Cladribine FDA Approval Comes with Boxed Warning Label

A majority of US multiple sclerosis (MS) patients will now have a treatment option that emphasizes a brief, efficient regimen. But it also comes with risks of malignancy.

At the end of last week, the US Food and Drug Administration (FDA) approved cladribine tablets (MAVENCLAD) as the first short-course therapy indicated for the treatment of relapsing-remitting MS (RRMS), as well as active secondary progressive MS (SPMS). According to manufacturer EMD Serono, the oral treatment is also the first of its kind to be backed by 2 years worth of proven clinical efficacy assessing for a 20-day maximum treatment period.

It’s been a long time coming for the brief-regimen drug. It was first approved for marketing in the European Union in September 2017, after years of clinical assessment in response to a 2011 FDA rejection that was based on concerns that cladribine is associated with cancer risks.

Its approval last week included a disclaimer that the drug not be prescribed to patients with clinically isolated syndrome due to a malignancy risk. It includes a boxed warning for potential malignancy and teratogenicity risks in treated patients.

Interestingly—and likely telling to the safety concerns associated with the drug—the exact therapeutic mechanisms of cladribine in patients with MS are still not fully known. Investigators currently believe the drug has a cytotoxic effect on B and T lymphocytes due to its impairment of DNA synthesis, which leads to a dose-dependent reduction in patient lymphocyte counts.

And though the benefit in cladribine may be in its shortened regimen, it comes with a caveat that resuming or supplementing dosing could increase the risk of malignancy after 2 years of care. Currently, investigators have not assessed the drug’s safety and efficacy more than 2 years after the completion of the 2 recommended treatment courses.

What data that did evidence its efficacy, safety, and tolerability was found in a clinical program that assessed 1976 treated patients for 9506 total patient years (4.8 mean treatment period plus follow-up). Clabribine resulted in a 58% relative reduction in annualized relapse rate (ARR) versus placebo (P < .001), and helped 81% of treated patients avoid any relapse after 2 years of short-course therapy. However, 63% of patients on placebo also had avoided relapse after 2 years (P < .05).

Treated patients reported a 33% risk reduction for three-month confirmed disability progression versus placebo patients, as per the Expanded Disability Status Scale (EDSS) (P < .05).

Common adverse reactions reported in more than 20% of treated patients in the pivotal phase 3 CLARITY trial included upper respiratory tract infection, headache, and lymphopenia. Patients administered cladribine reported 0.27 malignancies per 100 patient-years, versus just 0.13 malignancies per 100 patient-years in patients on placebo.

Though the drug has already been approved for marketing in approximately 50 other countries, its eventual re-consideration by the FDA has been followed with interest. In an interview with MD Magazine last year, James Stankiewicz, MD, assistant professor of Neurology at Harvard Medical School, called cladribine and siponomod—which also won FDA approval for RRMS last week—among the most interesting short-term developments in MS care.

“It has an interesting mechanism, so that patients get an oral pill just for like 5 days or so and then it carries them over for a year, then they would get reduced,” Stankiewicz said. “In general, I'd say that the efficacy of the drug is pretty good, and the safety profile looks pretty good, so I think that it'll be a good option for some patients.”

More focused on its usability as a short-term oral therapy, Thomas Leist, MD, PhD, director of the Comprehensive Multiple Sclerosis Center at Jefferson University Hospitals—and an investigator in cladribine’s clinical trial programs&mdash;expressed pleasure to its inclusion on the US market for MS care.

“With short treatment courses with pills taken for no more than 10 days in a year and no injections or infusions, MAVENCLAD is an efficacious new treatment option for MS,” he said in a statement. “MAVENCLAD is a welcome new oral treatment option for this heterogeneous and often unpredictable disease."