An expert discusses data for ofatumumab, the first self-administered anti-CD20 monoclonal antibody, in treatment-naïve patients with early relapsing multiple sclerosis in the phase 3 ASCLEPIOS I/II trials, and the advantage ofatumumab has over other anti-CD20 monoclonal antibody therapies. 

: The first study I’d like to talk about is entitled, “Benefit-risk of ofatumumab in treatment-naïve early relapsing multiple sclerosis patients.” This is obviously a post-hoc analysis of the large, combined ASCLEPIOS I and II trials of ofatumumab versus teriflunomide in relapsing MS [multiple sclerosis]. One of the questions that comes out of a study like this is about subgroup analyses, which were never predetermined to be looked at in the primary outcome but are nevertheless of interest. Could it be that ofatumumab is useful in patients who have just been diagnosed with MS or have not received any prior therapies whatsoever? Is there anything peculiar about this group? People think that they might be a bit more active compared with the other groups, or that they may have some adverse effect or safety issues that other groups do not have. It was worthwhile to look at, and I mention the caveat that any post-hoc analysis is not proof. If the effect of ofatumumab is lost in a group like this, one would wonder whether there would be some benefit in a larger study if there were more of these patients. You’re looking for the loss of a signal, rather than the game. When one looks at this group and compares the baseline characteristics of these patients to the group as a whole, you want to make sure that they are not standing out, other than the fact that they might have disease a bit earlier. Otherwise, they are similar, and that’s the case.

Compared to teriflunomide, which was the active comparator arm of this study, ofatumumab had a similar effect by reducing relapse rate about 50%. Three-month confirmed disability worsened by 38%. That was barely statistically significant. In fact, it was probably just out of the range of statistical significance. The 6-month risk was barely in the range at 46% with a P value of .044. I’m keeping this in mind. This is a subgroup analysis not powered to see these differences. When you have a lot of events, as on MRI, not surprisingly, there was a strong effect of reducing Gad [gadolinium]-enhancing lesions and new T2 lesions. What is of interest is whether there was an undue safety signal in this group, and so far, there was not. The serious adverse events were reported in similar percentages in both the treated with ofatumumab and teriflunomide groups. There weren’t any malignancies or any increase in infection rate.

In conclusion, the ofatumumab, which is the first self-administered form of anti-CD20 antibodies, showed a continued superiority to teriflunomide in the subgroup of newly diagnosed and treatment-naïve patients. It lowered relapse rates and MRI activity, and there was some borderline significance in time to confirmed disability worsening.

One of the questions is, why bother doing this type of subset analysis? I’m in Canada. Right now, we are awaiting approval of ofatumumab. It is not yet approved in Canada. It is approved in the United States, I believe as a first-line therapy for treatment of multiple sclerosis. We’re not sure how that’s going to read out in Canada. Nevertheless, if it’s a first-line therapy, you want to know that the efficacy is substantiated in a group of newly diagnosed or treatment-naïve patients who would probably be taking it first line. It would seem rather intuitive that it would be, but the analysis needed to be done. That’s why this study was presented.

We’re talking about the advantage of ofatumumab anyway over the other anti-CD20 therapies, which require visitation to an infusion center. People are worried about going anywhere these days with the potential of contracting COVID-19 [coronavirus disease 2019]. It is an advantage to be able to inject yourself, although you’re injecting more often than you would with the traditional anti-CD20 antibodies, which are infused every 6 months. The advantage is that you 

do not have to venture out to have these done at various centers or hospitals.

Ofatumumab vs Teriflunomide: ASCLEPIOS I/II RMS Trials

A key opinion leader highlights the OLKIOS phase 3b study evaluating ofatumumab’s continued efficacy in patients previously treated with traditional anti-CD20 therapy, as well as concerns about switching from a humanized anti-CD20 monoclonal antibody to a fully human monoclonal antibody.

: The next study is called the OLIKOS. It was all about whether ofatumumab would maintain efficacy in patients who are coming from traditional anti-CD20 therapies, which are given every 6 months. There was some concern about the continued efficacy of switching from a humanized anti-CD20 monoclonal antibody to a fully human monoclonal antibody. Might there be differences in patients who have maintained benefits? I can’t see why that would be, but one would be concerned about the safety of switching between monoclonal antibodies. 

