Bianca Weinstock-Guttman, MD

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.

Videos

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

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 

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

Chief Endpoints and Potential Significance: Phase 3b OLIKOS Trial

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

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

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

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 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

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.