“This new idea that progression in MS is present across the continuum [of disease], and is also more easily controlled earlier on, means that highly effective therapy as early as possible is a very reasonable clinical approach to patients.”

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, a number of presentations were given highlighting agents that are approved for use in patients at a variety of disease stages, ranging from clinically isolated syndrome (CIS) to secondary progressive multiple sclerosis (MS). Although MS is a field that is well-equipped with therapeutic options, the advantages of having high-efficacy therapies that can be used at almost any point in disease are somewhat obvious.

One such agent is ofatumumab (Kesimpta; Novartis), which Stephen L. Hauser, MD, professor of neurology, and director, UCSF Weill Institute for Neurosciences, and colleagues presented data on. Those findings suggest that ofatumumab is superior to teriflunomide (Aubagio; Sanofi) in newly diagnosed, treatment-naïve patients with multiple sclerosis (MS) who have low absolute relapse rates, very low MRI lesion activity, and prolonged time to disability worsening.

These findings also bring up the ongoing debate around whether early intensive (or induction) therapy or escalation therapy strategies should be utilized for patients with MS. As Hauser pointed out to 

 in this interview, the improved understanding of the role disease progression plays in the process of disease has given hints that initial or early treatment with therapies such as ofatumumab may provide better benefit.

REFERENCE
Gartner J, Hauser S, Bar-Or A, et al. Benefit-risk of ofatumumab in treatment-naïve early relapsing multiple sclerosis patients. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0192

Videos

ECTRIMS

The director of the UCSF Weill Institute for Neuroscience spoke to the advantages of having agents that can be used across the spectrum of MS, and the role disease progression plays early on.

Stephen L. Hauser, MD: Increasing Understanding of Disease Progression in MS

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, suggest that fatigue occurs in most patients with relapsing multiple sclerosis (MS) and influences daily functioning.

Presented by Lindsey L. Lair, MD, FAAN, senior Global Medical Affairs Leader-Neuroscience, Janssen Pharmaceuticals, the research aimed to measure MS fatigue and its impact on daily life in a real-world population using a survey that included that relapsing MS (RMS)-specific Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS).

On a score range from 0 to 100, higher scores indicated greater severity. Findings from the cohort of 142 patients with RMS revealed that fatigue levels are severe, with a mean FSIQ-RMS symptom domain score of 59.5 during a 7-day period.

Demographic and clinical questionnaires that included disease history and status, sleep, and social and emotional function were completed by the participants along with the FSIQ-RMS, which was administered daily for 7 days. Physical, cognitive/emotional, and coping subdomain scores were 45.1, 44.9, and 50.6, respectively, following the 7-day period.

Walking difficulties and fatigue were recorded as the 2 most impactful symptoms on daily functioning. Notably, 56% of the patient population experienced fatigue prior to MS diagnosis.

In total, 72% of patients were not currently relapsing and had a mean fatigue symptom domain score of 56.2, compared to 68 who had an active relapse. Lair and colleagues also noted that fatigue was rated the most impactful symptom on daily life by those with lower disability.

Patients without depression, which represented 56% of the population, still reported mean fatigue symptom domain scores of 53.7 compared to 67 in those with depression. Among those who reported a sleep disorder, a mean fatigue symptom domain score of 58.1 was recorded in 72% of the population. In contrast, those without a sleep disorder recorded a 63.3 mean fatigue symptom domain score.

The most common triggering factor for fatigue was heat exposure, which occurred in 82% of patients.

Disability and economic burden have both been associated with higher levels of fatigue in patients with MS. 

Another study presented at MS Virtual 2020

 revealed that patients with relapsing-remitting MS who were stratified by high levels of fatigue had greater comorbidity and economic burdens compared to those with MS who had low levels of fatigue.

The data from that study showed that the annualized number of outpatient visits, emergency room visits, and hospitalizations were greater for those with relapsing-remitting MS with high levels of fatigue compared to those with relapsing-remitting MS with low levels of fatigue.

Amy B. Sullivan, PsyD, ABPP, director of Behavioral Medicine at the Mellen Center for MS Treatment and Research at Cleveland Clinic, sat down with 

t the 2019 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC), 

and discussed how she approaches fatigue in MS from a behavioral standpoint. Watch the interview below.