OLIKOS was a 12-month prospective single-arm study because patients are moving from a previous therapy to this one with no comparator. They’re essentially looking at before and after. They had about 100 people who were being randomized through different centers throughout the US. These patients had been previously treated with at least 2 to 5 consecutive courses of either the ocrelizumab or rituximab molecules, both of which target anti-CD20. The last dose was between 4 and 9 months prior to enrollment. They also made sure that these patients were in the relapsing-remitting domain with EDSS [Expanded Disability Status Scale] scores lower than 5.5. They had to show some treatment effect of the previous anti-CD20 in that their B cells had to be substantially below 1%, which are essentially detectable levels in some laboratory tests.

In that sense, they were looking at patients who may have had a suboptimal response to CD20 in the past 6 months. Those patients were also of interest. The so-called suboptimal responders had to have at least 1 relapse, 2 or more Gad [gadolinium]-enhancing lesions or newer enlarging T2 lesions, or had discontinued anti-CD20 therapies because of infusion reactions or recurrent infections. These are the patients that they wanted to do without, so they were excluded for the purposes of seeing continued benefit. The investigators wanted to have no muddy waters here in terms of these patients who may not be responders to begin with.

All the patients were then put onto active therapy. They received the usual dosing. The primary end point was whether there would be a change in MRI at the 12-month mark following enrollment. Then they looked at a number of secondary end points, but didn’t report on everything, such as changes in immune markers, patient satisfaction with the switch, tolerability, and safety. The study design was presented, but we don’t have any results. This is something that’s being generated now, and we’ll have this result perhaps next year at the ECTRIMS [European Committee for Treatment and Research in Multiple Sclerosis] annual congress.

The benefit of such a study would be because, in the real world, there are a lot of people who are taking off-label rituximab. Now that ofatumumab is licensed as a product, maybe they could enroll onto a proper-labeled therapy for relapsing disease and avoid the necessity of coming to infusion centers to have these done. There is a potential, at least for rituximab, which is a humanized monoclonal antibody that is perhaps more associated with infusion reactions, to avoid those completely by moving to a self-administered subcutaneous injection. There are some theoretical and societal advantages of doing your own therapy, rather than having to go to a center, especially in the midst of a pandemic.

The likelihood is that a number of people are going to be making this transition in real life. Being able to show them that making the transition doesn’t affect the continued benefit of the anti-CD20 therapy is obviously a goal of this investigation. The other factor is that there are potential theoretical safety issues of moving from one monoclonal antibody to another in the context of treating MS [multiple sclerosis]. Would this raise any safety issues? One needs to show that that is not the case.

OLKIOS: Looking at Ofatumumab’s Continued Efficacy

An overview of the phase 3 OPTIMUM study involving ponesimod and how the reduction in MRI-based outcomes, including brain atrophy, is significant in supporting the clinical outcome of relapse rate reduction in patients with relapsing-remitting multiple sclerosis.

: The next study we’re going to talk about is another recently studied medicine that has yet to be approved anywhere in the world. This is ponesimod, which was tested against an active comparator, teriflunomide, in the relapsing-remitting population. That was called the OPTIMUM study. Ponesimod is a different S1P [sphingosine 1-phosphate] receptor agonist. There are now 4 or 5 of these drugs. This particular drug was looked at in the OPTIMUM study against teriflunomide and shown to be superior in terms of their primary outcome measure, which was relapse rate.

There have been a number of subanalyses that were planned as part of the OPTIMUM study, so this presentation focuses on the MRI-based outcomes in these patients. We have the top-line results, but we wanted to see what all the different detailed results were. We’re now looking at including prespecified MRI end points and NEDA, no evidence of disease activity, which is seen in some patients. The entire patient population was analyzed. This is not a subanalysis, per se, but looked more at the total MRI outcome. They looked at everything in terms of MRI activity, including brain atrophy as measured by the change in brain volume using the SIENA [Structural Image Evaluation Using Normalization of Atrophy] technique.

In this study, 87% of the patients completed the study and the images were available for analysis. They showed the continued significance of ponesimod’s superiority over teriflunomide on nearly every outcome measure out to week 108. They did it by various means, but in particular, when one looks at the changes in brain volume—in other words, the retardation or prevention of brain atrophy—the significance was there. The change from baseline was 0.91% in the ponesimod arm vs 1.25% in the teriflunomide arm. There was a significant reduction in T2 lesion load. I don’t want to give you all the numbers, but it was highly statistically significant. Mean number of new or enlarging T2 lesions was also statistically significant. The odds of having no new, enlarging T2 lesions on ponesimod vs teriflunomide were 1.7 to 1, or almost 2 times more likely. The mean number of new Gad [gadolinium-enhancing] T1 lesions, or hot lesions, was substantially reduced. Some reductions were out to point 3 or 4 zeros of significance.

