What’s New in MS Research – September 2024

Reviewed by MSAA Chief Medical Officer Barry A. Hendin, MD

From expanded treatment options and encouraging results from clinical trials of investigational therapies, to important information on MS, oral contraceptive use, and cardiovascular health, this edition of “What’s New in MS Research” reflects the extent and breadth of efforts to better treat multiple sclerosis and to enhance the overall health of people living with the condition.

 

FDA approves Ocrevus Zunovo^™ for 10-minute, twice-yearly injection

People with relapsing and progressive forms of MS now can receive Ocrevus^® (ocrelizumab) via intravenous infusion or Ocrevus Zunovo^™ (ocrelizumab and hyaluronidase-ocsq) by subcutaneous injection. Both forms of the disease-modifying therapy (DMT) are given twice-yearly after the initial dosing, with the infusion taking two-to-four hours and the injection delivered over approximately 10 minutes.¹

This new option for adults with MS and their clinicians to choose the route of administration for the DMT follows the Food and Drug Administration’s (FDA) approval earlier this month of Ocrevus Zunovo for treatment of relapsing multiple sclerosis (RMS) and primary-progressive multiple sclerosis (PPMS). The FDA approved Ocrevus for those uses in March 2017. Ocrevus and Ocrevus Zunovo are the only DMTs approved for the treatment of PPMS. Their FDA approval for use in RMS encompasses relapsing-remitting MS, active secondary-progressive MS, and clinically isolated syndrome.^2,3

The FDA’s approval of Ocrevus Zunovo was based on the results of the Phase III OCARINA II trial, which showed no clinically significant difference in blood levels of Ocrevus when administered subcutaneously versus intravenously, and a safety and efficacy profile comparable to that of the intravenous formulation. The global study included 236 people with MS.

Ocrevus Zunovo also demonstrated efficacy consistent with intravenously delivered Ocrevus, including suppression of relapse activity and MRI lesions in 97% of study participants through 48 weeks. Further, more than 92% of trial participants reported being satisfied or very satisfied with the subcutaneous administration of Ocrevus Zunovo.

Genentech, the biopharmaceutical company that manufactures and distributes the newly approved medication, explains that although the injection itself typically takes about 10 minutes, other procedures are involved. These include taking premedication a half an hour before the injection and being monitored for at least 15 minutes post-injection, starting with the second dose. (Please note that following the first dose, patients are monitored by their clinician for at least 60 minutes.) The total time for treatment with Ocrevus Zunovo, including premedications and post-injection monitoring (not including the initial dose), is estimated to be about an hour.

Ocrevus is a humanized monoclonal antibody designed to target CD20-positive B cells, a type of immune cell thought to be a key contributor to myelin (nerve cell insulation and support) and axonal (nerve cell) damage. This nerve cell damage can lead to disability in people with multiple sclerosis.

Ocrevus Zunovo combines Ocrevus with Halozyme Therapeutics’ Enhanze® drug delivery technology. The Enhanze® drug delivery technology is based on a proprietary recombinant human hyaluronidase PH20 (rHuPH20), an enzyme that locally and temporarily degrades hyaluronan – a chain of natural sugars – in the subcutaneous space. This increases the permeability of the tissue under the skin, allowing Ocrevus to enter, and enabling it to be rapidly dispersed and absorbed, into the bloodstream.

People with MS who are now taking Ocrevus in its intravenous form or who are considering starting or switching treatment should talk with their clinicians about this new option – and about all their treatment options – to explore which medication may be best for them.

 

FDA grants Fast Track designation to intranasal foralumab

The Food and Drug Administration (FDA) has granted Fast Track designation to intranasal foralumab, a fully human, anti-CD3 monoclonal antibody being developed by Tiziana Life Sciences for use in treating non-active secondary-progressive multiple sclerosis (na-SPMS).⁴

The designation, which Tiziana announced in late July, means the FDA will provide an expedited review process for data on the efficacy and safety of foralumab. The FDA’s Fast Track program is intended to speed the development and assessment of drugs that treat serious conditions and fill an unmet medical need.

Intranasal foralumab is designed to modulate the immune system and reduce neuroinflammation, which is a key factor in the progression of neurodegenerative diseases such as multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS). The company says that early clinical data indicate that intranasal foralumab can deliver therapeutic benefits with a favorable safety profile.

As of July 2024, 10 patients with na-SPMS had received foralumab in an open-label intermediate-sized Expanded Access (EA) Program, and that all patients had shown either improvement or stability of disease seen within six months of starting the medication. In addition, intranasal foralumab is being studied in a Phase IIa, randomized, double-blind, placebo-controlled, multicenter, dose-ranging trial in patients with na-SPMS.

