Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study

Abstract

Background: Cladribine is a synthetic deoxyadenosine analogue in development as an oral multiple sclerosis (MS) therapy. Objective: To report in detail the safety findings from the 96-week, phase III, double-blind CLARITY study, which evaluated treatment with cladribine tablets in relapsing-remitting MS. Methods: A total of 1,326 patients were randomized 1 : 1 : 1 to two short-course regimens of cladribine tablets (3.5 or 5.25 mg/kg cumulative dose over 96 weeks) or placebo. Safety assessments included monitoring for adverse events (AEs), routine physical and neurologic examinations and frequent laboratory parameter assessments. Results: Of the randomized patients, 88.6% completed treatment with cladribine tablets versus 86.3% with placebo. Lymphopenia was the most commonly reported AE in patients treated with cladribine tablets and was anticipated based on the mechanism of action. The incidence of infections was 48.3% with cladribine tablets and 42.5% with placebo, with 99.1% and 99.0% rated mild-to-moderate by investigators. Herpes zoster infections developed in 20 (2.3%) cladribinetreated patients; all cases were dermatomal. There were no herpes zoster infections in the placebo group. Nine (1.0%) patients experienced events related to uterine leiomyomas in the cladribine tablets groups versus one (0.2%) with placebo. Three isolated cases of malignancy were reported in cladribine-treated patients during the study; a fourth was reported during post-study surveillance. A pre-malignant cervical carcinoma in situ was also reported. The incidence of malignancies during the study did not exceed the expected rate in a population standardized for country, gender and age. Conclusion: The safety and tolerability profile observed in the CLARITY study together with the reported efficacy support the potential for cladribine tablets as an MS therapy.

Immunomodulatory medicines for multiple sclerosis: Progress and prospects

“…In a Phase III trial of 1,326 patients that were randomly assigned one of two cumulative doses of cladribine (3.5 mg or 5.25 mg/kg of body weight), cladribine significantly reduced relapse rates, the risk of disability progression, and MRI measures of disease activity at 96 weeks [Giovannoni et al, 2010]. However, because of safety concerns (e.g., lymphocytopenia, herpes zoster infections, and neoplasms including malignancies) were more common in cladribine than placebo recipients [Cook et al, 2011], approval was declined from the EMEA and the FDA, in 2010 and 2011, respectively. Following the FDA ruling, cladribine was withdrawn from the market in both Australia and Russia.…”

Update on reproductive safety of current and emerging disease-modifying therapies for multiple sclerosis

“…[41][42][43] Data on cladribine exposure in human pregnancy are limited. 43,44 A successful pregnancy following administration of cladribine to a patient with hairy cell leukemia was reported. 45 It is not known if cladribine crosses the placenta or is secreted in breast milk.…”

The future of multiple sclerosis treatments

“…Later, cladribine was tested as an oral agent for RRMS, tablets being taken in two cycles of few days per year [84]. Cladribine for RRMS was tested in the placebo-controlled CLARITY trial and reduced both the frequency and severity of relapses, and suppressing the MRI enhancing lesions at 6 months [87]. The recently reported results of a 120-week extension demonstrated that in a majority of patients, the clinical benefits on relapses and disability as well as on MRI outcome measures of 3.5mg/kg cladribine given in the first two years of the trial can be maintained for at least 4years [88,89].…”