Finally, the NEDA-3—which is no relapse, no new MRI lesions, and no disease or confirmed disability progression—shows the advantage of ponesimod over teriflunomide. The actual numbers here are 28% of the ponesimod patients vs 18.3% of the teriflunomide patients achieved NEDA-3. If you add in the atrophy, this is now called NEDA-4. If you have less than 0.4% per year of atrophy, in addition to not having a measured activity the traditional way, you’d be considered NEDA-4. Fifteen percent of participants on ponesimod vs 8.5% of those on teriflunomide reached the NEDA-4. That was also quite statistically significant.

However you slice and dice the MRI outcomes, the ponesimod shows superiority over teriflunomide on all these aspects. That is supportive of the clinical outcome, which is the reduction of relapse rate.

The whole point of doing these in-depth views of the MRI outcomes is to substantiate as much as possible that the clinical outcome, which is statistically significant, is meaningful.

It is meaningful in terms of all the different, more sensitive measures of disease activity that one can measure using MRI, including the important outcome of brain atrophy, which has coincided nicely over years with degree of disease progression. I say that because this particular study did not show superiority on the outcome measure of disease progression. For that matter, all of the comparator studies using S1P receptor agonists have failed to show this against their active comparator for a number of reasons. The active comparator, which in this case is teriflunomide, does have an effect on slowing disease progression. The study was not powered to look at disease progression as a primary outcome. One expects that disease progression in this early group would be very low. They don’t have the power to see that, but when you see it on atrophy, you get the sense that had they powered a study to look at disease progression, you might have seen a benefit.

OPTIMUM: Ponesimod Superiority in MRI-based Outcomes in RRMS

A discussion of evobrutinib’s long-term efficacy and safety among 4 dosing regimens and rationale for the regimen selected for phase 3 studies.

Mark Freedman, MD, MSc: The final trial to review here is another clinical study, which is also a follow-on from a published study of evobrutinib. Evobrutinib is one of the first BTK [Bruton tyrosine kinase] inhibitors that have come to bear in multiple sclerosis. It is 1 of 4 that are now being tested by the various companies to look at the effect of reducing relapse. This is not only because of their theoretical effect on B cells, but also because BTK inhibitors affect microphage and microglia, which might be driving some aspect of progressive disease. Hence, you’re going to get the B-cell phenomenon by reducing the B-cell output, but also perhaps affect another process that might be driving disease progression.

The evobrutinib original study looked at 4 different doses. This is an attempt to look at the long-term efficacy of evobrutinib going out to week 48. It looks at the long-term outcome of a phase 2 study, which was originally just a 6-month or 24-week trial looking primarily at MRI as an outcome measure. They decided to look at these longer-term impacts at 48 weeks, as measured by clinical outcomes such as relapse rates, time to relapse, change in EDSS [Expanded Disability Status Scale], and safety.

This was the original double-blind trial of 4 different doses of evobrutinib—25 mg once daily, 75 mg once daily, 75 mg twice daily, or the placebo—for the first 24 weeks. They were all continued on their original treatment blinded until week 40, except the placebo patients, who were rolled over. They were switched to the lowest dosage of 25 mg daily. Then, at week 48, they could go into an open-label extension through which they would initially receive 75 mg daily. That was for a median time of 48 weeks. Then, they would switch to 75 mg twice per day. One was looking well beyond the 48 weeks to week 60 on the open-label extension.

This is a smaller study in the realm of phase 2 versus phase 3, which we discussed before. The number of patients was much lower. We had 213 patients originally randomized. Of those, only 77% or so entered the open-label extension. Of those, 90% completed up to 108 weeks of treatment extension for the purposes of further analysis. There are 4 different groups that we’re looking at. For the patients initially receiving the placebo, 25 mg per day, 75 mg per day, or 75 mg twice a day in the double-blind period, 1 analysis looked at ARR [annualized relapse rate]. That was still quite low at 0.37. The ARRs were 0.37 for the placebo, and 0.52, 0.25, and 0.11 for the various doses of evobrutinib. It is interesting that the low dose had a slightly higher relapse rate than the original placebo, but the lowest rate was still seen at 75 mg bid [twice a day] at week 48. They then looked at similar numbers going out to week 108. The 0.11 at 75 twice a day was maintained to 0.12. 

