Recent Approvals for MS: Cladribine and Diroximel Fumarate

Fred D. Lublin, MD: How about cladribine, another new one?

Patricia K. Coyle, MD: Well, cladribine was due to be the first oral agent, and then they raised concerns about malignancy, and they decided to abandon it. They continued to follow the patients who were studied in the 2 trials that they had, and they wound up finding out after a number of years there wasn’t an increased malignancy rate. So it was approved more than a year-and-a-half ago in Europe, and then it was approved in March of 2019 here in the United States. So this is a prodrug that has durability. It’s a so-called induction agent, as I’ve used it, it’s a durable agent. You knock out lymphocytes, T and B cells for a prolonged period. You’re treated for 5 days in month 1, 5 days in month 2, then you don’t treat again for a year, then 5 days in month 1, 5 days in month 2. Then you don’t treat for the rest of that year or years 3 or 4.

There were 2 trials. CLARITY was the major phase 3 trial that looked at 2 different doses. They wound up going with the lower dose, 3.5 mg/kg, against placebo and showed very good efficacy in suppressing relapses, disability, and on MRI [magnetic resonance imaging]. ORACLE was their CIS [clinically isolated syndrome] trial, which was aborted early, but again it was set up the same way, CIS with placebo 3.5 or 5.25 mg/kg. They abandoned the higher dose. That was a fairly positive study in the data that they could analyze.

This is an interesting agent because the efficacy is probably in between the orals and the monoclonals. I think cladribine exists somewhere in between. It seems to be very well tolerated. And because you have such durability, you can talk about getting pregnant in between these doses and maybe having at least 3 years durability after you take the second course cycle. This is a very interesting agent, new oral agent for us.

Fred D. Lublin, MD: They have some intriguing data that in the second or third year, I forget which now, in CLARITY I guess it was, that the group that got continued dosing and the group that was on placebo did the same, which gets to this issue of durability.

Patricia K. Coyle, MD: Right, exactly. It looked like for most patients you didn’t need any treatment in year 3 and 4 if you went through the 3.5 mg/kg in the first 2 years.

Fred D. Lublin, MD: And the other is the lymphocyte levels don’t really get all that low here like some of the other ones.

Patricia K. Coyle, MD: It seems to be pretty well tolerated. Of course, off-label use of parenteral cladribine has been done by some limited MS [multiple sclerosis] neurologists for a number of years.

Fred D. Lublin, MD: Peter, mono and dimethyl fumarate.

Peter A. Calabresi, MD: Diroximel fumarate is a new FDA approved drug that’s a next-generation fumarate that basically has less GI [gastrointestinal] toxicity than Tecfidera, so that’s good. It doesn’t seem to get around the issues of flushing adverse effects, and the incidence of lymphopenia is really the same in Tecfidera. Interestingly, because it’s basically very quickly metabolized into monomethyl fumarate in the gut, they think that that causes less GI toxicity, and it’s thought that monomethyl fumarate is the active metabolite that’s conferring the efficacy of Tecfidera. So there was no study done to actually compare it versus placebo or do a phase 3 long-term efficacy. This is basically the same compound as Tecfidera. There were studies comparing the adverse effect profile between dimethyl fumarate and this diroximel fumarate. And as I said, the GI toxicity was significantly reduced, so that’s nice because that’s a big problem I think with dimethyl fumarate. Hopefully, that will be borne out over the long term.