Cladribine Gets Approval for Multiple Sclerosis


The EMD Serono product was approved based on data which displayed a significant decrease in the number of relapses experienced by patients with MS who had ≥1 relapse in the previous year, compared to placebo.

Dr Thomas Leist, PhD

Thomas Leist, MD, PhD, director of the Comprehensive Multiple Sclerosis Center at Thomas Jefferson University

Thomas Leist, MD, PhD

The FDA has approved cladribine (Mavenclad, EMD Serono), an oral therapy, for the treatment of relapsing multiple sclerosis (MS), as well as active secondary progressive MS. The treatment is not recommended for use among patients with clinically isolated syndrome.1

The purine analog is a synthetic agent that targets lymphocytes and selectively suppresses the immune system, with the goal of depleting lymphocytes in order to “reset” it. It was approved based on the data from a trial including more than 1300 patients with relapsing forms of MS, ultimately showing a significant decrease in the number of relapses experienced by patients who had ≥1 relapse in the previous year, compared to placebo.

“We are committed to supporting the development of safe and effective treatments for patients with multiple sclerosis,” Billy Dunn, MD, director of the Division of Neurology Products, FDA Center for Drug Evaluation and Research, said in a statement. “The approval of Mavenclad represents an additional option for patients who have tried another treatment without success.”

Thomas Leist, MD, PhD, director of the Comprehensive Multiple Sclerosis Center at Thomas Jefferson University, who was involved in the clinical development of cladribine, previously told NeurologyLive® that as an immune reconstitution therapy, it represents a novel approach toward the treatment of MS. These kinds of agents take away autoreactive immune cells and will enable a recrudescence of sorts of the immune system that is, notably he said, non-self-reactive.

“Obviously, these agents are associated with a reduction of immune cells, and so an infection risk is a potential concern,” Leist said. “As we looked at cladribine development, this infection risk was higher during a relatively short period of time when patients had low lymphocyte counts. In general, with cladribine, the lymphocyte counts are low, but Grade 3 and Grade 4 lymphopenias have only been observed in a small number of patients.”

Despite receiving a Complete Response Letter in 2010 requesting more data, the treatment was approved for use in Europe and has continued through the development pipeline. Now, it has data up to 10 years in some patients from 3 phase 3 clinical trials including CLARITY (NCT00213135), CLARITY-EXT (NCT00641537), and ORACLE-MS (NCT00725985), as well as the PREMIERE study (NCT01013350). The tablet is administered a maximum of 20 days over a period of 2 years, and thus far has shown consistent safety data and that No Evidence of Disease Activity-3 (NEDA-3) status can be maintained for up to 4 years post-treatment.2

“At [the Americas Committee for Treatment and Research in Multiple Sclerosis Forum] we presented some very interesting information which really characterized the long-term safety profile of cladribine, and we also talked about the sustained efficacy that we’ve seen, as well as some data for particular subgroups,” John Walsh, MD, vice president of US Medical Affairs in Neurology and Immunology at EMD Serono, told NeurologyLive® earlier this month. “In addition to that, the fact that we do have data in some patients now for up to about 10 years—particularly in terms of follow-up for safety—is something that is very important to us. It tells us a lot about a product that is not often seen at the time of approval.

“From an efficacy perspective, we looked at the severity and frequency of relapses. Hospitalization and steroid use are good markers that people often look to in order to understand the severity of patients who are experiencing relapse, and this analysis looked at all of our relapses as a whole, but also in a post-toxic fashion in those patients who have use of steroids and hospitalization. We showed a >50% reduction, irrespective of steroid or hospitalization,” Walsh continued.

According to the FDA, the treatment “must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. Mavenclad has a Boxed Warning for an increased risk of malignancy and fetal harm. Mavenclad is not to be used in patients with current malignancy. In patients with prior malignancy or with an increased risk of malignancy, health care professionals should evaluate the benefits and risks of the use of Mavenclad on an individual patient basis.”1

It is recommended that standard cancer screening guidelines are followed in those treated with cladribine, and it is not recommended to be used in patients who are pregnant and both men and women who do not plan to use effective contraception during treatment. Other warnings for its use include the risk of decreased lymphocyte counts, which should be monitored before, during, and after treatment. The agency noted that it may cause hematologic toxicity and bone marrow suppression so health care professionals should measure a patient’s complete blood counts before, during and after therapy.

The most common adverse events (AEs) reported by patients receiving Mavenclad in the clinical trials include upper respiratory tract infections, headache and decreased lymphocyte counts.

In NeurologyLive®'s Peer Exchange video series, Advances in the Diagnosis and Management of Multiple Sclerosis, a panel of experts, including Leist, spoke about the considerations for utilizing the therapy in the treatment of MS. Click to watch:


1. FDA approves new oral treatment for multiple sclerosis [press release]. Silver Spring, MD: FDA; Published March 29, 2019. Accessed March 29, 2019



G, Keller B, Jack D. Durability of NEDA-3 status in patients with relapsing multiple sclerosis receiving cladribine tablets: CLARITY extension. Presented at: ACTRIMS Forum; February 28 to March 2, 2019; Dallas, TX. Poster #3658. Accessed March 29, 2019.

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