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ECTRIMS Congress

Access daily, concise peer-reviewed reports from the Congress of ECTRIMS selected by the Neurology Today editors.

Tuesday, September 17, 2019

STOCKHOLM—Treatment with ofatumumab, the newest therapy for relapsing-remitting multiple sclerosis (MS), proved superior to teriflunomide in the twin ASCELPIOS trials, researchers reported here at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis.

ASCLEPIOS I and II are double-blind, active comparator-controlled, parallel-group, multicenter trials, the researchers reported. The patients were recruited from 37 countries. Patients were randomized to receive either ofatumumab 20 mg in subcutaneous injections every five weeks— following an initial loading regimen of 20 mg subcutaneous doses on days one, seven, and 14—or were assigned to receive teriflunomide 14 mg orally once daily for up to 30 months.

Treatment with ofatumumab was associated with more than a 50 percent relative reduction in the annualized relapse rate in both ASCLEPIOS l and ASCLEPIOS II trials—50.5 percent in the ASCLEPIOS 1 study (p<0.001), and a 58.5 percent reduction in ASCLEPIOS II (p<0.001), reported Stephen L. Hauser, MD, professor and director of the University of California, San Francisco Weill Institute for Neurosciences.

"Ofatumumab with the monthly 20 mg subcutaneous dosing regimen demonstrated high efficacy and a favorable safety profile," Dr. Hauser said in his presentation at the meeting.

Specifically, the annualized relapse rate among the 452 patients receiving teriflunomide in ASCLEPIOS l was 0.22; the rate was 0.11 among the 454 patients who received ofatumumab, he reported. The results were much the same in ASCLEPIOS ll, in which the 469 patients receiving teriflunomide experienced an annualized relapse rate of 0.25 compared with a relapse rate of 0.10 for the 469 patients assigned to ofatumumab.

In the pooled analysis, treatment with ofatumumab was associated with a 10.9 percent rate of confirmed disability worsening at three months compared with 15 percent of the patients on teriflunomide—a 34.4 percent relative risk reduction (p=0.002). Dr. Hauser also said 8.1 percent of patients on ofatumumab experienced six-month confirmed disability worsening compared with 12 percent of the patients on teriflunomide—a 32.5 percent relative risk reduction (p=0.002).

Dr. Hauser said treatment with ofatumumab also was associated with a dramatic decline gadolinium-enhancing T1 lesions. In ASCLEPIOS l, new lesions occurred in an average of 0.4523 patients on teriflunomide compared with 0.0115—a 97.5 percent reduction in these lesions (p<0.001). In ASCLEPIOS ll, the lesions occurred at a rate of 0.5141 in patients on teriflunomide and a rate of 0.0317 in patients on ofatumumab, a decrease of 93.8 percent (p<0.001). T2 lesions were reduced 82 percent in ASCLEPIOS 1 and by 84.5 percent in ASCLEPIOS 2 among patients treated with ofatumumab (p<0.001).

The clinical findings did not appear to come at a cost of significant adverse events, Dr. Hauser said. He reported that 84.2 percent of teriflunomide patients reported adverse events, but just 7.9 percent of those were classified as serious events; 83.6 percent of the ofatumumab patients experienced adverse events, but just 9.1 percent were labeled as serious. The most common adverse events were infections, occurring in 1.8 percent of teriflunomide patients and in 2.5 percent of ofatumumab patients. The only fatality in the study occurred as the result of an aortic hemorrhage in a teriflunomide patient.

Commenting on treatment with ofatumumab, Mar Tintore, MD, PhD, professor of neurology at Vall d'Hebron University Hospital in Barcelona, Spain, told Neurology Today At the Meetings: "The results are not surprising because ofatumumab is similar to rituximab and similar to ocrelizumab. It is not chimeric and is a human IgG monoclonal antibody against B cells. The mechanism of action is well known. It has the advantage that it is delivered subcutaneously so the patient does not have to spend a day in the hospital. The advantage for patients is significant in that they can do the treatment yourself. It is dosed monthly."

"As a physician we are a bit concerned because we cannot control the treatment," Dr. Tintore said. "With an intravenous infusion, we know that the patients are getting the medication. Ofatumumab also does not require pre-treatment with steroids as other drugs. There is a an up-titration period at first and then the doses are administered monthly."

The study was sponsored by Novartis  Pharma AG, Basel, Switzerland. Dr. Hauser disclosed relevant relationships with Annexon, Alector, Symbiotix, Bionure , Neurona,  F. Hoffmann-La Roche Ltd, and Novartis. Dr. Tintore disclosed relevant relationships with  Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Merck-Serono, Novartis, Roche, Sanofi-Aventis, and Teva Pharmaceuticals.