 

Fenebrutinib shows favorable impact on relapsing MS over 48 weeks

More than 95% of people with relapsing MS who took the investigational medication fenebrutinib had no relapses over 48 weeks of treatment and had no T1 gadolinium-enhancing lesions (T1-Gd+) on magnetic resonance imaging (MRI) at week 48, according to Roche, the biopharmaceutical company developing the disease-modifying therapy.⁵

Fenebrutinib works by inhibiting Bruton’s tyrosine kinase (BTK), an enzyme that regulates the development and activation of B cells, which are immune system cells that play a role in MS. BTK is also involved in the activation of other cells, such as macrophages and microglia, which affect immune and neurological function.

During the open-label extension period of the Phase II FENopta study, 96% of patients treated with fenebrutinib were free of relapses at one year and had no change in disability over 48 weeks as measured by the Expanded Disability Status Scale (EDSS). In addition, fenebrutinib treatment suppressed disease activity in the brain as measured by MRI scans. At 48 weeks, 99% of patients were free of T1 gadolinium-enhancing (T1-Gd+) lesions, which are markers of active inflammation.

The safety profile of fenebrutinib in the open-label extension was consistent with previously reported data on the medication. The most common adverse events occurring in more than 5% of patients were: urinary tract infection (8%), COVID-19 (7%), and pharyngitis (5%). Serious adverse events occurred in one patient.

Three Phase III clinical trials of fenebrutinib are under way, including the FENhance 1 and 2 trials in RMS and the FENtrepid trial in primary-progressive multiple sclerosis (PPMS). Data from these studies are expected at the end of 2025.

 

Tolebrutinib demonstrates efficacy in non-relapsing secondary-progressive MS

The investigational medication tolebrutinib delayed time to onset of confirmed disability progression (CDP) in people with non-relapsing secondary-progressive multiple sclerosis (nrSPMS) in the Phase III HERCULES study.⁶

That welcome news was announced in early September by Sanofi, the biopharmaceutical company developing tolebrutinib. The company noted that there currently are no FDA-approved therapies for nrSPMS, creating a significant unmet medical need.

Tolebrutinib is an oral medication that inhibits the activity of an enzyme known as Bruton’s tyrosine kinase. The enzyme, also referred to as BTK, plays a role in the development and activation of B cells, which are immune system cells that contribute to the development of MS. BTK also helps govern the activity of other cells involved in neurological and immune function.

The primary endpoint in the HERCULES trial was improvement over placebo in delaying time to onset of CDP in people with nrSPMS. Non-relapsing secondary-progressive MS was defined as having a SPMS diagnosis with an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5, no clinical relapses for the previous 24 months, and documented evidence of disability accumulation in the previous 12 months. Preliminary data on liver safety – which has been a concern with some BTK inhibitors – was consistent with data from previous tolebrutinib studies.

The GEMINI 1 and 2 studies evaluating tolebrutinib in people with relapsing MS did not show significance in the primary endpoint of reducing annualized relapse rate over Aubagio^® (teriflunomide). However, analysis of the key secondary endpoint of pooled six-month confirmed disability worsening (CDW) data showed a considerable delay in time to onset.

Meanwhile, Sanofi also is evaluating tolebrutinib in primary-progressive multiple sclerosis (PPMS). Results from its Phase III PERSEUS study, looking at how the medication affects time to onset of confirmed disability progression in people with PPMS, are expected in 2025.

 

Study finds no link between oral contraceptive use and later MS

Use of oral contraceptives is not associated with subsequent development of multiple sclerosis, according to an analysis of the health records of more than 4,400 women.⁷

Researchers reached that conclusion after evaluating long-term data on women who were patients at primary care clinics in London, United Kingdom, between 1990 and 2018. Eight hundred and ninety-one of the women had been diagnosed with MS at the time of the study. Another 3,564 women not diagnosed with the condition served as controls. The study’s authors focused on exposure to combined estrogen-progesterone or progesterone-only birth control pills zero-to-two years, two-to-five years, and more than five years prior to diagnosis in the women with MS, comparing their use of oral contraceptives during those time periods to that of the controls. They found no link between use of the medication and MS in any of those time periods.

Women, clinicians, and researchers have long wondered whether there may be such a link. Their concerns arise largely because MS is more common in females than males and because symptoms often appear when women are in their early-adult or middle-aged years, when they are most likely to be using oral contraception. Further, the body’s own sex hormones are believed to play a role in the development of MS.

