What’s New in MS Research: March 2021
Reviewed by MSAA Chief Medical Officer Barry A. Hendin, MD
The first quarter of 2021 has been marked by welcome news on the medical front, and those hopeful developments aren’t limited to the increasing number of COVID-19 vaccinations being given across the country. Significant strides in treating and understanding MS also have been made in these early months of the year, as detailed in this edition of “What’s New in MS Research.”
The Food and Drug Administration (FDA) this month approved Ponvory™ (ponesimod), an oral, once-daily disease-modifying therapy (DMT) for relapsing forms of MS, and recently gave the green light to a new route of administration for Plegridy® (peginterferon beta-1a). Favorable developments also include preparations for a Phase II study evaluating a novel synthetic molecule as an oral therapy for relapsing MS, and research evaluating Ocrevus® (ocrelizumab) in older adults with progressive forms of MS.
Much of the news reported below comes from the 2021 annual meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), which was conducted virtually from February 25-27, 2021.
Research presented at ACTRIMS and summarized here includes studies on the surprisingly high use of prescription opioids among people with MS and the surprisingly low proportion of MS patients who are shown their magnetic resonance imaging (MRI) pictures.
Spring is the season of warmer weather and longer days, albeit with some cloudy skies inevitably part of the mix. In step with the season, this installment of “What’s New in MS Research” provides a wealth of good news accompanied by a few concerning findings to keep in mind and, perhaps, discuss with your clinician.
The Janssen Pharmaceutical Companies of Johnson & Johnson announced on March 19, 2021 that the United States Food and Drug Administration (FDA) approved Ponvory™ (ponesimod) for the treatment of relapsing forms of multiple sclerosis (MS) in adults – including clinically isolated syndrome, relapsing-remitting, and active secondary-progressive forms of MS. This new disease-modifying therapy (DMT) is taken orally (by mouth) once daily and has been shown to reduce annual relapse rates and reduce disease activity as shown on magnetic resonance imaging (MRI), compared to treatment with an approved DMT, Aubagio® (teriflunomide). Ponvory should be available by prescription in April 2021.
Read MSAA’s full article here.
The Food and Drug Administration (FDA) last month approved a new intramuscular injection route of administration for Plegridy® (peginterferon beta-1a), a disease-modifying therapy (DMT) for relapsing forms of MS.1 The medication is marketed by Biogen, a Cambridge, MA-based biotechnology company.
The FDA first approved use of the interferon-based DMT in 2014. Since then, the medication has been administered subcutaneously, meaning that a short needle is used to inject the DMT into the tissue layer between the skin and the muscle.
Maha Radhakrishnan, MD, Biogen’s chief medical officer, says the newly approved intramuscular route of administration “gives new and current MS patients a different delivery method that has the potential to significantly reduce injection site reactions.”
Biogen noted that the FDA’s approval of the intramuscular (IM) administration of Plegridy is based on data evaluating bioequivalence and adverse reactions associated with IM administration compared to subcutaneous (SC) administration in healthy volunteers. Bioequivalence between the two dosing regimens was confirmed, and data showed that participants receiving Plegridy through IM administration experienced fewer injection site reactions than participants receiving SC administration (14.4% vs. 32.1%).
A biotechnology company that has developed a synthetic molecule designed to treat relapsing forms of MS is preparing to launch a Phase II trial that will evaluate the oral medication in people with MS.2
The company, Emerald Health Pharmaceuticals, announced that the study will evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of its investigational medication EHP-101. They will seek to enroll approximately 50 people who have RMS (relapsing-remitting and relapsing secondary-progressive MS) in approximately 20 sites in the United States and Australia.
Study subjects will receive escalating doses of EHP-101 once or twice daily over 24 weeks. The company said the dose levels were determined by the results of previous studies, including a Phase 1 study in 104 healthy people, that showed a good safety and tolerability profile for the medication. Beyond assessing safety and tolerability, the Phase II study will look at changes from baseline in brain lesion activity as measured by MRI, disease progression and disability status, and the proportion of relapse-free patients. The study also will examine patient-reported outcomes and the impact treatment has on several biomarkers. The company added that EPH-101 has a multi-modal mechanism of action and demonstrated disease-modifying potential in preclinical models of MS. The medication also is being studied for potential use in systemic sclerosis.