1. Azoulai M, Levy-Heidmann T, Morisseau V, et al. A real-world study characterizing symptoms and impacts of fatigue in US adults with relapsing multiple sclerosis using a novel disease specific scale. Presented at: MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P1004.

2. Le H, Ken-Opurum J, Maculaitis M, Sheehan J. Comorbidity and economic burdens of fatigue among patients with relapsing-remitting multiple sclerosis in the United States. Presented at: MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0857.

Articles

Patients with lower levels of disability tended to report fatigue as the most impactful symptom in daily life.

Fatigue Plays a Key Factor in Multiple Sclerosis Daily Functioning

"In the S1P class, the effects are that it starts rapidly, but they also stop rapidly. Within 1 week, lymphocytes are back to normal.”

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11-13, 2020, revealed that 

 20 mg resulted in consistently low levels of disease activity across relevant clinical and magnetic resonance imaging (MRI) outcomes in patients with relapsing-remitting multiple sclerosis (MS). The results of the study add to the already robust profile of ponesimod, which has shown efficacy against FDA-approved teriflunomide (Aubagio; Sanofi) in previous phase 3 studies.

Ponesimod, a selective sphingosine 1-phosphate receptor-1 (S1P) modulator, is designed to inhibit S1P protein activity, and in doing so, is believed to reduce the number of circulating lymphocytes that can cross the blood-brain barrier. Luc Truyen, MD, PhD, global head, Development and External Affairs-Neuroscience, Janssen Pharmaceutical, feels as though ponesimod’s design stands out among other MS treatments.

The MS treatment landscape has undergone a number of additions in the past decade and ponesimod could be the next one with its new drug application which was filed in March 2020. Truyen sat down with 

 to discuss the positives of a robust MS treatment landscape and why ponesimod stands above the rest.

The global head of Development and External Affairs-Neuroscience at Janssen Pharmaceutical detailed what makes ponesimod different from other currently FDA-approved treatments. 

Luc Truyen, MD, PhD: Advantages of Ponesimod as an S1P Modulator

Two-year findings from the phase 3b CHORDS study (NCT02637856) demonstrated that patients with relapsing-remitting multiple sclerosis (RRMS) see benefits from ocrelizumab (Ocrevus; Genentech) treatment despite having a suboptimal response to previous disease-modifying therapy (DMT).

The modified intention-to-treat (mITT) population included 576 patients, 48.1% of which were free of all protocol-defined events following treatment with ocrelizumab 600 mg. More specifically, freedom from relapse, gadolinium-enhancing (GdE) lesions, and new/enlarging T2 lesions occurred in 89.6%, 95.5%, and 59.5% of patients, respectively.

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020 by Bianca Weinstock-Guttman, MD, of Buffalo General Medical Center, the data also showed no confirmed disability progression (CDP) in 89.6% of patients over 96 weeks for those treated with ocrelizumab.

Weinstock-Guttman and colleagues found similar results in those who received 1 versus >1 prior DMT (50.9% vs 44.5%) for individual events (relapse: 90.% vs 89.2%; T1 GdE lesion: 95.8% vs 95.1%; new/enlarging T2 lesion: 61.4% vs 57.1%; 24-week CDP: 90.9% vs 87.9%). Notably, the adjusted annualized relapse rate (ARR) assessed in the ITT population over 96 weeks was 0.046.

Stable changes in Expanded Disability Status Scale (EDSS), defined as a <1-point change, occurred in 61.5% of the population. Improvements in EDSS, defined as ≥1-point decrease, occurred in 22.7% of patients. There were no deaths or new safety signals observed.

Among the 608 patients in the ITT population, the mean time since diagnosis was 4.2 years (standard deviation [SD], 3.03). The most frequently used DMTs prior to enrollment included glatiramer acetate (49.3%), dimethyl fumarate (35.4%) and fingolimod (20.1%).