Prior studies have yielded conflicting results, with some finding that hormonal oral contraceptives increased risk of MS and others indicating that the birth control pills actually lower risk.

By finding no association between oral contraceptives and risk for subsequent MS, this study – which its authors note is the largest population-based study on the issue conducted to date – might fall into the category of “no news is good news.”

 

Use of multiple nervous system medications increasing among people with MS

Several symptoms of MS, including pain, anxiety, depression, and spasticity, can be treated with medication. That’s the good news. The not-so-good news is that because many of the therapies prescribed to treat those conditions act on the central nervous system, the individual medications and interactions between medications can increase the risk for problems such as falls and cognitive decline.

While the potential negative effects of “polypharmacy” – the medical term for a person’s use of multiple medications – has always been a concern in MS, the issue is increasing in importance as more therapies become available and more people with multiple sclerosis make use of those treatments.

A recent analysis of data on more than 55,000 people with MS demonstrates why the benefits and potential downsides of polypharmacy require careful consideration by people with multiple sclerosis and their clinicians.⁸

The study examined insurance claims data from large commercial health plans and Medicare Advantage programs at different time points from 2008 to 2021. A person with MS was considered to be on central nervous system (CNS)-active polypharmacy if they were taking three or more CNS-active drugs for a period of more than 30 days. CNS-active drugs included antidepressants, antiepileptics, antipsychotics, benzodiazepines, opioids, and skeletal muscle relaxants.

Study researchers found that the percentage of women with MS receiving CNS-active polypharmacy rose from 19.8% in 2008 to 26.4% in 2021. The proportion of men with MS on CNS-active polypharmacy increased more modestly during that period, from 15.9% to 18.6%. The figures for both women and men were adjusted for age. The two most commonly prescribed medications contributing to CNS-active polypharmacy were gabapentin, which is often prescribed to treat nerve pain as well as epilepsy, and baclofen, which treats spasticity.

The study’s results bear consideration from a couple of different perspectives. First, as noted above, they show that more people are receiving treatment for their symptoms of MS and for other conditions they may have. Second, they underscore the fact that increased use of medications needs to be accompanied by increased awareness of potential side effects.

People with MS who are taking multiple medications should not stop taking any prescribed therapy without first consulting their clinician. Rather, they should take the following four simple steps to ensure that they are receiving the maximum benefit from their medications while minimizing possible downsides.

The first step is to ensure that all of their clinicians are aware of all the medications they are taking, including those prescribed by other providers. The second step is to ask the physician or pharmacist about the potential side effects of a therapy each time a new medication is recommended or prescribed. The third step is to periodically review the full medication list with their neurologist to confirm that all prescriptions are still necessary. The fourth and final step is to promptly inform the neurology provider any time they experience a new issue or an existing one becomes worse to ensure that it is not linked to medication use.

 

Does moderate alcohol consumption reduce risk of disability progression in MS?

A Swedish study involving more than 9,000 people with MS found that low and moderate consumption of alcohol was associated with a reduced risk of physical worsening compared to not drinking.⁹

Researchers divided the study participants into four groups based on their reported drinking habits at the time of MS diagnosis. The groups were non-drinking, low alcohol consumption, moderate alcohol consumption, and high alcohol consumption. Alcohol consumption levels were based on reported weekly intake, with different ranges for men and women. For example, low alcohol consumption was defined as less than 50 grams per week for women and less than 100 grams per week for men.

The researchers followed study participants for up to 15 years, using Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impact Scale 29 (MSIS-29) scores to track the course of the individual’s MS. The association between low and moderate consumption of alcohol and reduced risk of worsening disability was seen only in people who had relapsing-remitting (as opposed to primary-progressive) MS at disease onset. Further, the trend was more pronounced in women than in men. High alcohol consumption did not significantly affect disease progression, researchers said.

These results, while intriguing, need to be considered in context. First, as the researchers note in their article, earlier studies of this topic have yielded conflicting findings, with some identifying an association between alcohol use and MS disease progression and others reporting an apparent benefit from modest alcohol use. Second, while the Swedish study has important strengths because it looks at a large patient population over a long period of time, it is in no way the last word on the subject. Third, alcohol has many other effects – most of them negative – on a person’s overall health. So, this study’s findings may provide reassurance for those who occasionally drink alcohol, but the findings are not cause for teetotalers to pop the cork or for current drinkers to order another round.

 

Identifying gaps in access to care among people with MS

A survey of 4,914 people with MS found that more than one in five respondents were not able to access care from healthcare professionals such as mental health counselors and occupational therapists.¹⁰

The survey was conducted in Fall 2022 and was completed by people with MS who participate in the North American Research Committee on Multiple Sclerosis Registry (NARCOMS). Eighty-one percent of survey respondents were women and the average age of respondents was 64.4 years.