Going out to week 48, the cumulative probability of qualified relapse was consistent across the groups and was lowest at the highest dosage of evobrutinib through to week 96. At that point, the relapse rate remained low at 0.2. The estimated time for randomization, in those 20% of patients who had a qualified relapse, was 3 times longer for the patients that initiated evobrutinib 75 mg twice daily during the double-blind period than for patients in the other arms or placebo. It looks like the 75 mg twice daily is the dosage of interest going forward. The safety profile in the extension study failed to reveal anything new compared with the double-blind period. The message here is that the 75 mg twice a day dosage also happened to correlate with the best result and the optimal occupancy of tyrosine kinase. I believe this is the dosage that they’re going forward with in the phase 3 studies.

Because phase 3 is now ongoing and recruiting at the dosage of 75 mg twice daily, one wants to understand the rationale for choosing that dosage. Although it may not have been readily evident at 24 weeks from the phase 2 primary outcome measure, the continued study and open-label extension of evobrutinib supports the moving ahead with the 75 mg twice a day dosing in phase 3.

Rationale for Selected Dosing Regimen of Evobrutinib in Phase 3 Studies 

Dr Mark Freedman shares exciting takeaways from the 8th Joint ACTRIMS-ECTRIMS meeting, including the utility of serum biomarkers of disease activity.

: I’ve been asked to comment on some highlights from the 8th joint meeting of ACTRIMS [Americas Committee for Treatment and Research in Multiple Sclerosis] and ECTRIMS [European Committee for Treatment and Research in Multiple Sclerosis], which was held for the first time virtually in September in 2 parts. The entire meeting was a few weeks ago, and then this past weekend, they held late-breaking sessions where we saw some interesting data being presented. I can’t say that there is a top message. There has been so much presented over those several days, but in terms of new clinical trials, one of the most important standouts was a surprise phase 3 trial looking at masitinib, which is a unique tyrosine kinase inhibitor focused in on mast cells as part of the innate immune system. It looked primarily at nonactive progressive forms of multiple sclerosis [MS]. Those would be primary progressive MS and secondary progressive MS cases that do not have any relapses or MRI activity in recent times. You would think this would be the hardest group in which to show a difference.

They looked at 2 different doses of masitinib and showed that the low dose actually did slow disease progression substantially, compared with placebo, in this nonactive group of patients, both in PP [primary progressive] and SP [secondary progressive] disease. Although the higher dosage did not have a significant effect, it looks like it may have been because placebo patients didn’t get worse. They set this up a bit strangely because the 4.5 mg and 6 mg doses were actually separate studies. They had their own placebo groups in each. In the future, what would look like the placebo group from 1 that did progress perhaps needs to look at the 6 mg dose. The drug was also poorly tolerated. There were a lot of GI [gastrointestinal] and skin adverse effects with the higher dose, so this is a drug that’s going to move forward into a new study looking at 4.5 mg/kg per day, since it has cracked the ice in this progressive group of patients for whom we lack good therapies. That was a really important takeaway.

Another takeaway from this meeting is the promotion of this notion of serum biomarkers being able to get a hint at what’s going on in this disease process without having to do MRIs or examine patients. We have a marker of disease activity. One of them is serum neurofilament light [NfL], and there were numerous presentations corroborating what has already been observed. It can predict which patients are going to get worse. It can predict relapse. It can predict MRI activity. As I remember, one study showed patients who were monitored regularly for their levels in the large Swiss registry. When the levels shot up, these were patients who were very likely to have continued activity. You could do these measurements in patients who are on a therapy thinking that they’re doing well, but if this number shoots up, you can say, “Maybe we should consider a change in therapy before something bad happens.” This is where that type of marker is going.

What do you do in patients who have progressive disease and don’t have much activity? That’s where the neurofilament light falls off, because it’s really driven by the active loss of axons. In the more progressive forms of MS, you don’t have this inflammatory activity anymore. Not surprisingly, the predictability of neurofilament light falls short, but a new marker, which is the serum GFAP [glial fibrillary acidic protein], has also been looked at by the Swiss. They showed that, especially in these nonactive forms of progressive MS, GFAP might be a marker that these patients are getting worse. 

What it really gives us is the opportunity to now look at NfL and GFAP together to get a hint at activity and disease progression. Both of those are now giving us some insights on the disease, whereas before, we had to wait until things happened before we knew. It’s possible now that we have therapies that are potentially targeting progressive MS to slow disease progression. The hardest thing to understand is that if you gave someone one of these therapies that slow disease progression, but they progressed anyway as they did in the clinical studies—they just progressed slower than their placebo counterparts—patients don’t have placebo counterparts to measure themselves against. How do we know we’re winning this battle? How do we know we’re slowing disease progression faster than what would have happened in nature? One of these markers might be an indicator that the treatment is working, that even though the patients have progressed a bit, we’ve managed to lower those markers. That would give us an indication of a treatment effect. That was a very important evolution.