Additional data on ocrelizumab from the phase 3b CASTING study

A pair of datasets from that study suggested that patients treated with the agent experienced high rates of no evidence disease activity (NEDA) status regardless of prior DMT exposure. Furthermore, after the 2-year treatment period, 492 of 658 patients (74.8%) qualified for NEDA status (with MRI re-baselined at Week 8 of treatment). The highest rates of NEDA were observed in those who were enrolled due to only MRI activity (80.6%). Those with only relapses achieved NEDA at a rate of 75.1% compared with 70.5% in patients with both MRI and relapse activity.

FDA accepted its supplemental biologics license

 application for a version of ocrelizumab with a shorter administration time for the treatment of relapsing and primary progressive MS. The sNDA was accepted by the FDA based on 

 study, a double-blind, prospective sub-study to the open-label, single-arm, phase 3b ENSEMBLE (NCT03085810) trial.

 of ocrelizumab in January, reflecting new information about infusion reactions, vaccinations, and risks in specific patient populations.

1. Weinstock-Guttman B, Bermel R, Cutter G, et al. Ocrelizumab treatment in patients with RRMS who had suboptimal response with one or more prior disease-modifying therapies: CHORDS 2-year results. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0221.

2. Wiendl H, Comi G, Oreja-Guevara C, et al. Ocrelizumab Phase IIIb efficacy from CASTING: 2-year NEDA (MRI re-baselined) subgroup rates in RRMS patients with a suboptimal response to prior DMTs. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0219.

3. US FDA and EMA accept applications for Roche’s OCREVUS (ocrelizumab) shorter 2-hour infusion time [press release]. Basel, Switzerland: Genentech; Published April 20, 2020. Accessed September 21, 2020. globenewswire.com/news-release/2020/04/20/2018330/0/en/US-FDA-and-EMA-accept-applications-for-Roche-s-OCREVUS-ocrelizumab-shorter-2-hour-infusion-time.html

4. Drug Safety-related Labeling Changes (SrLC). US FDA website. January 15, 2020. Accessed September 21, 2020. accessdata.fda.gov/scripts/cder/safetylabelingchanges/index.cfm.

Treatment with ocrelizumab can improve freedom from individual events in patients with relapsing-remitting multiple sclerosis regardless of suboptimal DMT response in the past. 

Ocrelizumab Holds Benefit for Relapsing MS Patients With Prior Suboptimal DMT Response

, September 12–16, 2020, included findings from a survey conducted by Indu Subramanian, MD, and colleagues that shed light on the impact of loneliness as a predictor of disease severity in patients with Parkinson disease.

All told, the data identified that being lonely or socially isolated can be extraordinarily detrimental for patients and their well-being. Subramanian, who is the director of the VA Southwest Parkinson’s Disease Research, Education, and Clinical Centers and a member of the faculty at UCLA, noted that patients with reports of feeling lonely had higher PRO-PD scores, even more so than those who smoked and had high stress levels.

To learn more about the importance of patient-focused measures, especially amid the ongoing global pandemic, 

: What were the main takeaways from this survey?

 We have this way of measuring quality of life called the PRO-PD scale. Laurie Mischley, ND, PhD, who's a collaborator of mine, looked at the scale and it seems to be validated against our normal measures of quality of life. It's quite a patient-centered quality of life scale, actually, because it includes a number of things that the NIH had wanted to be included in patient-centered outcomes. So much of the research that we do and spend a lot of time talking about is actually completely not patient-centered.

What we showed is actually something like tremor, which is like the most obvious Parkinson disease symptom, and when you think about a patient with Parkinson, you think about someone who is maybe stooped over with a tremor. That actually doesn't have much to do with quality of life. But if you have a lot of friends, it can actually improve your quality of life significantly. And if you don't have any real relationships, it can actually be very, very bad for your quality of life. It really impacts a lot of the nonmotor issues that we talk about with Parkinson patients. Things like depression and anxiety, insomnia, apathy, those things are actually tremendously impacted by this issue of being socially isolated. That can be very powerful for a patient with Parkinson. That really can determine how they're doing on a day-to-day basis much more than anything we measure in a clinic with a physical exam or some of the scoring that we do traditionally.

How important is it to have a more patient-centered approach to care?

