Fred D. Lublin, MD: Cladribine has had an interesting developmental pathway. They did 2 phase 3 studies some time ago—early in the 2000s—called ORACLE MS and CLARITY. One was in clinically isolated syndrome, and the other was in relapsing-remitting patients. They were fairly typical studies of the time, but the drug didn't get approved because of safety concerns, especially around malignancies.
However, additional data were obtained. Not clinical trial data, but additional safety data were obtained. The company reapplied for approval based on additional safety data and these 2 older studies, which succeeded against placebo in decreasing relapse rate. This got approved. The approval mentions in the label that there is a risk of malignancy, but it was felt to be an acceptable risk compared to the benefit. The drug is conveniently dosed. It is dosed orally for just 2 weeks annually. You don't have to take it again. Interestingly enough, there are some long-term data that suggest a prolonged effect, even after you stop the drug. Another interesting aspect: Even though it has effects primarily on lymphocytes, it didn't cause a lot of significant lymphopenia.
In the labeling for cladribine, even though they did a clinically isolated syndrome study, which was ORACLE MS, they did not receive labeling from the FDA to treat clinically isolated syndrome. I think there were reasons for this. They didn't think the safety justified that.
Robert J. Fox, MD: One long-standing question about fingolimod has been whether a lower dose could be similarly effective and have lower risks. The lowest dose that was studied in the original phase 3 trials was 0.5 mg. Although it was found to be effective, it had some safety concerns. It has left people wondering whether a lower dose could be almost or just as effective and have a better safety profile.
The ASSESS study compared the standard 0.5-mg dose of fingolimod to a lower dose—0.25 mg—and an injectable therapy, glatiramer acetate. The trial was double-blinded, so patients didn't know what therapy they would get, and the outcomes were typical of MS [multiple sclerosis] trials looking at annualized relapse rates and new lesions on MRI [magnetic resonance imaging]. Not surprisingly, the 0.5-mg dose was found to be more effective than glatiramer acetate both in annualized relapse rate and in reducing new lesions on MRI.
The 0.25-mg dose was somewhere in between. The 0.25-mg dose wasn't more effective than glatiramer acetate, but it was numerically somewhere between the 0.5 mg dose results and the glatiramer acetate results. What this suggests is that 0.5 mg of fingolimod is probably the ideal dose, and that going to a lower dose probably, although we're not sure of this, does lower the efficacy.
Fred D. Lublin, MD: We've been using dimethyl fumarate since 2013. It's been an effective oral therapy. One of the main adverse effects of it is GI [gastrointestinal] upset, including abdominal pain, nausea, vomiting, and diarrhea. More recently, diroximel fumarate was tested. This drug behaves a little differently in the GI tract, but it's converted to monomethyl fumarate just like dimethyl fumarate is. So, the mechanism of action on MS would be the same. When they did the study of diroximel fumarate, there were fewer GI complications seen than in patients taking dimethyl fumarate.