Takeaways From ACTRIMS-ECTRIMS 2020 Meeting

Data from the phase 3 ASCLEPIOS I/II open-label extension study, differentiators between anti-CD20 agents, and the role patient decision-making may play in treatment choice.

: We just had approval of ofatumumab within the last month or so. It was studied in a phase 3 program called ASCLEPIOS. That study is in long-term extension—ALITHIOS. Dr Hauser and colleagues presented a poster at ECTRIMS looking at patients who were newly diagnosed with MS [multiple sclerosis] who were previously untreated. This represented about a third of the ASCLEPIOS population. Patients were defined as having had the diagnosis within the past 3 years and not having been on any prior treatments. What they found is that when compared with teriflunomide, relapses were reduced by about 50%. Gadolinium-enhancing lesions were reduced by about 95% by year 2. T2 lesions were reduced by 82%. Just looking at the T2 lesions within the second year, those were reduced by over 90%.

In addition, they looked at year 2 NEDA [no evidence of disease activity]. It’s been somewhat of an aspirational end point that incorporates relapses, MRI lesions, and progression. In looking from year 1 to year 2, they found that NEDA rates were about 92%. Overall, the results are very strong in the primary study, ASCLEPIOS, across all patient groups. But in this earlier-diagnosed cohort, we see very strong results with high NEDA rates when you re-baseline and look at it over the second year of the trial.

What we’re finding is that the anti-CD20s, as a class, are highly effective in relapsing forms of MS. We’re seeing really tremendous imaging results with all these different therapies. We have 2 approved: ocrelizumab and ofatumumab. They demonstrate remarkable reductions in new and enhancing lesions. 

Ocrelizumab has been presenting additional data on phase 4 programs. One of them is called ENSEMBLE, which is looking at an infusion that given at a faster rate. Instead of the 3½-hour infusion, it’s a 2-hour infusion. Similar to the ASCLEPIOS analysis, they’re finding that NEDA rates in the second year are above 75%, 80%, 85%. In relapsing forms of MS, we are seeing excellent results with all the anti-CD20s, which is very fortunate for patients. This gives us some great options.

Now that we have a couple anti-CD20s to choose amongst, and both look like they have excellent efficacy and very balanced safety, one of the main differentiators, obviously, is the route of administration. Ocrelizumab is traditionally infused over 3½ hours. In practicality, that means the time—getting to the infusion center, getting a seat and IV [intravenous], and then mixing up the medication, being observed afterward—could pretty much be the full day. This may reduce it to half a day, and regulatory agencies are looking at this more carefully. 

Some patients would rather do an injection at home, and that would be 12 injections per year instead of 2 infusions per year. Patient decision-making will factor into treatment selection. I don’t have a great sense in these early days as to where things will go. I suspect patients will, in large part, want to do more injections at home, especially for new starts. I also feel like patients on ocrelizumab, at least in the short term, are probably going to feel comfortable sticking with what they know, which is coming in for the infusions.

The coronavirus pandemic is a bit of a concern, but the hospitals, in general, are taking very strong precautions. Patients still have reluctance, perhaps, but there’s a lot of screening and rigorous cleaning and mask wearing in the hospitals. Overall, hospitals are not a likely place to get it, relatively speaking.

Phase 3 ASCLEPIOS I/II Open-Label Extension Study: Ofatumumab vs Teriflunomide 

A key opinion leader underscores pivotal endpoints from the ongoing OLIKOS study and potential significance in treating multiple sclerosis.

: OLIKOS is a 1-year open-label study. In reviewing the study design and some of the key outcomes, the plan is to enroll 100 patients who are stable on ocrelizumab and switch them to subcutaneous ofatumumab. Patients will be followed out to a year, and investigators will evaluate imaging, disability measures, quality of life, adverse events, and different B-cell and neurofilament parameters. It’s a small study looking at the safety, tolerability, and some open-label efficacy endpoints in a short duration upon switching from one method of administration to another.

The significance, perhaps, is that it can provide some data on when such a switch can be made. The return of B cells with ocrelizumab can be quite prolonged. Off the top of my head, I wonder whether a switch would be made after a long duration off ocrelizumab or whether you would empirically start it at 6 months or so. In the OLIKOS study, they did empirically start it at the 6-month time frame, plus or minus a month here or there. This may provide some guidance and insight regarding what would be the treatment practice if a patient, for whatever reason, wanted to go from 1 formulation to another.