I think it's quite important to care about what patients care about and be more patient-centered. I think that not only do we identify this with our survey, but we also have come up with possible solutions to help it, which is exciting because so much of what we're talking about with COVID-19 is this doom and gloom, and I kind of frame it in the framework of the fact that Parkinson in and of itself is a pandemic. There's been a doubling of Parkinson patient cases in the last 40 years or so, and they say that by 2040, it will double again. We have a huge number of an expanding population of patients, and we haven't fully figured out why that is. Then, we have this loneliness pandemic, which honestly affects every person on the planet, it doesn't matter who you are, if you're rich or poor, or whatever. I mean, that is a pandemic that has kind of been a silent killer in some ways, and then we have this third pandemic that's influencing these other 2—the COVID-19 pandemic—which is really limiting our ability to see our patients and make dramatic changes with their pills, and we're just trying to keep our patients safe.

What are those interventions that can help?

We have some powerful possibilities to intervene. What we were titling social prescribing, which is a concept that has been established out there, but it's not very well known about. This is a concept of literally prescribing a social intervention or social connection to our patients. So. I can say, “Mr. Smith, I know that you're lonely and you don't have anyone who cares about you.”

We have this actually new VA intervention, where there were a number of volunteers that used to come physically into the VA—anyone's ever been to the VA, you probably have been greeted by a volunteer in the lobby—and those folks are being told to stay home to keep them safe. Some of them are family members of veterans, or the widows of veterans, and that's their identity, helping other veterans. And now we've told them to stay put in their homes for the last 6 months. There's this new intervention called the Compassionate Contact Corps, and they're matching these volunteers with veterans through a survey, seeing if they were in the same branch of the military, what their favorite movie is, their favorite hobbies, et cetera, and connecting people, hopefully with like interests. Then, these volunteers will actually be either doing a digital sort of meeting, if they can get our patients to participate with that type of technology.

We're also actually proactively calling people on the phone, which is really exciting. Just a simple phone call can actually make a huge amount of difference for somebody. There's actually been some data on the benefits for the volunteers as well, which is pretty exciting. So we’re actually helping with designing a few questions to put into that survey and seeing if that changes as people are working with each other and helping each other out. I'm quite excited because veterans who get lonely are actually at much higher risk of depression and anxiety. Suicide actually is really high in this population and then also so is substance abuse. We really have to be careful with these populations and be proactive and make sure that we're taking care of them.

But the intervention that I mentioned is actually a VA-specific intervention of social prescribing, but there have actually been other models of that, including one that the National Health System just wrote about in the 

. But they are doing it using link workers to connect isolated people with social interventions. It's a known kind of a thing that is being written about.

Who was involved in the survey population?

The actual survey that we did, even though I work at a VA, included thousands of patients from the general PD population, and there's a lot of women actually that were in the survey and younger women who were not that advanced. So, it's not the standard veteran population that I see day to day. I do work with research and all areas of this sort of interface of integrative medicine and I people tend to come to me because I am a boarded neurologist with a movement sort of background that has a yoga teacher training, as well as an integrative medicine background, which I don't think there really are very many of—maybe one other person on the planet—so I ended up working and collaborating with people.

Are there any distinct differences between the general Parkinson population and veterans with Parkinson disease?

Veterans in general are definitely, at baseline, a tougher population. They tend to be stoics. Then, there's a stigma associated with loneliness, so you actually have to come in and talk to people about it. Sometimes people think if they have a mental health issue, there's a huge stigma. Men are much less likely to identify with this problem and be honest about it, and that's my main VA population. So, I think just normalizing it and saying that this happens to all of us is helpful.

How important do you feel it is to recognize loneliness, particularly in the midst of a global pandemic?

I gave a talk like this the other day and had a colleague actually in a different part of the country write an email and reach out to me because they were lonely and battling a lot of these sorts of issues with feeling not in control of their emotions and things around that. I think this is something that we as a community need to realize affects all of us. That any one of us could become lonely. You could be happily married and still be lonely, so it's really out there, and it is something that we have to proactively identify. There's possibly a neighbor that lives on your street that could have this, be battling this, and just a simple phone call or dropping off something—a nice card for them, saying thinking about you, or something—can help. I think we're all socially connected as a basic human need.

