The Canadian Agency for Drugs and Technologies in Health (CADTH) has recommended that oral cladribine (Mavenclad) be reimbursed by provincial drug plans for the treatment of relapsing-remitting multiple sclerosis (RRMS). Patients who are eligible for oral cladribine are those with an inadequate response or poor tolerability with one prior disease-modifying therapy (DMT), and who have had at least one relapse within the previous 12 months.
CADTH is a quasi-governmental organization that provides healthcare decision-makers with recommendations on the use of drugs and medical devices in the Canadian healthcare system (except for Quebec). A CADTH recommendation is required before provincial formularies will consider reimbursing a drug. A favourable recommendation also encourages private third-party payers to add the drug to its list of insured medications.
Oral cladribine was approved for use in RRMS in November 2017. The drug is administered as tablets for two treatment weeks (4-5 days) per year for two years; the cumulative dose is 3.5 mg/kg.
The recommendation for public reimbursement was based on CADTH’s Canadian Drug Expert Committee (CDEC) review of the phase III CLARITY trial (Giovannoni et al. N Engl J Med 2010;362:416-426). In that study, cladribine was superior to placebo in reducing the annualized relapse rate (57% reduction) and was associated with a decreased risk of three-month confirmed disease progression compared with placebo (33% risk reduction). Overall, 80% of cladribine-treated patients (vs. placebo 61%) were relapse-free over the course of the study.
Supporting data included the long-term extension of the CLARITY trial (Giovannoni et al. Mult Scler 2018;24:1594-1604); a subgroup analysis of patients with high disease activity (Giovannoni et al. Mult Scler 2018; epublished April 1, 2018); a network analysis indirectly comparing oral cladribine with other DMTs (Siddiqui et al. Curr Med Res Opin 2018;34:1361-1137); and an unpublished health economic study.
CDEC stated that cladribine provides an alternative DMT for patients and offers a different safety profile. Although there are numerous other DMTs available for RRMS, CDEC said that there remains a need for drugs with alternative modes of administration and action. In addition, the Committee noted that many second-line DMTs are associated with potentially serious adverse effects, and cladribine may offer an alternative with a different safety profile.
The MS Society of Canada echoed the need for additional therapies, stating in its CDEC submission that only one-half of surveyed MS patients believe their current therapy is effective in managing their disease.
In its safety review, CDEC found that a similar proportion of patients experienced serious adverse events with cladribine (8%) and placebo (6%). The most common adverse effects were headache and lymphopenia. There were no notable differences in the risk of infections with cladribine compared to placebo; the sole exception was for herpes zoster, which occurred in 2% of cladribine-treated patients (vs. placebo 0%). No cases of progressive multifocal leukoencephalopathy (PML) have been reported in MS patients treated with oral cladribine. The proportion of patients who withdrew from CLARITY due to an adverse event was similar in the cladribine and placebo groups (1% for both groups).
CADTH’s conditions for reimbursement were use of oral cladribine in patients who had been previously treated with another DMT, management by a specialist with experience in the diagnosis and management of RRMS, and a price reduction. The CADTH condition of a relapse in the preceding year is not a requirement for use of oral cladribine in the Health Canada-approved product monograph.
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