OLKIOS Phase 3b Trial: Pivotal Endpoints and Potential Significance

An overview of ponesimod’s cardiac safety data demonstrated by the phase 3 OPTIMUM study and its potential impact on first-dose observation recommendations.

: Ponesimod is another S1P that is presenting data. It’s currently in development. We have a number of S1Ps available. Just in the last year, year and a half we’ve had ozanimod and siponimod. Ponesimod is another selective S1P modulator. They did a large study on the drug vs teriflunomide and showed very good efficacy that was very much consistent, I feel, with the other S1P modulators, which also had head-to-head studies.

In this study, they evaluated patients receiving ponesimod. The way cardiac events are mediated, in terms of getting around the first-dose observation, are 2-fold. First, there’s a dose titration. We’ve seen this with siponimod and ozanimod. Second is the selectivity of the S1P1 receptor perhaps having relatively less effect on the bradycardia.

In this study, they had 565 patients on ponesimod. Again, the comparator was teriflunomide. There were no major cardiovascular events looking at strokes, MIs [myocardial infarctions], or anything along those lines in this population. They did find very low rates of bradycardia in the ponesimod arm, and nobody that had any cardiac issues needed to be discontinued from the study. Very few patients had bradycardia or low-grade heart block. I think 3 patients had heart rates under 40. They looked at if you had cardiac risk factors not, and those with no cardiac risk factors had very low rates of any bradycardia. I can’t speak precisely about how this matches up in the analysis to the other ones. We know that in terms of the other medications, the regulatory agencies were optimistic, in that the first-dose observation did not need to be done on everybody—just high-risk patients. This type of data might inform that decision when the FDA and the EMA [European Medicines Agency] and other regulators look at what might be recommended for ponesimod. We’ll have to wait and see what the decision is.

OPTIMUM Phase 3 Trial: Ponesimod’s Cardiac Safety Data

A discussion regarding the use of ozanimod compared with teriflunomide as treatment for multiple sclerosis utilizing statistical matching, and the role S1P receptor modulators play in clinical practice.

: There’s always a great desire to have more head-to-head comparisons. These trials are very expensive and difficult to recruit. One strategy is to do statistical matching. Specifically, propensity-based matching analyses can be done so you can look at existing data. Here, the authors looked at existing clinical trials and matched them on baseline characteristics. They were able to provide some analysis of a comparison between ozanimod and teriflunomide.

From my perspective, the S1Ps, as a class, seem to rate a bit better in regard to efficacy, compared with some of the other oral therapies and injectable therapies. Even though there has not been a direct comparison with ozanimod and teriflunomide, you would suspect there may be some benefit. Like we were talking about with the ponesimod study, that trial did use teriflunomide. There is a precedent that an S1P was effective compared with a DHODH inhibitor.

What they found in this propensity-matched weighted analysis was that the relapses were reduced, I think, by 27%, and disease progression was reduced by about 22%. These are nice data to have. With these propensity-matched analyses, you need to be a bit cautious, because they assume you know all the confounders and differences between the populations measured. It adds to the literature, but we always need to be careful about over-interpreting these data. It’s good to have them in instances where no data exist, but a direct head-to-head study is always preferred.

This is very much in line with our notion of where efficacy fits, in terms of standard or moderate efficacy vs high efficacy. I would say that most MS [multiple sclerosis] clinicians would say that the monoclonal antibodies represent our high-efficacy therapies and that we have a middle efficacy bin, and S1Ps likely fit in that bin. It’s very much in line with how we conceptualize the treatments and how we balance efficacy and safety across these different options.

Ozanimod Compared to Teriflunomide Utilizing Statistical Matching

Dr Robert Naismith shares key takeaways from the 8th ACTRIMS-ECTRIMS 2020 meeting, including the impact of anti-CD20 therapy compared with other agents on the risk of severe disease from COVID-19.

: This meeting was a phenomenal success. Over 6200 people were registered and attended. For the times that we’re in, that’s tremendous. It represents a real need for MS [multiple sclerosis] information and discussion. It was perfect timing to have this meeting. There will be another meeting of ACTRIMS [Americas Committee for Treatment and Research in Multiple Sclerosis] in February. That’s going to be held virtually, so hopefully we’ll continue to be able to provide this quality information and have another great with everybody’s help.