I was really impressed with the data that you know, loneliness is, can impact actually sleep, it can impact our thoughts. If we get so lonely, it actually makes us hyper-vigilant and start thinking about the world in a very paranoid kind of way where we’ll fixate on all the negative stuff. I actually have a colleague with who I am writing something with currently, he's a doctor in Barcelona. In their lockdown, the patients weren't allowed to go out of even their little apartments to go outside. These patients became so lonely and sensory deprived that they all they got was some news once in a while, and they actually started getting psychotic and really anxious and depressed. It really changed their mental state. I think it is it's almost like being in solitary confinement sometimes. We've somehow created some of these situations for our patients in hopes to keep them safe right now, so I think we just have to be really mindful of that.

I think a lot of even my colleagues are just going through a lot in and of themselves with burning out, they're working nonstop on these Zoom meetings with really not a lot of true connection with each other. Part of the beauty of working together in medicine is the teamwork and the checking in with each other and knowing about how your team is doing. I lead a team and so much of what I do is just making sure that we're all doing okay, and that's not easy to do when you’re wearing PPE with masks and a face shield all day long. I can't hug my patients or colleagues and it's a very disconnected way that we're interacting, honestly. It's been, it's been very tough.

I will say I'm hosting a number of my colleagues on a virtual support group for patients, and it's been really nice to see them actually through this type of modality. We kind of get off the line and are like “I miss you; I haven't seen you in 6 months!” Normally, we would have seen each other 3 times at different meetings, and it's just a very different way that we're interacting with even our medical colleagues and health care providers right now. I think we just have to be mindful and vigilant, even in our own selves and with our close colleagues, and just make that extra phone call to check-in or schedule a virtual happy hour with somebody that you know that has just been working nonstop and hasn't had a break. If you to give them a hug—even if it's virtually—I think can be really, really helpful to just share the common human experience of what we're all going through right now.

REFERENCE
Subramanian I, Mischley L, Farahnik J. Loneliness/Social Isolation as a Risk Factor for Worsened Parkinson Disease Severity. Presented at MDS Virtual Congress; September 12–16, 2020.

The director of the VA Southwest Parkinson’s Disease Research, Education, and Clinical Centers spoke to the importance of patient-focused interventions in PD.

The Importance of Patient-Centered Care in Parkinson Disease

“Many experts in the MS area feel—and it’s certainly my feeling—that we want to minimize or halt progression as early as possible, even at the beginning of disease when progression may be more difficult to detect by our routine methods of interrogation.”

Stephen L. Hauser, MD, and colleagues presented data at 

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, suggesting that ofatumumab (Kesimpta; Novartis) is superior to teriflunomide (Aubagio; Sanofi) in newly diagnosed, treatment-naïve patients with multiple sclerosis (MS) who have low absolute relapse rates, very low MRI lesion activity, and prolonged time to disability worsening.

Notably, these findings were consistent with the overall study population of ASCLEPIOS I and II, the pivotal trials for the agent. All told, compared to patients on teriflunomide, ofatumumab reduced annualized relapse rates (ARR) by 50.3% (0.09 vs. 0.18; 

<.001). As well, 3-month Confirmed Disability Worsening (CDW) risk was reduced by 38% (10.1% vs 12.8%; 

= .065), and 6-month CDW risk was reduced by 46% (5.9% vs 10.4%; 

 = .044). Gadolinium-enhancing T1 lesions per scan were cut by 95.4% (0.02 vs 0.39: 

 <.001) and new/enlarging T2 lesions per year were lowered by 82.0% (0.86 vs 4.78, 

To find out more about these data and how they translate clinically for the physician community, 

 reached out to Hauser, who presented the data and is a professor of neurology at, and director of, the UCSF Weill Institute for Neuroscience.

REFERENCE
Gartner J, Hauser S, Bar-Or A, et al. Benefit-risk of ofatumumab in treatment-naïve early relapsing multiple sclerosis patients. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0192.

The director of the UCSF Weill Institute for Neuroscience offered his perspective on data presented at MS Virtual suggesting ofatumumab’s benefit in patients with MS who were treatment naïve.

Stephen L. Hauser, MD: Ofatumumab in Treatment-Naïve Patients With MS

Preliminary phase 1 safety data (NCT03283826) on the investigational off-the-shelf, allogeneic Epstein-Barr virus (EBV)-targeted T-cell therapy ATA188 (Atara Biotherapeutics) suggest that the agent is well tolerated in adult individuals with progressive forms of multiple sclerosis (MS).