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ECTRIMS Abstract 336: Hauser SL, Bar-Or A, Cohen J, et al. Efficacy and safety of ofatumumab versus teriflunomide in relapsing multiple sclerosis: Results of the phase 3 ASCLEPIOS I and II trials.

Tuesday, September 17, 2019

STOCKHOLMWith multiple choices for the treatment of multiple sclerosis (MS) available, the question is where does one start? That question was unanswered here at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis following a debate on whether to charge ahead with the most potent therapy or go with solid treatment that can be escalated later if there is a disease breakthrough.

The use of highly potent disease modifying agents upfront—an attempt to induce remission—appears successful in a high percentage of MS patients and should be the path taken, suggested Alasdair Coles, MBChB, PhD, professor of neurology at Cambridge University in the United Kingdom.

That policy might be exposing patients to increased risks of infection—without any guarantees that the induction therapy will prevent the disease from reappearing down the road, so a policy of escalating treatment as needed should remain the therapy of choice, argued Emmanuelle Waubant, MD, PhD,  FAAN, professor of neurology at the Weill Institute for Neurosciences at the University of California, San Francisco.

During the debate, Dr. Coles cited studies that show early treatment with alemtuzumab—one of three induction therapies in MS aside from autologous hematopoietic stem cell therapy and treatment with cladribine—was able to induce long-lasting disease suppression.

"Can an induction therapy lead to long-lasting disease suppression with a restricted window of risk? Is this better than continuous dosing with escalation?" he asked rhetorically and then answered with studies that have been performed using alemtuzumab.

He cited a phase 2 study of 60 MS patients followed for 12 years. One-third of the patients received two cycles of alemtuzumab at baseline and year one and didn't need any other treatment; another 38 percent of patients required an additional booster of alemtuzumab during their 12-year follow-up, and 29 percent of the patients required two or more alemtuzumab therapies. The annualized relapse rate in that cohort was less than one percent.

In larger pivotal trials, Dr. Coles illustrated that treatment with alemtuzumab compared with interferon therapy had similar outcomes, with about 50 percent of the alemtuzumab patients being free of relapses over the nine-year course of follow-up.

He said that with alemtuzumab therapy there was a risk of serious infection that persisted during the time that alemtuzumab was being administered; that patients were advised against pregnancy for about three years, and the cone of the risk of autoimmunity extended for four years, and those risks were repeated if there was the need for another treatment cycle.

Dr. Coles acknowledged that there wasn't likely to be a perfect induction therapy any time soon, but he thought that patients would trade off 11 days of therapy for years of freedom from progressive MS.

Taking a different position, Dr. Waubant said that if induction isn't always successful, and it exposes patients to harm from infection and autoimmunity for long periods of time, it isn't ready for prime time. "True induction therapy with long-term safety and efficacy data are not yet available," she argued.

"The lack of long-term follow-up means we really don't know what this treatment strategy does, most of these studies are small, they weren't always randomized, and have focused on the early impacts and not on the long-term impacts after discontinuing treatment," she said.

On the other hand, Dr. Waubant said, "Early traditional disease-modifying therapy initiation is effective and safe for most patients with clinically isolated syndromes or relapsing-remitting multiple sclerosis."

She said that treatment escalation has shown that it will prevent patients from moving to secondary progressive MS, can save money, prolongs quality adjusted survival, and was no different in preventing increase in disability when compared to early intensive therapy.

Dr. Waubant suggested that patients with early MS be monitored carefully clinically and with yearly MRI and then most to early escalation if warranted.

Dr. Coles disclosed relevant relationships with BTG, Millennium, Ilex, Genzyme, and Sanofi. Dr. Waubant disclosed relevant relationships with Novartis, Roche, Biogen, Jazz Pharmaceuticals, Emerald, and DBV.

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ECTRIMS Abstract 301: Waubant E. Why escalation therapy is the preferred principle over treatment induction.

Tuesday, September 17, 2019

STOCKHOLM—The use of the neurofilament light chain biomarker—which can be assessed thorough peripheral blood samples—has the potential to change the way multiple sclerosis (MS) is diagnosed and treated, one of the pioneers in the field said here at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis.

In his presentation Jan Lycke, MD, PhD, professor of clinical neuroscience at the University of Gothenberg in Sweden, said he can envision a time when serum neurofilament light chain analysis will be included as part of the complex prognostic process that determines if a person with MS truly has achieved "no evidence of disease" status.