Of course, the coronavirus pandemic is 1 of the big things on peoples’ minds in regard to MS care. A number of analyses were presented at ACTRIMS-ECTRIMS [European Committee for Treatment and Research in Multiple Sclerosis in September]. The biggest risk factors for severe disease from COVID-19 [coronavirus disease 2019] seem to be age and disability. The odds ratio of a negative outcome, whether it’s an ICU [intensive care unit] admission or intubation or death, seems to be within those 2 categories—those who are older and those who are more disabled.

In looking at all the different treatment options, there was a very slight increased risk associated with the anti-CD20s compared with other agents. This risk wasn’t as high, relatively speaking, in terms of the age and the disability parts, but it’s interesting that there did seem to be a persistent risk across several different studies with the anti-CD20s.

In looking at anti-CD20s and high disability and older age, there does not seem to be a synergistic effect. I think we need to balance treating MS appropriately and make sure the disease doesn’t cause additional injury to myelin and axons. Certainly, patients taking medicines like this need to be cautious about isolation, masks, washing hands, and stuff like that, which I think they’re doing. There are more data to come. There are a lot of people looking at this issue because it’s so important.

Key Takeaways from the 8th ACTRIMS-ECTRIMS 2020 Meeting

Ofatumumab vs Teriflunomide: Phase 3 ASCLEPIOS I/II Open-Label Extension Study

Chief Endpoints and Potential Significance: Phase 3b OLIKOS Trial

An overview of the CLARITY extension trial and the potential role for cladribine in disability improvement.

: One interesting study presented at this meeting was evaluating the disability improvement in relapsing-remitting multiple sclerosis [MS] receiving cladribine tablets. Benefit was evaluated by the Expanded Disability Status Scale [EDSS]. The study is introducing a new way to evaluate and assess the improvement in the disability of MS patients. Previously, when we evaluated improvement in patients with MS, we included the incidence of change, so a decrease in EDSS score was 1 point, depending on the severity vs 5 points in a patient more disabled and maintained for 6 months. This new statistical evaluation is looking not only for the onset of improvement but also for the duration and maintenance of improvement. 

This new statistical measure was applied to the CLARITY extension study that was an initial cladribine study of 2 years that compared cladribine treatment, 2 different dosages, with placebo. After 40 weeks of bridging, the patients were enrolled in the CLARITY extension study. Patients who were on placebo were started on cladribine, and patients that were previously on cladribine were divided on continuing the therapy versus placebo. That was an additional 2 years, so altogether with the bridging, it was 5 years at the end of the study. 

The result of this study extension is comparing the baseline with 5 years later, so the primary outcome looked at the prevalence of improved EDSS between the 2 groups—the patients who initiated therapy from the beginning vs the ones who were initiated later on during the extension study. The results did show that patients who initiated the therapy from baseline compared with the ones later, had an improvement of 15% at 2 years vs 9% for the later group. This was pretty much maintained at 5 years, with the early group maintaining a 12.7% improvement vs 8.6%. At this time, the difference reached significance. 

We would be very interested to measure not only how the patients are progressing but also how they are improving. Initially, the improvements were changing in the opposite direction than progression and maintaining for 6 months, but this time, the question comes up, “If the patient improved, is this improvement maintained? Or after 6 months, does it go away?” That this is very interesting and an important point, and it may bring us much more realistic information on patients’ status, if indeed improvement was maintained for 6 months or for a much longer period of time. The new statistical method looking for not only incidence but also the duration of improvement is important. 

This study showed that starting the therapy early on—2 years before and even a little more with a bridge in between—has a higher chance to improve and maintain the improvement vs the 1 that started later on. Again, this new statistical method was applied for patients treated on cladribine.

The only concern I have on the early group of patients is that on the extension part, some of the patients were re-treated. In the early group of patients, half of them were receiving an additional 2 cladribine treatments while half were on placebo. It’s difficult to tease out if any of this improvement was in patients in the early group, in the patients who had additional treatment or in the ones who had only 2 initial treatments. But altogether, it’s supporting what we had before: patients initiating therapy also have less progression. This new study shows that they have a higher chance of improvement and maintaining improvement within at least 5 years than initiating therapy later on.

CLARITY Extension Trial: Disability Improvement With Cladribine

A discussion of COVID-19 in MS global data-sharing initiative and its significant preliminary trial data on anti-CD20 disease-modifying therapies.

