Medicine & Research

Six years ago, no oral agents had been approved by the U.S. Food and Drug Administration or the European Medicines Agency for the treatment of patients with multiple sclerosis. There appeared to be a race between several products (i.e., cladribine, fingolimod, and laquinimod) to be the first oral agent approved in either the U.S. or Europe for the treatment of patients with MS. According to Dr. Ben Thrower, medical director of the Multiple Sclerosis Institute at the Shepherd Center in Atlanta, many experts felt that cladribine would be the first oral agent approved by the FDA for the treatment of MS.

A New Drug Application for oral cladribine as a short-course therapy for patients with MS was submitted to the Food and Drug Administration in September 2009. The NDA submission was supported by evidence from the CLARITY study, which evaluated the effects of oral cladribine in 1,326 people with RMS. Patients in the CLARITY study received either short-courses of oral cladribine or placebo. After two years, the patients who received oral cladribine had fewer MS relapses and less disability progression, than those who received a placebo. These findings were presented at the 61st annual meeting of the American Academy of Neurology in April 2009 and more recently published online in The New England Journal of Medicine in January 2010.
 
Regulating authorities in both the U.S. and Europe were concerned about the reports of cancer in the CLARITY study. In March 2011, the FDA informed EMD Serono/Merck that it would not approve oral cladribine as a treatment for MS without more safety information. Around the same time, the European Medicines Agency also rejected cladribine’s application.
 
Since the FDA and European Medicines Agency refusal of cladribine, three oral agents have been approved for the treatment of patients with RMS. These products include fingolimod, dimethyl fumerate, and teriflunomide. These products generally have comparable efficacy and safety data compared to the other disease-modifying therapies currently approved by the FDA.
 
Since the decisions by the FDA and European Medicines Agency, more data on oral cladribine as a treatment for patients with MS have become available. Based on these new data, EMDSerono/Merck announced in 2016 that the European Medicines Agency has accepted for review the Marketing Authorization Application of cladribine as a therapy for patients with the RMS. According to Luciano Rossetti, Head of Global R&D for the Biopharma business, Merck, “Although there are multiple therapies available for relapsing-remitting MS, there is still a significant unmet medical need with a focus on efficacy, dosing, durability and safety. We believe that cladribine tablets, if approved, would have a first-of-its-kind dosing regimen and serve as an important therapeutic option for patients with relapsing-remitting MS.”
 
The submission to the European Medicines Agency is based on results from three Phase III clinical trials – CLARITY, CLARITY extension, and ORACLE MS – and the Phase II ONWARD trial. In these trials, treatment with oral cladribine significantly reduced relapse rates and the risk of disability progression and development of new MS lesions, compared to placebo. Together with interim, long-term follow-up results from the prospective registry PREMIERE, the new MAA also comprises follow-up data of more than 10,000 patient years of exposure, with some patients having a follow-up period surpassing eight years.
 
According to Dr. Thrower, many clinicians in the U.S. are awaiting the decision of the European Medicines Agency. A positive decision could lead EMD Serono/Merck to resubmit a NDA to the FDA.