The data include those patients dosed up to April 2020 (n = 25), each of which received ≥1 dose of ATA188. Ultimately, there were no events worse than grade 3 reported. In total, 2 treatment-emergent serious adverse events (AEs) were noted: a grade 2 incidence of muscle spasticity, which was not related to therapy, and a grade 3 incidence of MS relapse, which was considered possibly related to treatment.

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, by Amit Bar-Or, MD, the Melissa and Paul Anderson President's Distinguished Professor of Neurology, Perelman School of Medicine, University of Pennsylvania.

“It was very well-tolerated, and the good news is that we are not seeing that even with the longer-term dosing of patients with these cells going out to 21 months, 24 months, we're not seeing augmentation of safety issues,” Jakob Dupont, MD, executive vice president, and head of global research and development, Atara Biotherapeutics, told 

. “One of the aspects of ATA188 is that it's a very specific treatment. These T cells are really directed against only EBV-expressing infected cells, and so we don't have a lot of off-target toxicity because of that.”

Progressive and Relapsing-Remitting Multiple Sclerosis Share Similar Fatigue Severity

As well as the generally low-grade AEs that were observed, there were no dose-limiting toxicities, cytokine release syndrome, graft-versus-host disease, or infusion reactions reported. “With a lot of cell therapies, whether it's CAR-T or whatever it may be, you can see neurological symptoms, you can see cytokine release syndrome and so forth, and we really don't see those types of effects with our treatment because, again, the specificity of our EBV T cells. They're not directed against the patient's own self-antigens, if you will,” Dupont noted.

The first part of this included 4 cohorts of patients who received escalating doses to determine the recommended dose for the second part of the study. The participants were followed for 1 year, and then given the option to participate in a 4-year open-label extension (OLE) at the recommended dose, which was determined by Cohort 3.

In addition to the safety measures, sustained disability improvement (SDI)—defined as improvement in Expanded Disability Status Scale (EDSS) or Timed 25-Foot Walk (T25FW) at 2 or more consecutive time points—was assessed, as well as Fatigue Severity Scale (FSS), 12-item MS Walking Scale (MSWS-12), MS Impact Scale-29 (physical; MSIS-29), and whole-brain volume. The efficacy end points were assessed in all 4 cohorts (n = 24) at the 6-month mark, and in the first 3 cohorts (n = 17) at 12 months.

A higher proportion of patients who were treated with ATA188 showed sustained disability improvement (SDI) with an increasing dose. At 6 months, 6 patients met SDI criteria, and at 12 months, 5 patients did so. This was driven by EDSS score in all but 2 patients at both time points. In cohorts 1, 2, and 3, every patient with SDI at the 6-month time point maintained that status through 12 months.

Additionally, those who achieved SDI at any time point maintained it at all future time points and tended to show improvements in fatigue, physical function, and MRI whole brain volume at 1 year. As of June 2020, OLE data from the 15-month time point were available for 4 individuals: 3 had SDI at 6 and 12 months that was maintained to that point.

“We are encouraged by what we’re seeing in the clinical trial because when we get into Cohort 3, we are seeing sustained disability improvement in these patients…this isn’t just 1 point in time where we’re seeing a patient doing better today,” Dupont said.

REFERENCE
Pender M, Hodgkinson S, Broadley S. Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive forms of multiple sclerosis. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0226.

Atara Biotherapeutics’ allogeneic EBV-targeted T-cell therapy, ATA188, is well-tolerated in phase 1, with a dose identified for the randomized placebo-controlled portion of the study.

Investigational Drug Targeting Epstein-Barr Virus Shows Promise for Progressive MS

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, revealed that there are no between group differences 

 in average fatigue severity or fatigue interference 

among persons with progressive multiple sclerosis (MS) or relapsing-remitting MS (RRMS).

Tracy Herring, PhD, senior fellow, Multiple Sclerosis Rehabilitation & Wellness Research Center, University of Washington, who presented the data, noted that “given the similarity between fatigue and its correlates for both progressive and relapsing forms of MS, future research should consider if the interventions that work for fatigue management in people with relapsing forms of MS work similarly for people with progressive forms of MS.”

