An overview of clinical trial data supporting the use of cladribine as treatment for relapsing multiple sclerosis (MS).
Amy Perrin Ross, APN, MSN, CNRN, MSCN: Let’s discuss the rationale for using some of the newer therapies for MS [multiple sclerosis], and we’ll start off with the discussion about cladribine. I’ll ask Pat to take it away on this.
Patricia Melville, RN, MSN, NP-C, MSCN:As Stephanie said before, we have so many new therapies out—oral therapies, infusion therapies, platform therapies of the interferons and the glatiramer acetate—and it can be overwhelming both for us as clinicians and the patients. Cladribine is one of the newer oral therapies. It’s been on the market about a year or 2, and has been studied extensively in patients with relapsing MS and in patients with CIS, or clinically isolated syndrome. It’s worthwhile to review the MOA [mechanism of action] of cladribine. It exhibits selective cytotoxicity, and it involves rapid and sustained reductions in CD4 and CD8 T cell populations, and rapid—but short lived—CD19 B-cell counts.
I want to discuss the ORACLE-MS study. This is a randomized placebo-controlled trial of cladribine in patients who presented with CIS before they developed MS. This study was done back in 2008 through 2010. Back then we were able to use placebo groups, and now we rarely will use a placebo-controlled trial, particularly for CIS or relapsing MS. The primary endpoint for this trial was conversion to clinically definite MS, according to the Poser criteria. A secondary endpoint was looking at the time to conversion to clinically definite MS, looking at the 2005 McDonald criteria. Earlier, Bryan spoke eloquently about the McDonald criteria.The Poser criteria was older criteria that was developed in 1983, before the advent of MRIs [magnetic resonance imaging], or the widespread use of MRIs—they were just becoming available at that point. The MRIs that we had back in the 1980s would probably look like taking a picture of somebody’s brain with their iPhone and getting just as good of an image as those MRIs were.
All joking aside, this was a study that looked at 3 different groups. There was a group of placebo patients, a group of cladribine 3.5 mg/kg, and another group of cladribine 5.25 mg/kg. As we’re all aware, the 3.5 mg/kg is the approved dose that is currently being used. Once again, they were looking at the effect of cladribine on the conversion from CIS to relapsing MS. Adverse events were similar across the treatment groups, with the exception of lymphopenia. Lymphopenia was present in a dose-dependent manner. There were infections, but they were similar between the cladribine and the placebo groups. There were about 2% to 3% of patients taking the cladribine 3.5 mg/kg who discontinued due to infections, and there was recovery of lymphopenia with the 3.5 mg/kg group at 9 weeks. This was very encouraging. There were 2 cases of malignancies in the ORACLE-MS study. There was 1 case of thyroid cancer, and the association of that was unclear. There was another case of squamous cell carcinoma that occurred in a patient who was fair skinned, an avid tanner, and lived in Florida, so you wonder if there may have been other factors that could have played into that.
The results of the study showed a robust treatment affect. Time to conversion was delayed using both the Poser and the 2005 McDonald criteria. There were also significant measures on radiographic outcomes: Significant reduction in the number of T2 lesions, new and enlarging, GAD-enhancing [gadolinium-enhancing] lesions, and combined unique active lesions compared with placebo.
At the most recent ACTRIMS [Americas Committee for Treatment and Research in Multiple Sclerosis] forum, there were a few posters presented that looked at cladribine. There was one that looked at the risk of conversion to secondary progressive MS within 2 years. This was a post hoc analysis. Secondary progressive MS was not recorded during the trial, so they used proxy measure by looking at EDSS [Expanded Disability Status Scale] functional system scores. They found that the risk of progressing to secondary progressive MS within 2 years of treatment, or needing a walking aid, was significantly reduced with cladribine 3.5 mg/kg vs placebo. This is regardless of whether they started out with an EDSS of 3 or less, or they entered the study at baseline with an EDSS of 3.5 or greater. This is interesting information because that’s an area where we’re deficient in that we don’t have good treatments for our secondary progressive MS patients, so that’s important data to look at.
Another question that comes up about cladribine is regarding the duration of the effect, and there was another poster at ACTRIMS 2020 that looked at that. They looked at time to first relapse over the duration of CLARITY and into the CLARITY extension study.
Now, we didn’t talk about the CLARITY study, but the CLARITY study looked at relapsing MS patients. They found that there was a comparable relapse-free status over time in patients who continued cladribine compared with those that transitioned to a placebo group, which demonstrated the durability of efficacy that extended beyond year 1 and year 2. As we’re aware, with cladribine, the dosing of it is unique. Year 1, they take 4 to 5 days of medication for 2 consecutive months, then not again until year 2. Then they take month 1 and month 2, 4 to 5 days of medication. This abstract demonstrate the durability of that effect of the medication beyond year 2.
Amy Perrin Ross, APN, MSN, CNRN, MSCN: Thank you all so much. I would like to thank this wonderful panel, Christen Kutz, Stephanie Agrella, Bryan Walker, and Patricia Melville for this wonderful discussion. I’d like to thank you, as an audience, for watching NeurologyLive® Peer Exchange. If you enjoyed the content, I suggest that you subscribe to the NeurologyLive® newsletters to receive information about upcoming Peer Exchange segments and other content available to you. Thank you all so much.
Transcript edited for clarity.