What is the recommended treatment regimen for Mavenclad (cladribine) in highly active multiple sclerosis?

Mavenclad (Cladribine Tablets) Treatment Regimen for Highly Active Relapsing Multiple Sclerosis

Mavenclad is administered as a cumulative dose of 3.5 mg/kg body weight over two years, consisting of two annual treatment courses, with each course comprising two short treatment weeks (4-5 days) separated by one month, followed by no treatment for at least two years. 1, 2

Dosing Schedule

Year 1:

• Month 1: 4-5 days of treatment
• Month 2: 4-5 days of treatment (one month after Month 1)
• Months 3-12: No treatment

Year 2:

• Month 13: 4-5 days of treatment
• Month 14: 4-5 days of treatment (one month after Month 13)
• Months 15-24: No treatment

Years 3-4:

• No additional treatment required 1, 2

Administration Details

• Timing: Take tablets on an empty stomach, at least 3 hours after food, and wait at least 30 minutes before eating, as food delays absorption (median Tmax increases from 0.5h to 1.5h) and reduces maximum concentration by 29% 2
• Bioavailability: Approximately 40% oral bioavailability with rapid absorption 2
• Mechanism: Cladribine preferentially depletes lymphocytes through intracellular accumulation (30-40 fold versus extracellular concentrations within 1 hour), targeting the key cells underlying MS pathogenesis 1, 2

Critical Monitoring and Treatment Modifications

Before initiating Year 2 treatment, absolute lymphocyte count (ALC) must be assessed: 3

• If ALC is Grade 0 (normal) or Grade 1 lymphopenia: Proceed with Year 2 treatment as scheduled 3
• If ALC is Grade ≥2 lymphopenia: Postpone Year 2 treatment until ALC recovers to Grade 0-1 3
• If prolonged Grade 2-4 lymphopenia persists beyond the maximally permitted postponement period: Consider treatment discontinuation (affects <1% of patients) 3

This postponement algorithm reduces the risk of severe lymphopenia during Year 2 while preserving efficacy, with approximately 92% of patients not requiring any treatment postponement 3

Safety Profile and Key Adverse Events

Lymphopenia is the most characteristic adverse event (7.94 adjusted adverse events per 100 patient-years versus 1.06 for placebo), which is expected given the drug's mechanism of action 4

Herpes zoster infection risk is increased (0.83 versus 0.20 adjusted adverse events per 100 patient-years for placebo), though no cases of systemic, serious disseminated herpes zoster have been attributed to cladribine tablets 4

Periods of severe lymphopenia (<0.5 × 10⁹ cells/L) are associated with increased infection frequency, but the nature of these infections does not differ from the overall patient group 4

No increased risk of overall infections or opportunistic infections (except herpes zoster), and no evidence of increased malignancy rates compared to placebo-treated patients or matched reference populations 1, 4

Clinical Efficacy

The CLARITY trial demonstrated that this regimen reduces clinical relapse, disability progression, and MRI-assessed disease activity over 96 weeks in adults with relapsing-remitting MS 1

Importantly, the CLARITY extension study showed no additional clinical benefit from continuing cladribine tablets beyond the first two annual courses, supporting the 2-year treatment, 2-year no-treatment approach, though MRI activity was more notable in a subset who discontinued 1

Post hoc analyses demonstrated that benefits in patients with high disease activity (HDA) relapsing MS were sometimes greater than in patients without HDA 1

Unique Advantages

This represents the first short-course oral disease-modifying drug for MS, requiring only 20 days of oral treatment over 2 years to deliver 4 years of disease control, offering significant convenience compared to continuous therapies 1, 5

The pharmacokinetics show rapid lymphocyte distribution and retention (as parent drug or phosphorylated metabolites), resulting in targeted, durable lymphocyte reduction that explains the prolonged efficacy without continuous dosing 2