The study, which included 573 community-dwelling individuals with MS, looked at outcome measures such as fatigue severity and fatigue interference and used T-test and chi-square analyses to compare group differences.

Researchers also used multiple regression analysis to examine the extent to which the association of risk factors with fatigue severity and interference are moderated by MS subtype. They found that longer MS disease duration was associated with lower average fatigue severity (

 <.001) for persons with progressive MS compared to persons with RRMS (

In an effort to identify common demographic risk factors, Herring and colleagues found that having a college degree or higher was associated with higher fatigue interference in persons with progressive MS (

As the investigators previously noted, future studies will confirm whether interventions for patients with progressive MS can be used for those with RRMS. Fatigue increase has been documented as a major symptom that can impact quality of life for those with MS.

Another study presented at MS Virtual 2020 revealed that patients with RRMS who were stratified by high levels of fatigue (RRMS+HF) had 

 compared to those with low fatigue (RRMS+LF) and individuals with MS.

The data showed that the annualized number of outpatient visits, emergency room visits, and hospitalizations were greater for those with RRMS+HF (15.5 [±15.4]; 1.3 [±3.5]; 0.9 [±2.6]) compared to those with RRMS+LF (11.5 [±17.6]; 0.7 [±2.0]; 0.4 [±1.6]) and non-MS (7.4 [±11.3]; 0.5 [±2.5]; 0.4 [±2.8]) groups.

1. Herring T, Alschuler K, Knowles L, et al. Differences in correlates of fatigue between relapsing and progressive forms of multiple sclerosis. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P1090.

2. Le H, Ken-Opurum J, Maculaitis M, Sheehan J. Comorbidity and economic burdens of fatigue among patients with relapsing-remitting multiple sclerosis in the United States. Presented at: MS Virtual 2020 Joint ACTRIMS-ECTRIMS meeting, September 11–13, 2020. Abstract P0857.

Future research may help better characterize whether fatigue interventions aimed at one patient population may be effective in the other. 

New results from the phase 3b CASTING study (NCT02861014) suggest that a wide range of disease-related and demographic subgroups of patients with multiple sclerosis (MS) who are treated with ocrelizumab (Ocrevus; Genentech) achieve high rates of no evidence of disease activity (NEDA) status after 2 years. This status was reached regardless of prior exposure to disease-modifying therapies (DMTs).

Additionally, a second dataset from CASTING revealed that individuals with relapsing MS who had a suboptimal response to prior treatment experienced symptom improvement after 2 years across the majority of domains measured by SymptoMScreen, a patient-reported outcome tool designed to rapidly assess symptom limitations across 12 symptoms commonly reported in MS. These gains were most pronounced for sensory, fatigue, and vision-related symptoms.

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, the first set by Heinz Wiendl, MD, head, Weindl Lab, Clinic for Neurology, Institute for Translational Neurology, University Hospital Münster, and the second set by Ilya Kister, MD, associate professor, Department of Neurology, NYU Grossman School of Medicine, and director, Neuromyelitis Optica Treatment and Research Program, NYU Langone Health.

Wiendl and colleagues’ data included 680 patients with a baseline Expanded Disability Status Scale (EDSS) score of 2.1 (standard deviation [SD], 1.1), of which 411 (60.4%) had been treated with 1 prior oral or injectable DMT and 269 (39.6%) had been treated with 2 prior DMTs. MRI-only disease activity was the reason for enrollment for 167 patients (24.6%) while 238 (35%) had only relapse, and 275 (40.4%) had both.

After the 2-year treatment period, 492 of 658 patients (74.8%) qualified for NEDA status (with MRI re-baselined at Week 8 of treatment). The highest rates of NEDA were observed in those who were enrolled due to only MRI activity (80.6%). Those with only relapses had NEDA at a rate of 75.1% and those with both had a rate of 70.5%.

Ozanimod Shows Long-Term Safety, Efficacy in Open-Label Extension

NEDA rates did not vary by age at baseline when patients were stratified by those aged 40 years and younger (74.7%) and those older than 40 years (75%).

