Multiple Sclerosis Society of Canada

Cladribine



Overview:
  • Brand name: Movectro (EMD Serono - Merck)
  • Route of administration: oral
  • Type: anti-lymphocyte compound
  • Emerging treatment for: RRMS
  • Status: In Phase III of clinical trials
How it Works:

Cladribine selectively targets and accumulates in certain types of white blood cells (lymphocytes), such as disease-causing T cells. By interfering with a target cell’s ability to process DNA, it leads to the depletion of disease-causing lymphocytes and results in reduced inflammation. Since cladribine is easily destroyed in normal cells except for blood cells, it can result in relatively few side effects as the drug does not target other, healthy cells.

Cladribine is approved by Health Canada in an injectable form for the treatment of hairy cell leukemia.

Research and Results:

A phase III clinical trial (CLARITY) tested the safety and efficacy of oral cladribine in 1,326 participants living with relapsing remitting MS. The randomized, double-blind trial compared the effects of two doses of cladribine (3.5 mg/kg, and 5.25 mg/kg) against a dummy treatment (placebo) and followed the participants for up to 2 years. Treatment with cladribine caused a 58% reduction in annual relapse rate compared to placebo at the lower dose and 55% at the higher dose. Participants taking cladribine also had a lower risk of sustained disability progression at 3 months and had fewer brain lesions as seen on imaging scans. An extension study evaluated the long term safety and efficacy of cladribine over 2 additional years after treatment with cladribine had ended. Unpublished results that were presented at the 2016 American Academy of Neurology meeting showed that the benefits of cladribine were maintained over the course of the additional 2 years.

A phase III clinical trial (ORACLE MS) was conducted to determine if cladribine can reduce the risk of conversion to MS in those who have experienced a first clinical demyelinating event (i.e. those with clinically isolated syndrome – CIS). The trial was conducted in 616 participants, who received either low or high dose cladribine, or placebo. Both doses of cladribine significantly delayed the conversion to MS in those with CIS compared to placebo.

A phase II trial (ONWARD) evaluated the safety and effectiveness of cladribine as an add-on treatment to interferon-beta (IFN-beta) in participants who had experienced at least one relapse while on IFN-beta therapy. Participants were randomized to receive either cladribine and IFN-beta or placebo and IFN-beta. In findings presented at the 2016 American Academy of Neurology meeting, those treated with cladribine and IFN-beta were 63% less likely to experience relapses than those on placebo and IFN-beta after 2 years. Cladribine as an add-on treatment also reduced the number of brain lesions on imaging scans.

Adverse Effects Reported:

Both the Food and Drug Administration (FDA) in 2009 and the European Medicines Agency (EMA) in 2010 rejected the licence application for cladribine due to concerns of cancer, as cases were observed in the treatment group during the CLARITY trial. The application for license was subsequently discontinued. However, further research has demonstrated that the risk of cancer in participants treated with caldribine was not increased compared to participants receiving treatment in earlier phase III trials for other, approved disease-modifying therapies. Merck has restarted the license application process to the EMA. The MS Society will monitor updates on the submission as well as submissions to the FDA and Health Canada, which are also expected.

Adverse effects of cladribine reported in trials to date include infections due to a reduction in the number of circulating white blood cells. Other common side effects have included headaches and common cold symptoms. A small proportion of participants have experienced shingles.

References:

1. Giovannoni G et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. NEJM 2010;362(5):416-26.

2. Hartung HP, et al. Development of oral cladribine for the treatment of multiple sclerosis. J Neurol. 2010;257(2):163-170.

3. Pakpoor J, et al. No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol Neuroimmunol Neuroinflamm. 2015;2:e158.