Health Canada has approved cladribine tablets for the treatment of adults with relapsing-remitting multiple sclerosis (RRMS), to reduce the frequency of clinical exacerbations and delay the progression of disability. The drug, marketed as Mavenclad, may be used for newly-diagnosed patients, but is generally recommended in MS patients with an inadequate response or poor tolerability to a prior MS therapy.
Cladribine will be available as 10-mg pills, with dosing determined by body weight. The drug is administered for 4-5 days in weeks 1 and 5 in Year 1, and weeks 1 and 5 in Year 2. The cumulative dose is 3.5 mg/kg over two years.
Cladribine is an immunosuppressant that selectively depletes T and B cells (for the mechanisms of action, see Cladribine: intermittent immunosuppression in MS, NeuroSens, September 21, 2017), Approval was based on the results of the phase III CLARITY trial (Giovannoni et al. N Engl J Med 2010;362:416-426), which randomized subjects to placebo or cladribine 3.5 mg/kg or 5.25 mg/kg for two years. The annualized relapse rate was 0.14 with cladribine 3.5 mg/kg versus 0.33 with placebo, a reduction of 58%. The mean number of active T2 lesions was reduced 73.4% compared to placebo; the number of gadolinium-enhancing lesions was reduced 85.7% versus placebo. The proportion of patients with no evidence of disease activity (NEDA) was 47% (Giovannoni et al. Lancet Neurol 2011;10:329-337). (See also Cladribine tablets – Updated efficacy and safety results, NeuroSens, November 28, 2017).
Prior to initiating cladribine tablets, patients must have a normal lymphocyte count, and should be evaluated for tuberculosis, hepatitis B and hepatitis C virus. Varicella zoster (VZV) status should be checked; vaccination at least 6 weeks prior to cladribine initiation is recommended in patients who are VZV antibody-negative. A baseline MRI is recommended to rule out progressive multifocal leukoencephalopathy (PML) in patients with prior exposure to an MS therapy that may be associated with PML (i.e. natalizumab, dimethyl fumarate, fingolimod). Cladribine is contraindicated in women who are pregnant or breastfeeding. Female and male patients should be advised to use effective contraception for at least six months after the last dose of cladribine tablets.
During treatment, a lymphocyte count should be obtained prior to Year 2 dosing, and periodically during the treatment course and thereafter. Re-dosing in Year 2 or thereafter should only be performed in patients with Grade 0-1 lymphopenia; re-dosing may be delayed up to six months to enable lymphocyte counts to recover in patients with Grade >2 lymphopenia. There is an increased risk of infection, most notably herpes zoster, during periods of severe lymphopenia. Antiviral prophylaxis should be considered during periods of Grade 4 lymphopenia (< 200 cells/mm³). No cases of PML have been reported with cladribine tablets in MS, but physicians should remain vigilant for clinical symptoms or MRI findings suggestive of PML, particularly if patients were switched from another MS therapy with a risk of PML.
The most common adverse events associated with cladribine tablets were headache (25.8% vs. 20.9% with placebo), lymphopenia (19.9% vs. 1.2%), upper respiratory tract infection (11.2% vs. 9.0%), nausea (10.6% vs. 9.9%), and back pain (7.6% vs. 6.4%). The incidence of herpes zoster was 2.0% versus 0.2% with placebo. In clinical studies and long-term follow-up, the incidence of malignancy was similar with cladribine tablets and placebo.