occurred at a higher incidence with cladribine relative to placebo. There was also no increase in malignancy rates for cladribine relative to placebo.