Cladribine (also known as Mavenclad™)
Experimental Medications: Administered Orally
- Oral medication taken for a maximum of 20 days over two years
- Being studied in RRMS
Cladribine, which is marketed in several countries under the trade name Mavenclad, selectively targets the immune system’s B cells and T cells, leading to depletion of those cells. This is followed by a distinct pattern of “reconstitution,” as new B cells and T cells are produced. The medication has an interesting dosing regimen, with two annual courses given for a maximum of 20 days over two years. Its developers note that this approach avoids continuous suppression of the immune system.37
This medication received marketing authorization from the European Commission in August 2017. In December 2017, Canadian health authorities approved cladribine as a monotherapy for the treatment of adults with RRMS to reduce the frequency of clinical exacerbations and delay the progression of disability. Merck has said it plans to seek regulatory approval in other countries, including the United States.37
In announcing the Canadian approval, Merck noted that cladribine generally is recommended for patients who have had an inadequate response to, or are unable to tolerate, one or more other MS therapies. They added that in clinical trials, cladribine demonstrates efficacy across key measures of disease activity in patients with RRMS, including disability progression, annualized relapse rate, and MRI activity.37
In the 96-week, Phase III CLARITY trial, 1,326 patients with RRMS were randomized in a roughly 1:1:1 ratio to receive 3.5 mg of cladribine per kilogram (kg) of body weight, 5.25 mg/kg. Cladribine, or placebo, was given in two or four short courses for the first 48 weeks. This was followed by two short courses starting at Week 48 and Week 52, for a total of 8 to 20 days of treatment per year.38
Patients receiving cladribine at either dose had annualized relapse rates that were less than half the rate of individuals receiving placebo. Roughly 79 percent of the cladribine-treated patients did not have a relapse over the 96-week study period, as compared to 61 percent of people in the placebo group. Individuals receiving cladribine, at either dose, also had a lower risk of sustained progression of disability and a greater reduction in the number of brain lesions identified on MRI relative to the placebo group. However, patients receiving cladribine had a higher rate of adverse events. In particular, lymphopenia – abnormally low counts of white blood cells that play a role in fighting infection – was seen in 21.6 percent of those receiving the lower dose of cladribine, 31.5 percent of those on the higher dose of cladribine, and just 1.8 percent of people in the placebo group. Similarly, 20 patients receiving cladribine reported herpes zoster infection, while no one in the placebo group developed this infection.38
Other studies in the cladribine clinical development program include:
- The CLARITY extension study: a two-year Phase III placebo-controlled study, following on from the CLARITY study to evaluate the safety and efficacy of cladribine over four years.
- The ORACLE MS (Oral Cladribine in Early MS) study: a two-year Phase III placebo-controlled study to evaluate the efficacy and safety of cladribine as a monotherapy in patients at risk of developing MS because they have experienced a first clinical event suggestive of MS.
- The ONWARD (Oral Cladribine Added ON To Interferon beta-1a in Patients With Active Relapsing Disease) study: a Phase II placebo-controlled study to evaluate the safety and tolerability of adding cladribine to interferon-beta therapy in RMS patients who have experienced breakthrough disease while on interferon-beta.
- PREMIERE (Prospective Observational Long-term Safety Registry of Multiple Sclerosis Patients Who Have Participated in Cladribine Clinical Studies) trial: an interim long-term follow-up data from the prospective registry, PREMIERE, to evaluate the safety and efficacy of cladribine. This will include more than 10,000 patient years of data with more than 2,700 patients included in the clinical trial program, and more than 10 years of observation in some patients.37
At the Joint ECTRIMS-ACTRIMS Meeting in October 2017, Czech investigators reported that cladribine has an effect on relapses comparable to Gilenya® (fingolimod), and an impact on MS-related disability similar to Gilenya and interferon-beta. They added that cladribine may be associated with superior recovery from disability relative to Gilenya, interferon-beta, and Tysabri® (natalizumab).
They reached those conclusions by analyzing one-year relapse and disability outcomes for more than 5,200 patients in an MS registry. Using a method called propensity-score matching, they compared similar types of patients taking the various medications. While the size of the cladribine group was small – 37 patients versus 1,410 to 1,940 for the other three groups – statistical analyses supported the validity of the findings.39