: We are all concerned with COVID-19 [coronavirus disease 2019], every one of us, and specifically as providers for MS [multiple sclerosis] patients. There are many registries going on today trying to determine the risk of MS patients developing COVID-19. Sure enough, many patients have a COVID-19 infection. We want to know how they are doing and if the disease-modifying therapies [DMTs] the patients are on is making a difference.

The preliminary data from this big data-sharing registry showed the older age, progressive MS, and higher EDSS [Expanded Disability Status Scale] were associated with a higher frequency of severe outcomes. The anti-CD20 DMTs—patients on ocrelizumab and rituximab—were also associated with higher hospital admission risk. The adjusted prevalence ratio was higher on ocrelizumab, 119; rituximab, 158. Higher ICU admission was 3 times more for ocrelizumab and 4 times more for Rituxan. The need for artificial ventilation risk was 3 times more for ocrelizumab and 7 times more for Rituxan. This was compared with the dimethyl fumarate. 

Further analysis was looking for all 3 outcomes as related to negative adverse effects with ICU [intensive care unit] admissions being associated with both anti-CD20 treatment compared with the other DMTs. All 3 outcomes combined for patients treated on anti-CD20 vs the rest of the treatment showed higher hospitalization rate, 149 adjusted prevalence ratio; ICU admission, 2 times more; and ventilation need, 3 times more. Additional increased risk, compared with natalizumab, was 199 higher risk for hospitalization; 2 times more for ICU; and ventilation, 2.84. 

An additional thing that I didn’t present is that although the anti-CD20, also ocrelizumab, as well as Rituxan, show a higher risk for complication from COVID-19, it still seems that ocrelizumab had fewer adverse effects than Rituxan. It’s not clear why. The presenter considered that this may be related to the difference in the way the 2 anti-CD20 therapies are binding to their receptor. The consideration is that Rituxan binding to the receptor in the same area of the anti-CD20 is stronger, so that could eventually explain why the patients on Rituxan were having more difficulties and more complication from the infection vs the patients that were treated with ocrelizumab.

COVID-19 in MS Global Data-Sharing Initiative Anti-CD20 Therapy Results 

Dr Bianca Weinstock-Guttman discusses the impact of the results from the COVID-19 in MS Global Data Sharing Initiative has on clinical practice.

: This is important information that we should pay attention to. As practitioners looking at this data, we have to think about the importance of keeping the MS [multiple sclerosis] under control vs safety now during the COVID-19 [coronavirus disease 2019] period. For patients very active with inflammatory elements, relapses, and active MRIs, we will go for active and more efficacious therapy. However, for patients for whom anti-CD20s are also recommended, such as progressive and maybe older patients, we have to be more considering in this regard, especially because we know that aging and the increase in ability may increase the risk for COVID-19 complications. 

Additionally, during this period of time, we considered that patients who are already on medication may maintain a benefit if we try to increase the period of time between the infusions.

A question being raised that we hoped we’d receive the answer to and get a vaccination is response to vaccine. Will the patients on anti-CD20 therapy be able to mount the response from vaccine as we expect to? That would be a different consideration that we’ll be looking into when we have these vaccines.

I can say that in our clinic— it may be different in other clinics—the patients with active relapsing-remitting disease who were initiated on ocrelizumab or are on Rituxan, if they have the so-called neuromyelitis optica, very active disease, we continued the therapy at a 6-month basis. Maybe we had a delay for 1 month, but before delaying we were evaluating their B cells, the CD19, and restarted with 1 or 2 months delay. This was only between March and April.

For patients we used the anti-CD20 therapies on—those with progressive disease—many of them were having higher disability and may be more aged. For older patients, we did delay therapy, and for a few of them we discontinued the therapy altogether. We were monitoring very closely patients with relapsing disease and active disease, and it’s easier to follow in preventing relapses and preventing MRI activity. For a patient with progressive disease, we are only trying to determine if they remain stable. 

As mentioned, based on these data and on a previous consideration before obtaining the data, we did take in these measures and continue to do so. Very active patients, before starting on this medication, we continued with them. We had a very short period that we extended within March and April, but we’re now going back to every 6 months. For patients with progressive disease, we are considering increasing the timing between, and maybe even part of them discontinued therapy because of the concern.

Impact of Results From the COVID-19 in MS Global Data-Sharing Initiative 

Rapid Readout: Expert Perspectives on Multiple Sclerosis - Data from the 8th Joint ACTRIMS-ECTRIMS Meeting 2020

Experts in multiple sclerosis review top data presented at the 8th joint ACTRIMS-ECTRIMS meeting. 