Fred D. Lublin, MD: Tom, the next drug we expect to come along for relapsed/remitting disease is going to be cladribine, which is approved in Europe. It was tested some time ago but then was brought back to the regulators for reconsideration. Tell us a bit about the data set there and where we might think we’d be using it.
Thomas P. Leist, MD, PhD: As you mentioned, oral cladribine has had a relatively long development with some discontinuity during the development. At this point, we have essentially 3, respectively 4, data sets supporting this medication. The first one is a trial in a first event in a CIS [clinically isolated syndrome] population, or CIS/early MS [multiple sclerosis] population. That’s the ORACLE trial. We have the CLARITY study as a second one, and then, very importantly, more recently reported, the CLARITY extension. And we have, because of the duration of the whole development, a relatively robust underlying data set from a follow-up registry that gives all the information regarding the long-term or longer-term safety of the agent.
The ORACLE trial started, as we have previously discussed, at the first event—for patients with a first attack. In this particular study, there was a very significant difference between the patient’s own placebo, respectively, with the patients that were untreated. It also led to a decrease of the patients that actually had McDonald MS by fulfilling next lesions. And I’m talking about the 2005 criteria for the diagnosis of multiple sclerosis.
The second study, the CLARITY and CLARITY extension, is interesting because with cladribine tablets, the patient gets a course of tablets in the first year and a course of tablets in the second year. The 2 courses are 2, 1-week courses set apart by 1 month. That’s the totality of the treatment. At the 2-year mark, this led to a very significant reduction of the relapse rate and also attenuation of the disability progression. Interestingly, in the extension study of the CLARITY study, there were patients attributed to ongoing treatment with cladribine through annual cycles, and there were patients that didn’t get any further treatments in year 3 and 4. The patients in the always-treated group, so 4 annual courses, did comparatively about the same as the patients that had no further treatment in year 3 and year 4 following the treatment. So this raises the question of whether an agent such as cladribine that leads to a targeted transient reduction of B and T cells could lead to a selective immune reconstitution, where essentially the cells that are autoreactive get partially eliminated and then a nonautoreactive immune system will be repopulated.
Where is this agent ultimately going to fit in to our armamentarium? That depends a little bit where it ultimately will be indicated by the FDA. But the data sets that are there will potentially justify a use in early patients based on the ORACLE CIS trial. But it certainly also would indicate patients with activity, with higher than the average activity in the relapsing forms of multiple sclerosis.