The providers who survey participants said were needed but inaccessible included:

• Complementary providers, such as practitioners trained in chiropractic manipulation, mind-body interventions, and other forms of complementary care, (35.5%)
• Allied health providers, such as dietitians and nutritionists (24.2%)
• Occupational therapists (22.7%)
• Mental health providers (20.7%)

Survey participants who reported not having access to needed providers tended to have lower health-related quality of life scores than those who were able to see providers when needed.

On the one hand, it is heartening that the list of most-inaccessible providers did not include neurology and primary-care clinicians. On the other hand, given the importance of receiving comprehensive care from a multi-disciplinary team, problems with securing appointments with the healthcare professionals listed above underscore the need for further efforts to meet the full range of needs of people with MS.

 

Examining the impact of cardiovascular disease on the course of MS

Multiple sclerosis and cardiovascular disease (CVD) frequently co-exist and often add up to worse MS disability progression, a team of researchers report.¹¹

The researchers followed 276 people with MS over an average of 14.9 years. Twenty-eight of those people had CVD – defined as hypertension, hyperlipidemia, diabetes, or heart disease – at baseline. Another 185 people developed CVD during the course of the study period, while 63 did not have CVD. Researchers examined how the three groups differed in terms of confirmed disability progression (CDP).

They found that people who had CVD at the start of the study period or who developed cardiovascular disease during that period had confirmed disability progression an average of 2.5 years sooner than people without CVD (13.4 years vs. 15.9 years). The results were statistically significant.

The study findings reinforce the point that one of the most important steps people can take to manage their MS is to maintain their overall health, particularly in terms of attention to good heart-health behaviors.

 

Study finds that the sNfL biomarker is under-utilized in clinical decision-making

Given the rapid pace of advances in our understanding of MS, clinicians can face challenges in deciding when and how to make use of a new means of assessing the condition. On the one hand, they want their patients to have the benefit of the latest approaches. At the same time, they want to ensure that a promising test is well supported by the evidence.

In recent years, clinicians have wrestled with this dilemma in considering how blood levels (serum) of a protein called neurofilament light chain (sNfL) should guide their treatment decisions. The protein is expressed by nerve cells, or neurons, and elevated levels in the blood and cerebrospinal fluid have been shown to be markers of the damage that occurs to those cells in MS and other neurological diseases. As more and more studies have shown that sNfL can be a useful tool for assessing disease severity and monitoring response to treatment, clinicians have taken varied approaches to incorporating sNfL data into their decision-making.

A recent study from Spain suggests that more clinicians need to give more weight to sNfL levels in shaping their treatment plans.¹² Researchers presented 116 neurologists with nine case studies. In each case study, the person either was experiencing a first demyelinating MS event or had relapsing-remitting MS. Two-thirds of the neurologists focused their practices solely on MS and related conditions, while the remaining one-third treated a variety of neurologic disorders.

The study’s primary outcome was “therapeutic inertia” (TI), which refers to a clinician (in this case, a neurologist) not starting a new treatment or not intensifying an existing treatment when a patient’s sNfL level has increased, indicating an increase in disease activity. The participating neurologists were given nine case studies (noted above), and were asked how they would treat these patients if they were also experiencing an increase in the blood’s sNfL level.

If no change was made to the patient’s treatment in response to this increase, this would represent therapeutic inertia (TI), and it would be recorded as one point. If this was the situation with all nine patients, the doctor would receive a score of nine, indicating a high level of therapeutic inertia (TI). Conversely, a lower score would indicate a lower degree of therapeutic inertia (TI).

The participants’ average TI score was 3.65, meaning that the neurologists did not change treatment plans based on elevated sNfL levels in roughly one-third of the cases. More than 90% of the physicians demonstrated TI in at least two cases. As might be expected, TI scores were higher in those neurologists who did not focus exclusively on MS and other demyelinating diseases.

As noted, managing MS is challenging and requires a judicious approach that avoids being overly aggressive or overly conservative. This study indicates that when it comes to making use of an important marker of disease course, many clinicians could benefit from embracing a newer tool.

 

Later diagnosis of MS correlates with tougher course, researchers say

How does the course of MS tend to differ based on a person’s age at diagnosis?

