The professor of clinical neurology, and director of the MS Division and Multiple Sclerosis Center of Excellence at University of Miami discussed the EMD Serono agent’s history and advantages for the patient community.
Kottil Rammohan, MDIn mid-2019, cladribine (Mavenclad; EMD Serono) was approved as an oral therapy for the treatment of relapsing multiple sclerosis (MS), as well as active secondary progressive MS. The synthetic agent targets lymphocytes and selectively suppresses the immune system, with the goal of depleting those lymphocytes in order to “reset” the system.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. Its unique dosing regimen has offered patients a more convenient method of medication administration, and up to 10 years of data from its clinical development program, consisting of the CLARITY (NCT00213135), CLARITY-EXT (NCT00641537), ORACLE-MS (NCT00725985), and PREMIERE (NCT01013350) studies.To find out more about how cladribine got to this point and what it offers the MS patient community, NeurologyLive spoke with Kottil Rammohan, MD, professor of clinical neurology, and director, MS Division and Multiple Sclerosis Center of Excellence, University of Miami.
NeurologyLive: Could you provide a brief overview of how cladribine got to this point through its development?
Kottil Rammohan, MD: It was after the discovery of the cause for the bubble babies who are born immunodeficient. And when those children were studied, what was found was they were perfectly normal in every way, except they had no lymphocytes. The lymphocytes were severely, severely depleted. Then the enzyme that was the basis of that abnormality was discovered to be adenosine deaminase—ADA—and adenosine deaminase deficiency led to the severe lymphopenia that was seen in these patients.That gave the idea for Ernie Bueller and his colleagues at Scripps to potentially utilize this as a mechanism to deplete lymphocytes—they were looking mainly for hematological and oncological reasons to do it—and what they did was to put a chlorine molecule on deoxyadenosine and that literally recreated the ADA deficiency that was seen in these children. The molecule had the ability to be toxic to lymphocytes, and the beauty of it was that you could adjust the dose and control the lymphopenia. That was the beginning of cladribine, and cladribine became the drug of choice for hairy cell leukemia, a type of leukemia in which it was extremely effective, and then people started looking at the lymphocyte as a target for a variety of autoimmune disorders, including multiple sclerosis. The story goes that Ernie Bueller’s sister, who had multiple sclerosis, was treated by Jack Sipe from Scripps. It was an IV formulation—nobody knew the dose to use at the time—so a very large dose was used. But it clearly was effective in controlling progression of MS, and that led to a whole series of trials of the IV formulation until the tablet was discovered.The tablet is about 40% efficient compared to the IV formulation. The dose is 60% more, so the comparable dose tablet will achieve the same thing as the IV formulation. So, it was very convenient. The drug has a very short half-life, but in the time that is it is in the body, it goes after the lymphocytes, so the effect of the drug is long-lasting. Even though the half-life is only a few hours, the drug has a lasting effect on producing lymphocyte depletion.
Could you provide a brief overview of the CLARITY study and its extension?