Dr. Lycke, who has been publishing journal articles on the use of neurofilament light chain as a biomarker in MS since 1998, discussed the evolution of the biomarker, which was first found and identified in cerebrospinal fluid, and then later found to be available through blood samples.

A series of studies determined that neurofilament light chain is increased during all clinical courses of MS and that the appearance of light chain is three to10 times normal levels during the period of relapses, he explained. Moreover, increases have been observed in patients who have MRI enhancement and in those with new T2 lesions.

"Neurofilament light chain levels correlate with other inflammatory biomarkers in the cerebrospinal fluid," he noted in his featured lecture. "Neurofilament light chain levels correlate with brain atrophy in clinically isolated syndrome."

Dr. Lycke illustrated that while neurofilament light chain levels are far lower in the serum than in cerebrospinal fluid, the levels spike similarly in response to brain injury.

"Neurofilament light chain in the serum/plasma is an attractive multiple sclerosis biomarker for clinical use," he said, for these reasons:

  • It can capture both inflammatory and degenerative processes.
  • It can measure neuro-axonal damage and degeneration.
  • It is accessible, easy, and quick to measure.
  • It has good correlation with clinical endpoints.
  • It is a prognostic marker of disease activity and progression/degeneration.
  • It is responsive to MS therapy and may predict the effect of that treatment on clinical endpoints.

Dr. Lycke also cautioned that there are some problems with the use of neurofilament light chain in the clinic. In particular, the neurofilament light chain biomarker does not discriminate from brain injury due to illness from such conditions as head trauma; levels of neurofilament light chain are age dependent; there may be day-to-day fluctuations in levels; and different measuring tools may be used in different clinics.

When these problems are resolved, Dr. Lycke predicted neurofilament light chain would "be used for early risk assessment for disease severity and prognosis and will support the selection of MS therapy. It will also be used to monitor treatment response and to monitor disease activity."

Commenting on the presentation, session moderator Jonatan Salzer, MD, PhD, associate professor of neurology at the University of Umea in Sweden, told Neurology Today At the Meetings: "Serum neurofilament light chain assessment is coming into regular practice as a way to measure treatment effects. It is an easier process for the patient because it requires just blood and not a lumbar puncture. However, we still need further studies to confirm how use of neurofilament light chain can be used as a biomarker. And it will not completely replace the use of cerebrospinal fluid, which can be used to determine other factors and conditions," he said.

Dr. Lycke disclosed relevant relationships with Biogen, Novartis, Teva and Genzyme/Sanofi Aventis, and Almirall. Dr. Salzer disclosed relevant relationships with Biogen Idec, Teva Pharmaceuticals, Sanofi Genzyme, and Synapsys.

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ECTRIMS Abstract 282: Lycke J. Moving from CSF to blood: Monitoring disease activity in MS using serum neurofilament light protein.

Tuesday, September 17, 2019

STOCKHOLM—The use of a wrist-worn accelerometer, or smartwatch, has the potential to help assess levels of disability remotely in patients with multiple sclerosis (MS), researchers reported here at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Data from the smartwatch may help distinguish differences in mobility among patients who may score the same on tests but can move differently in real world situations, the researchers said.

"A person living with MS who needs a cane to get around and is classified on the Expanded Disability Status Scale [EDSS] with a score of 6.5 may be able to walk 7,000 steps a day while another person with the same classification may only walk 500 steps," said the study's lead author, Valerie Block, PT, a post-graduate fellow at the Weill Institute for Neurosciences at the University of California, San Francisco.

To help understand how walking ability in the clinic and in the real world differs, Block and colleagues fitted 492 patients, 311 who had secondary progressive MS, with the smartwatch that counts steps and other parameters of daily life. The data were collected and stored in a dedicated cloud, which allowed analysis by researchers. The average steps count in the first 30 days of the trial was 3,699.

Block said that steps counted appeared to have significant correlation with overall disability, walking speed, patient-reported physical and mental health, as well as cognitive impairment. It also correlated with MRI findings such as normalized brain volume, brain grey matter volume, and brain T1 lesion volume.

"This is the first study to use remote active monitoring in a large phase 3 study," Block reported in her presentation.

The study is part of the SPI2 trial, a phase 3 study investigating the efficacy and safety of MD1003 – high-dose pharmaceutical grade biotin in patients with primary and secondary progressive MS.

Block said that by using smartwatch technology,  the average daily step count will give researchers a representation of what people actually do in their environment, rather than what they are capable of doing in a clinic setting. She also noted that "steps can capture change when traditional methods are unresponsive."

She said that previous work has shown that step counts do reflect changes over time in the EDSS, with lower step counts related to increased disability in the patients scores on the scale. And sometimes, decreases in STEPS can occur without it showing up in broad measures such as EDSS, she said.