The impact of disease-modifying therapies (DMTs) on MS often is easier to evaluate in younger adults than older people. This owes in part to the fact that younger people tend to have more inflammatory disease activity, providing a clearer baseline against which to measure the effect of a medication. Similarly, older people are less likely to have relapses, diminishing the utility of measuring changes in annual relapse rate as a marker of medication efficacy. Further, older people are likely to have more comorbid conditions – such as osteoarthritis or diabetes – making it difficult to determine whether impaired mobility, fatigue, or another symptom is due to MS or some other cause.
To better understand the impact of the DMT Ocrevus® (ocrelizumab) in older people with multiple sclerosis, researchers recently analyzed data on people with progressive forms of MS who were age 56 years and older.3
Ocrevus is an anti-CD20 therapy, meaning that it exercises its effects on the CD20 molecule found on the surface of the immune system’s B cells. These cells are believed to play a role in the development of MS. Ocrevus is approved by the FDA to treat both relapsing and progressive forms of MS. Clinicians also sometimes use another anti-CD20 therapy, rituximab, to treat MS. However, rituximab is not approved for use in MS, although the FDA has approved its use for a number of other diseases.
The researchers focused primarily on 24 patients for whom they had data for two years before those people began either Ocrevus or rituximab and for two years after they started taking Ocrevus. Seventy percent of those people had been on another type of DMT before beginning anti-CD20 therapy.
After analyzing their results, the investigators reported, “We found no difference in two-year clinical endpoints for patients while on ocrelizumab [Ocrevus] compared to prior to [starting] anti-CD20 therapy, though there was a trend toward decreased CDP [confirmed disability progression] on ocrelizumab that our study was not sufficiently powered to analyze.”
The investigators noted that larger studies are needed to examine this issue.
It often is difficult to understand how different MS symptoms are linked to various aspects of the condition, and how different disease characteristics influence the effectiveness of treatment.
To fill in some of the missing pieces of the puzzle, researchers recently investigated whether the beneficial effects on fatigue seen with the just-approved DMT Ponvory™ (ponesimod) were affected by patients’ level of disease activity.4
The Phase III OPTIMUM study compared 20 mg of Ponvory with 14 mg of Aubagio® (teriflunomide). Both are oral agents with once-daily dosing. On March 19, 2021, the FDA approved an application from Janssen Pharmaceuticals for use of Ponvory in relapsing forms of MS.
The OPTIMUM trial examined endpoints including impact on fatigue and on having no evidence of disease activity as measured by relapses, MRI lesions, and disease progression (NEDA-3). At Week 108 of the study, Ponvory had improved baseline fatigue to a greater extent than teriflunomide, and 28% of patients receiving Ponvory met the criteria for NEDA-3, compared with 18% of patients in the teriflunomide group.
In a subsequent analysis, researchers from Janssen found that the improvement in fatigue that Ponvory achieved relative to teriflunomide was seen both in patients who had evidence of disease activity (EDA) at Week 108 and in those who met the NEDA-3 endpoint.
The good news in that finding is that disease activity does not seem to blunt the beneficial impact that Ponvory has on fatigue. The bad news, as the researchers articulated in their study conclusion, is that the finding suggests that “addressing classical clinical efficacy (NEDA/EDA definition) might not be sufficient in addressing fatigue” in people with relapsing MS.
The importance of addressing MS-related fatigue with medications and other interventions was underscored by another analysis conducted by researchers from Janssen, who in this study collaborated with investigators from other organizations.5
The study analyzed data on 4,077 people with MS, examining what proportion had fatigue at baseline and on follow-up, and looking at other clinical factors, such as the presence of other health conditions. The patients’ mean age was 49 years, and 75% were female.
The researchers applied three different definitions for fatigue. Patients met the broadest definition if:
- A physician had listed fatigue-related disease codes in their medical records, and/or;
- They had received prescriptions for more than two stimulant drugs; and/or;
- They had received prescriptions for more than two sleep agents or for a sleep study.
Applying that broad definition, 48% of people had fatigue at baseline, meaning 12 months before they received their first DMT, and 87% of those patients continued to have fatigue 12 months after they started the medication. Meanwhile, 42% of people who did not report fatigue at baseline met the criteria for fatigue at follow-up, meaning 12 months after starting a DMT.
Comorbid conditions were more common among people who had fatigue at baseline compared with those who did not, including depression (found in 16% of people with baseline fatigue and 3% without fatigue), anxiety (26% vs. 10%) and cardiovascular disease (30% vs. 24%).