A team of Turkish researchers examined that question by analyzing data on 658 people with MS.¹³ They divided the study participants into three groups:

• Early onset (EOMS), meaning diagnosis before 18 years of age (117 people)
• Adult onset (AOMS), for diagnosis at 20 to 40 years of age (499 people)
• Late onset (LOMS), signifying diagnosis at age 55 or older (42 people)

The researchers then used measures including the Timed 25-Foot Walk Test, Multiple Sclerosis Walking Scale-12, Single Leg Standing Test, Activity-Specific Balance Confidence Scale, Nine-Hole Peg Test, and Restless Legs Syndrome Severity Scale to assess the different groups.

They found that people with late-onset of MS had greater disability, worse lower-extremity functional status, and a greater likelihood of moving from first-line treatments to more advanced therapeutic interventions than people who were diagnosed before age 18 or from age 20 to 40.

While noting that the relatively small number of people with late-onset MS in their study meant that their findings needed to be validated in a larger study, the researchers concluded that people who develop MS at age 55 or older require enhanced attention from clinicians in terms of evaluation and selection of therapies.

 

References

1. Genentech. FDA approves Ocrevus Zunovo^™ as the first and only twice-a-year 10-minute subcutaneous injection for people with relapsing and progressive multiple sclerosis. September 13, 2024. South San Francisco, California. Available at https://www.gene.com/media/press-releases/15036/2024-09-13/fda-approves-ocrevus-zunovo-as-the-first. Accessed September 20, 2024.
2. Ocrevus^® (ocrelizumab) injection, for intravenous use. [Prescribing information]. South San Francisco, CA. Genentech, Inc. June 2024.
3. Ocrevus Zunovo^™ (ocrelizumab and hyaluronidase-ocsq) injection, for subcutaneous use. [Prescribing information]. South San Francisco, CA. Genentech, Inc. September 2024.
4. Tiziana Life Sciences, Ltd. Tiziana Life Sciences granted FDA fast track designation. July 24, 2024. New York, New York. Available at https://www.tizianalifesciences.com/tiziana-life-sciences-granted-fda-fast-track-designation/. Accessed September 19, 2024.
5. Roche. Roche’s fenebrutinib demonstrated near-complete suppression of disease activity and disability progression for up to 48 weeks in patients with relapsing multiple sclerosis. September 4, 2024. Basel, Switzerland. Available at https://www.biospace.com/press-releases/roches-fenebrutinib-demonstrated-near-complete-suppression-of-disease-activity-and-disability-progression-for-up-to-48-weeks-in-patients-with-relapsing-multiple-sclerosis. Accessed September 10, 2024.
6. Sanofi. Tolebrutinib meets primary endpoint in HERCULES phase 3 study, the first and only to show reduction in disability accumulation in non-relapsing secondary progressive multiple sclerosis. Sept 2, 2024. Available at https://www.sanofi.com/en/media-room/press-releases/2024/2024-09-02-05-00-00-2938875. Accessed September 11, 2024.
7. Zhang Q, Noyce AJ, Robson J, et al. No association between oral contraceptive exposure and subsequent MS: a population-based nested case-control study in primary care. Mult Scler J. 2024;30(9):1221-1226.
8. Naizer H, Wozny J, Krause TM, Huson E, Freeman L. Trends in central nervous system-active polypharmacy among people with multiple sclerosis. Mult Scler J. 2024;30(9):1139-1150.
9. Wu J, Olsson T, Hillert JA, et al. Association between alcohol consumption and disability accumulation in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2024;11:e200289. doi:10.1212.
10. Marrie RA, Lancia S, Cutter GR, Fox RJ. Access to care and health-related quality of life in multiple sclerosis. Neurology. 2024;14(6): https://doi.org/10.1212/CPJ.0000000000200338
11. Wick TR, Jakimovski D, Reeves J, et al. Comorbid onset of cardiovascular diagnosis and long-term confirmed disability progression in multiple sclerosis: A 15-year follow-up study. J Neurol Sci. 2024 Sep 15:464:123156. doi: 10.1016/j.jns.2024.123156. Epub 2024 Jul 29.
12. Saposnik G, Monreal E, Medrano N, et al. Does serum neurofilament light chain measurement influence therapeutic decisions in multiple sclerosis? Mult Scler Relat Disord. 2024 Aug 23:90:105838. doi: 10.1016/j.msard.2024.105838.
13. Ozakbas S, Kaya E, Aslan T, et al. Comparative analysis of cognitive and physical characteristics in late-onset, adult-onset and early-onset multiple sclerosis patients. Mult Scler Relat Disord. 2024 Aug 6:90:105810. doi: 10.1016/j.msard.2024.105810.

 

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
Edited by Susan Wells Courtney, MSAA Senior Writer