Additionally, the NEDA rates across disease-related subgroups were the highest in the subgroups of those with baseline EDSS score <2.5 (77.2%), those with ≤1 relapse prior to enrollment (78.2%), and the event leading to enrollment occurring ≥6 months prior to study entry (75.8%). These groups were highest compared to their counterpart subgroups of those with EDSS scores of ≥2.5 (70.8%), with >1 relapse prior to enrollment (66.3%), and with the event leading to enrollment occurring <6 months prior to entry (71.0%).

Those who received 1 prior DMT experienced higher rates of NEDA (77.6%) than those with 2 prior DMTs (70.3%), and the rates remained generally high when stratified by the last prior DMT received before enrollment—interferons, 81.1%; glatiramer acetate, 73.9%; dimethyl fumarate, 73.8%; teriflunomide 69.8%; fingolimod, 68.9%.

Meanwhile, the dataset presented by Kister et al. included the same cohort of patients to evaluate SymptoMScreen. Each domain of the tool is scored on a 7-point Likert scale, ranging from 0 (not affected) to 6([total limitation), and domain scores are summed to calculate a total score ranging from 0 to 72. SymptoMScreen was performed at baseline, Week 48 (which made up the 1-year interim data) and Week 96 (which made up the 2-year final data).

Their findings showed that the total SymptoMScreen mean score reflected mild symptom burden at baseline (15.19 [SD, 12.67]) and improved significantly through the second year (13.62 [SD, 12.51]; 

 <.001). As mentioned, there were significant improvements reported by patients for sensory symptoms (Δ-0.28; 

 <.001). Additionally, there were marked gains in symptoms of depression (Δ-0.15; 

As well, the proportion of patients with ≥1 symptom causing at least moderate limitation (defined as a domain score ≥4) decreased from 31.6% at baseline to 26.3% at Year 2.

Non-significant improvements in symptom burden after 2 years were reported in the domains of walking (Δ-0.1), cognition (Δ-0.10), anxiety (Δ-0.07), bodily pain (Δ-0.05), hand function (Δ-0.03), and bladder control (Δ-0.01). There was a non-significant worsening was observed in the spasticity domain (Δ+0.04).

REFERENCES
1. Wiendl H, Comi G, Oreja-Guevara C, et al. Ocrelizumab Phase IIIb efficacy from CASTING: 2-year NEDA (MRI re-baselined) subgroup rates in RRMS patients with a suboptimal response to prior DMTs. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0219.
2. Kister I, Cutter G, Buffels R, Clinch S, Kuenzel T, Vermersch P. Improvements in patient-reported SymptoMScreen scores among ocrelizumab-treated patients with RRMS: 2-year results from the CASTING clinical trial. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P1039.

A pair of datasets from the phase 3b CASTING study of ocrelizumab (Ocrevus; Genentech) suggest that patients treated with the agent experienced high rates of no evidence of disease activity status regardless of prior DMT exposure.

Ocrelizumab Treatment Results in High NEDA Rates, Improvements in MS Symptoms

"Today, which is 8 and a half years after we started this, there is still 197 patients on ponesimod 20-mg. To me, as a clinician, that talks to the long-term safety and tolerability of ponesimod very eloquently.”

Ponesimod (Janssen Pharmaceutical), a selective sphingosine 1-phosphase receptor-1 (S1P) modulator, has shown previous success in phase 3 studies, most notably in OPTIMUM (NCT02425644). A new phase 2b core study and its extension looked at the long-term effects of ponesimod in patients with relapsing-remitting multiple sclerosis (RRMS) across a median exposure of 8.02 years.

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, showed that treatment with ponesimod 20-mg resulted in consistently low levels of disease activity across relevant clinical and magnetic resonance imaging (MRI) outcomes, including lowered annualized relapse rates (ARRs) and confirmed disability accumulation (CDA). To understand more about the results and the impact this study has, 

Truyen, global head, Development and External Affairs-Neuroscience, Janssen Pharmacuetical, provided more context of the phase 2b study and its extension, as well as why the data is clinically meaningful.

The global head of Development and External Affairs-Neuroscience at Janssen Pharmaceutical discussed the results of a phase 2 core and extension study of ponesimod in patients with relapsing-remitting multiple sclerosis. 

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