Researchers said that the broad definition of fatigue that they applied was likely to more accurately identify patients suffering from the condition than narrower definitions based solely on diagnostic codes.
The identification of lesions on magnetic resonance imaging (MRI) plays a key role in MS management, with decisions about starting or adjusting disease-modifying therapy often based on the number, location, and size of lesions seen on the sophisticated imaging.
Despite the importance of MRI in guiding treatment decisions, 38% of people with MS participating in a recent survey said they were never or only rarely shown their MRI pictures. This despite the fact that 95% of those people said they would like to be shown the images and that 97% were aware of the rationale for using brain MRI to look for new, enlarging or enhancing lesions.6
Those findings emerged from a study of more than 2,100 people with MS who are enrolled in the North American Research Committee on MS (NARCOMS) registry.
Another key finding from the study: Roughly two-thirds of patients reported that their clinicians had not talked with them about potential safety concerns with the intravenous contrast dye used for brain MRIs.
Noting the centrality of MRI findings in developing treatment plans, the study authors noted, “Opportunities exist in optimizing the patient experience of shared decision-making surrounding MRI in MS care. Providing patients the opportunity to see their actual MRI pictures during clinical encounters and discussing potential safety concerns of the repeated use of contrast agents represent two such opportunities.”
Before the COVID-19 pandemic came to dominate the health headlines – and our lives – in 2020, the opioid epidemic was perhaps the most ominous medical news of 2019, when opioid-related overdoses claimed more than 49,000 lives across America.7
Against that backdrop, a study showing that 21% of people with MS take prescription opioids prompted its authors to conclude that “better pain management treatment options, including non-pharmacologic options, are needed for people with multiple sclerosis and pain.”8
The authors, who are affiliated with the VA Portland Health Care System, reviewed questionnaires completed in 2013 and 2014 by 282 people with MS. Fifty-eight of the respondents – or 21% of the total – reported using prescription opioids, with the rate ranging from 14% of respondents in Baltimore to 25% in Portland.
Forty-four people in the group reported taking opioids daily, while 10 said they took the medication as needed, and three reported short-term use following an injury or surgery.
It’s important to note that the medical community and public health officials have made a concerted effort to reduce opioid prescribing in the years since the study subjects completed their questionnaires. However, the fact that more than 50% of people with MS have chronic pain – and that this surprising proportion of study participants reported opioid use – underscores the authors’ conclusion about the need for broader and better pain-management options.
People with MS who take disease-modifying therapies (DMTs) have almost twice the risk of developing a serious viral infection as people with MS who do not take the medications, according to a recent study involving more than 15,000 adults with MS.9
The study, which examined electronic medical record data from 2006 to 2018, also found that the overall risk of infection was 15% higher among DMT users, while there was no significant difference between the two groups in risk of serious bacterial infections. The risk of non-serious viral and bacterial infections were 2.65 times and 1.5 times greater, respectively, among DMT users relative to those not using the medications.
Among people with MS taking DMTs, women were at greater risk for infection than men. The researchers also found that having another serious health condition in addition to MS more than tripled the risk of infection in DMT users.
These data, while concerning, do not identify a new risk related to DMTs but rather provide further statistical dimension to a known issue that needs to be considered in context.
Every medication powerful enough to provide a benefit carries the potential for adverse effects as well as positive ones. Disease-modifying therapies (DMTs) are no exception to this rule. While the medications have revolutionized the treatment of MS and greatly enhanced the lives of hundreds of thousands of people, researchers, clinicians, and patients long have recognized their potential to increase susceptibility to infection. And while findings of increased risk for certain types of infection are never good, the baseline matters greatly. For example, if the baseline risk is 0.5% and a doubling increases that risk to 1%, that is a far different matter than a baseline risk of 10% increasing to 20%.
People with MS who are concerned about these findings should talk with their clinician rather than making any unilateral changes to their treatment plan. As the study showed, several factors influence the impact a medication has on a person, and examining each person’s specific situation is the best way for clinicians and patients to arrive at a shared decision about the best course of action.
Correcting enduring inequities in all aspects of American life has become a major societal focus over the past year or more, with healthcare receiving its share of much-needed attention.
A recent study involving more than 2,000 people with MS shows that this effort needs to encompass the treatment of multiple sclerosis.10
Researchers from the University of Pittsburgh School of Medicine, Harvard Medical School, and Columbia University’s Irving Medical Center used economic and MS disease status measures to examine how socioeconomic status (SES) affected neurological outcomes.
