The Development of Cladribine Tablets for the Treatment of Multiple Sclerosis: A Comprehensive Review
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REVIEW ARTICLE
The Development of Cladribine Tablets for the Treatment of Multiple Sclerosis: A Comprehensive Review Kottil Rammohan1 · Patricia K. Coyle2 · Elke Sylvester3 · Andrew Galazka3 · Fernando Dangond4 · Megan Grosso5 · Thomas P. Leist6
© The Author(s) 2020
Abstract Cladribine is a purine nucleoside analog initially developed in the 1970s as a treatment for various blood cancers. Due to the molecule’s ability to preferentially reduce T and B lymphocytes, it has been developed into an oral formulation for the treatment of multiple sclerosis (MS). The unique proposed mechanism of action of cladribine allows for the therapy to be delivered orally over two treatment-week cycles per year, one cycle at the beginning of the first month and one cycle at the beginning of the second month of years 1 and 2, with the potential for no further cladribine treatment required in years 3 and 4. This review summarizes the clinical development program for cladribine tablets in patients with MS, including the efficacy endpoints and results from the 2-year phase III CLARITY study in patients with relapsing–remitting MS (RRMS), the 2-year CLARITY EXTENSION study, and the phase III ORACLE-MS study in patients with a first clinical demyelinating event at risk for developing MS. Efficacy results from the phase II ONWARD study, in which cladribine tablets were administered as an add-on to interferon-β therapy in patients with RRMS, are also summarized. A review of all safety data, including lymphopenia, infections, and malignancies, is provided based on data from all trials in patients with MS, including the initial parenteral formulation studies. Based on these data, cladribine tablets administered at 3.5 mg/kg over 2 years have been approved across the globe for various forms of relapsing MS.
1 Introduction Multiple sclerosis (MS) is a chronic, inflammatory, immunemediated demyelinating and neurodegenerative disease of the central nervous system (CNS). It is one of the most Enhanced Digital Features To view enhanced digital features for this article, go to https://doi.org/10.1007/s40265-020-01422-9 * Kottil Rammohan [email protected] 1
Multiple Sclerosis Center, University of Miami, Miami, FL, USA
2
Multiple Sclerosis Comprehensive Care Center, Stony Brook University, Stony Brook, NY, USA
3
Merck KGaA, Darmstadt, Germany
4
EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany
5
EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany
6
Comprehensive MS Center, Jefferson University, Philadelphia, PA, USA
common causes of serious neurological disability in young adults, and one of the most prevalent neurological disorders in the world [1]. In 2016, the estimated global prevalence of MS was 2.2 million, an increase of 10.4% from the age-standardized MS prevalence in 1990 [2]. Among the more than 2 million people with MS, more than 900,000 are thought to reside in the United States (US) [3]. About 85% of pati
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