"These data  support the study of steps as an exploratory outcome measure in clinical trials for progressive MS," Block said. The study is ongoing.

Commenting on the study, Annette Langer-Gould, MD, PhD, regional lead for clinical and translational neuroscience for the Southern California Permanente Medical Group at Los Angeles Medical Center, told Neurology Today At the Meetings, "The [smartwatch] technology may be able to give us a better sense of how our patients get around. In addition to just understanding their movements, it also may allow us to detect depression and if they are engaging socially. This study can be useful in understanding the patients who are using a cane."

The study is sponsored by MedDay Pharmaceuticals. Block disclosed relevant relationships with MedDay Pharmaceuticals. Dr. Annette Langer-Gould had no relevant disclosures.

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ECTRIMS Abstract 217: Block V, Alexander A, Papinutto N, et al. Remotely monitored ambulatory activity correlates with MS disability not only for ambulation but also for MRI atrophy metrics, cognition and quality of life: Baseline analysis from the SPI2 clinical trial of MD1003 in progressive MS.

Tuesday, September 17, 2019

STOCKHOLM—Getting multiple sclerosis (MS) patients to walk the plank may give doctors early insight into how well they are handling balance and gait issues, researchers reported here at the congress of the European Committee for Treatment and Research in Multiple Sclerosis.

In patients with early stage MS—those with scores of 0–1.5 on the Expanded Disability Status Scale (EDSS)—performance on a balance board indicates if they are having problems with gait and stride, and this may be related to falls, said Victoria Leavitt, PhD, assistant professor of neurology at Columbia University Medical Center in New York. Dr. Leavitt presented the data on behalf of Rachel Brandstadter, MD, and colleagues from Mount Sinai Hospital in New York.

"Earlier detection of subtle balance disturbance can lead to prompt referral for rehabilitative intervention for patients at risk of falls," she said in her presentation.

In early MS, Dr. Leavitt said that gait disturbances are not uncommon. Of 149 patients with an EDSS score of 1.5 or less, 36 patients or 24.2 percent, expressed that they felt they had experienced at least mild gait disturbance.

In the study, Dr. Leavitt and colleagues put patients through a series of balance tests and observed that compared with healthy controls, patients even with very low EDSS scores did worse. In the postural sway test, the theta score for controls was 0.939; for patients diagnosed with multiple sclerosis is was 0.677—a higher score is preferred (p=0.002).

The research team designed two balance board tests, using one board 4.5 inches wide and 0.75 inches high, and a second board 1.5 inches wide and 1.5 inches high. On both measures of balance, controls did better. Controls had a score of 0.713; patients had a score of 0.586 (p<0.001), Dr. Leavitt reported.

She noted that despite having low disability as registered by the EDSS and a normal timed 25-foot walk test, the patients still reported abnormalities in their gait. Overall, 31.5 percent of patients reported at least mild gait disturbance.

"Only dynamic balance reliably discriminated between patients reporting no versus mild gait difficulty," Leavitt reported. "Balance tasks were more correlated with all MRI metrics than were walking tasks and EDSS."

Thirty percent of patients reported either a fall or near-fall after one year, and eight patients reported moderate to severe fall-related injuries, including long bone fractures. Poor dynamic balance was the only performance task independently predicting falls, she said.

Commenting on the study, Asaff Harel, MD, a neurologist at Lenox Hill Hospital and assistant professor of medicine at Hofstra University/Northwell Health in New York, told Neurology Today At the Meetings, "In short, clinicians are not very familiar with the testing being presented, but these tests are certainly feasible and could be incorporated into standard-of-care clinical evaluation."

"Physicians are aware that our clinical tools are limited in detecting subtle disease-related abnormalities. The more sensitive the test, the more abnormalities can be found."

Gait dysfunction is common, according to Dr. Harel, and he added that it would be useful to have "a more sensitive metrics to predict high-risk individuals and those who would benefit from intensive physical therapy or assistive devices."

"While a physician's time is highly limited in the current era of medicine, this test likely would not require a physician to be present to administer. Hence, I believe that it could be incorporated," he said. 

"As future research, it would be interesting to determine whether individuals at high-risk of future fall would benefit from intensive physical therapy. However, larger numbers are necessary for such a study."

Dr. Leavitt disclosed relevant relationships with Healios LLC. Dr. Harel disclosed no relevant relationships with industry.

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ECTRIMS Abstract 177: Brandstadter R, Ayeni O, Krieger S, et al. Detection of subtle gait disturbance and future fall risk in early multiple sclerosis.