After adjusting for age, sex, race/ethnicity, disease duration, and use of DMTs, they found a strong association between higher socioeconomic status in 2015 and better neurological outcomes in 2018 to 2019.
While the findings may not be surprising, the very fact that they are not suggests that societal complacency is a factor in the poor outcomes experienced by poorer people who have MS.
Low levels of Vitamin D at diagnosis of MS is associated with an increased likelihood for cognitive impairment at that point in the disease process and with earlier onset of disability in subsequent months and years.11
That was the main finding from an Italian study involving 60 people with MS. The patients’ mean age at diagnosis was 39.5 years. Two-thirds of the patients were women. Eighty-five percent of the people studied had hypovitaminosis D – the medical term for low levels of Vitamin D – at diagnosis.
Sixteen patients, or 27% of the total, had cognitive impairment, and the researchers found that those patients had more severe hypovitaminosis D than others. No patients with sufficient vitamin D levels at diagnosis were impaired cognitively. Over a mean follow-up period of two years, the researchers also looked at how patients’ MS Severity Scores and Age-Related MS Severity Scores varied by initial Vitamin D level. While the correlation in this area was weaker, the investigators did find increased disability in people with lower Vitamin D levels at diagnosis relative to those with higher initial levels of the vitamin.
What is not known is whether providing Vitamin D supplementation to people with low levels at diagnosis can affect cognitive function or slow the pace of subsequent disability. The research team that conducted this analysis plans to investigate that issue in a larger study.
1Biogen Inc. Biogen announced FDA approval of Plegridy® (peginterferon Beta-1a) intramuscular injection for multiple sclerosis. February 1, 2021. Available at https://investors.biogen.com/news-releases/news-release-details/biogen-announces-fda-approval-plegridyr-peginterferon-beta-1a. Accessed March 10, 2021.
2Emerald Health Pharmaceuticals. Emerald Health Pharmaceuticals starts activities for initiation of Phase 2 clinical study in multiple sclerosis. March 8, 2021. Available at https://emeraldpharma.life/wp-content/uploads/2021/03/Emerald-Health-Pharmaceuticals-Starts-Activities-for-Initiation-of-Phase-2-Clinical-Study-in-Multiple-Sclerosis.pdf. Accessed March 11, 2021.
3Epstein S, Fong KT, Levine L, et al. Evaluation of ocrelizumab in older progressive multiple sclerosis patients. [ACTRIMS 2021 [P073].
4Keenan A, Turkoz I, Murray R, Ait-Tihyaty M. MS fatigue: treatment effect of ponesimod in RMS patients with and without disease activity. ACTRIMS 2021 [P034].
5Cole M, Le H, Verma S, et al. Identifying and characterizing fatigue in patients diagnosed with multiple sclerosis on disease-modifying therapies using real-world evidence. ACTRIMS 2021 [P163].
6Shirani A, Zabad R, Solomon A, et al. Shared decision-making and MRI on multiple sclerosis: patient experience, gaps, and opportunities. ACTRIMS 2021 [P171].
7National Institute on Drug Abuse. Overdose death rates. Available at https://www.drugabuse.gov/drug-topics/trends-statistics/overdose-death-rates. Accessed March 4, 2021.
8Hugus CL, Joos S, Sajeev N, et al. One in five (20%) of people with multiple sclerosis use prescription opioids. ACTRIMS 2021 [P221].
9Rukmangadachar LA, Al-Hammadi N, Kallal C. Hinyard L. Infection risk associated with multiple sclerosis disease modifying therapies: Retrospective study from a nationally distributed US cohort. ACTRIMS 2021 [P164].
10Boorgu D, Venkatesh S, Lakani CM, et al. The impact of socioeconomic status on neurological outcomes in multiple sclerosis. ACTRIMS 2021 [P215].
11Virgilio E, Vecchio D, Crespi I, et al. Serum vitamin D level at diagnosis as a marker of impaired information processing speed and early disability in multiple sclerosis patients. ACTRIMS 2021 [P158].
For More Information
For general information or to speak with a trained Client Services Specialist, please call MSAA’s Helpline at (800) 532-7667, extension 154. Questions to MSAA’s Client Services department may also be emailed to MSquestions@mymsaa.org.
Written by Tom Garry, Medical Writer
Reviewed by Dr. Barry Hendin, MSAA Chief Medical Officer