le efficacy endpoints were exploratory.
The magnitude of the effect in reducing the frequency of relapses and slowing disability progression in patients receiving the 3.5 mg/kg dose over 2 years was maintained in years 3 and 4 (see section 4.2).
Efficacy in patients with high disease activity
Post-hoc subgroup efficacy analyses have been conducted in patients with high disease activity treated with oral cladribine at the recommended 3.5 mg/kg cumulative dose. These included
• patients with 1 relapse in the previous year and at least 1 T1 Gd+ lesion or 9 or more T2 lesions, while on therapy with other DMDs,
• patients with 2 or more relapses in the previous year, whether on DMD treatment or not.
In the analyses of the CLARITY data, a consistent treatment effect on relapses was observed with the annualised relapse rate ranging from 0.16 to 0.18 in the cladribine groups and 0.47 to 0.50 in the placebo group (p <0.0001). Compared to the overall population, a greater effect was observed in time to 6-month sustained disability where cladribine reduced the risk of disability progression by 82% (hazard ratio = 0.18, 95% CI [0.07, 0.47]). For placebo the 10th percentile for disability progression was reached between 16 and 23 weeks, while for the cladribine groups it was not reached during the entire study.
Secondary progressive MS with relapses
A supportive study in patients treated with cladribine as an add-on to interferon-beta vs. placebo + interferon-beta also included a limited number of patients with secondary progressive MS (26 patients). In these patients, treatment with cladribine 3.5 mg/kg resulted in a reduction of the annualised relapse rate compared to placebo (0.03 versus 0.30, risk ratio: 0.11, p <0.05). There was no difference in annualised relapse rate between patients with relapsing-remitting MS and patients with secondary progressive MS with relapses. An effect on disability progression could not be shown in either subgroup.
Patients with secondary progressive MS were excluded in the CLARITY study. However, a post-hoc analysis of a mixed cohort including CLARITY and ONWARD patients, defined by a baseline EDSS score of ≥3.5 as a proxy for secondary progressive MS, showed a similar reduction in annualised relapse rate compared to patients with an EDSS score below 3.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with MAVENCLAD in all subsets of the paediatric population in multiple sclerosis (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Cladribine is a prodrug that has to be phosphorylated intracellularly to become biologically active. Cladribine pharmacokinetics were studied following oral and intravenous administration in MS patients and patients with malignancies, and in in vitro systems.
Absorption
Following oral administration, cladribine is rapidly absorbed. Administration of 10 mg cladribine resulted in a cladribine mean Cmax in the range of 22 to 29 ng/mL and corresponding mean AUC in the range of 80 to 101 ng•h/mL (arithmetic means from various studies).
When oral cladribine was given in fasted state, median Tmax was 0.5 h (range 0.5 to 1.5 h). When administered with a high-fat meal, cladribine absorption was delayed (median Tmax 1.5 h, range 1 to 3 h) and Cmax was reduced by 29% (based on geometric mean), while AUC was unchanged. The bioavailability of 10 mg oral cladribine was approximately 40%.
Distribution
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