Experts in neurology present long-term efficacy and safety data of oral DMTs in the treatment of MS and share their perspective on the real-world significance.
Ahmed Zayed Obeidat, MD, PhD: This brings us to talk about long-term efficacy and safety data of oral DMTs [disease-modifying therapies]. Part of the focus of today’s session is to talk about the oral DMTs and various efficacy data, whether it’s from clinical trials and long term, open label, or from the real world. You mentioned a bit about the differences between real world and clinical trial long-term efficacy and safety data. Let’s touch on the various oral medication classes, their efficacy long term, and then the safety. Are we seeing something different long term than what was seen in the pivotal clinical trials? And are we seeing anything different in the real world vs in the clinical trials?
Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: Probably the most obvious example was with natalizumab, which wasn’t an oral therapy. In the clinical trials we didn’t see PML [progressive multifocal leukoencephalopathy], it only came out afterward. When you monitored the patients longer term, that’s when it came out. When you look at long-term evaluation of clinical trials, you’re getting a sense of what might be a safety issue. But keep in mind, if the drugs aren’t working, the patient has stopped them. So the first thing you want to look at is how many of the patients in the long-term trial were in the original. There’s always attrition. Who left the study? Who’s not available for the count at the end? These may be individuals who’ve already had adverse events, and therefore, they’re not contributing to it. You’re kind of getting a bit of information, but I don’t think you’re getting the whole picture.
Ahmed Zayed Obeidat, MD, PhD: Because of selection bias in that group, especially in the open label.
Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: Totally.
Ahmed Zayed Obeidat, MD, PhD: This where you see numbers, if only 20% of the original patients continued to open label, what happened to the other 80%?
Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: And we don’t know.
Ahmed Zayed Obeidat, MD, PhD: We don’t know. That’s the main thing.
Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: The other thing is as you get into clinical trials, these patients are chosen mostly for their risk of having the event in question that you’re trying to measure. In the relapsing-remitting multiple sclerosis studies, there are certain criteria that are used to select patients who are considered high risk for having an attack, but at the same time, are low risk for having any adverse event. Anybody who’s got other comorbidities, complications, drug-seeking behavior, are smokers, or all sorts of things are excluded.
Ahmed Zayed Obeidat, MD, PhD: Excluded, yes.
Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: So you’ve cherry-picked the good ones who are at high risk of an event, and now you’re following them long term. That’s not a real-world picture.
Ahmed Zayed Obeidat, MD, PhD: It’s not representative of everyone else, right?
Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: Yes. As soon as you go out in the real world with the drug, we give it to everybody, and it’s really important to collect that kind of information and say, now that people have had a chance to use this drug for the last 5 years, have we discovered something that was not discovered in the original clinical trial? And often we do. That gets you a better sense of, oh well, we didn’t expect this, interesting. So maybe we shouldn’t be giving it to patients with hypertension, or maybe diabetics should be excluded from this. That sort of thing will come out from real-world evidence, and it’s important to collect that information and not just rest assured that the clinical trials give you everything you need to know.
Ahmed Zayed Obeidat, MD, PhD: Some of the others things we don’t get from clinical trials sometimes are different age groups. A majority of people are excluded if they’re 55 and older in the relapsing studies, and also children.
Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: And pediatric patients.
Ahmed Zayed Obeidat, MD, PhD: Yes, and pregnancies. For these things we don’t get from clinical trials, we must rely on real-world data because pregnancies happen in the real world. It’s not as strict as a clinical trial where….
Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: There’s a registry. Often the sponsor of [the therapy] is collecting information about the pregnancy. Was it a completed pregnancy, were they aborted, were the children born normally, is there anything with the children later in life? This is the kind of information you’re going to get from the real world; you’re not going to get it from the clinical trial.
Ahmed Zayed Obeidat, MD, PhD: For the oral therapies, any new safety issues that came from real-world data? Let’s say, S1P [sphingosine-1-phosphate] modulators, or fumarates, or teriflunomide, we’ll talk about oral cladribine also. Was there any new signal that came from the real world that wasn’t seen in clinical trials that we know of?
Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: I’m going to say for the most part no. There weren’t any surprises. The PML issue is something that has come out only after the clinical trials. We know that natalizumab is not in an exclusive club, it’s not the only drug that has PML associated. There have been a number of PML cases with fingolimod, the first-generation S1P. There are very few to no reports of PML with the newer generation S1Ps, but I don’t think we have enough exposure to know.
Ahmed Zayed Obeidat, MD, PhD: The duration. We need time to determine, right?
Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: There have been cases with dimethyl fumarate. I haven’t seen it with diroximel fumarate or monomethyl fumarate yet. But the potential is there, especially in individuals who end up with lymphocytopenia, which would be a clear indication to stop the fumarates. We haven’t seen any at all with teriflunomide, so that’s probably, of all the orals, the safest. It’s also the one that has an antidote. It’s the only one where you can take something and get it out of your system.
Ahmed Zayed Obeidat, MD, PhD: Yes, you can wash it out in 11 days.
Transcript edited for clarity