What’s New in MS Research: January 2021

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

The expression, “Here’s hoping this year is better than the last” has particular poignancy as we transition into 2021. Happily, much of the recent news regarding multiple sclerosis (MS) provides cause for considerable hope, as reflected in the study results and other reports featured in this month’s iteration of “What’s New in MS Research.”

That news includes encouraging results from late-stage trials of the investigational agent ublituximab, Phase III trials gearing up to evaluate two investigational medications in the Bruton’s tyrosine kinase inhibitor (BTK) class, and reassuring findings on COVID-19 outcomes in people with MS.

Other developments on the positive side of the ledger include Food and Drug Administration (FDA) approval of a shortened infusion time for Ocrevus^® (ocrelizumab) for many patients, and new approaches for enhancing the diagnosis of MS, predicting its course over time, and categorizing the cognitive-function challenges faced by many people with MS. Conversely, the closing months of 2020 brought disappointing news, also summarized below, on the potential role of high-dose biotin in progressive MS.

Beyond the positive or negative nature of any single study or development, however, the sheer breadth of research being conducted in MS is reason to be confident that substantial further progress awaits in 2021 and beyond. Drawing from studies published in peer-reviewed journals, presentations given at the September 2020 joint meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), corporate press releases, and other sources, this installation of “What’s New in MS Research” provides positive news during challenging times.

FDA approves shorter infusion time for Ocrevus^® (ocrelizumab)

People with multiple sclerosis (MS) who have not had prior serious infusion reactions (IRs) now can have the disease-modifying therapy Ocrevus^® (ocrelizumab) infused over 2 hours rather than over the 3.5-hour period that has been the standard approach for administering the humanized monoclonal antibody.¹

The FDA approved the reduced infusion time in December, after reviewing results of the ENSEMBLE PLUS study. That study involved 580 people with relapsing-remitting MS. One half of the participants received Ocrevus infused over 2 hours, while the other half received the medication over the 3.5-hour period that the FDA specified when it approved Ocrevus in 2017.² The frequency of IRs was similar between the two groups – with 24.6% of those in the 2-hour cohort and 23.1% of those in the 3.5-hour group having a reaction. Further, the majority of IRs were mild or moderate; none were serious, life-threatening, or fatal. Ninety-eight percent of reactions in both groups of people resolved without complication.¹

Ocrevus targets CD20-positive B cells. In recent years, B cells – white blood cells that are components of the immune system – have been recognized as playing an important role in MS on many levels. They interact with T cells, another type of white blood cell, to help prompt an immune response. They produce inflammatory cytokines, small proteins that help facilitate inflammation. B cells also evolve into plasma cells that produce antibodies.

Ocrevus, which is administered twice yearly, is approved for relapsing forms of MS, primary-progressive MS, and clinically isolated syndrome.

Positive topline results from two studies of ublituximab

People with relapsing forms of MS who received the investigational monoclonal antibody ublituximab had annualized relapse rates (ARRs) of less than 0.10 in two 96-week trials, according to TG Therapeutics, the New York-based company developing the medication.³

The Phase III trials, ULTIMATE I and ULTIMATE II, compared ublituximab with the FDA-approved disease-modifying therapy Aubagio^® (teriflunomide). Reduction in ARR was the primary endpoint in both trials. Topline results released by TG Therapeutics in mid-December showed that ublituximab reduced the annualized relapse rate by roughly 60% relative to teriflunomide in ULTIMATE I and by approximately 50% compared to teriflunomide in ULTIMATE II.

Like Ocrevus^® (ocrelizumab), ublituximab is an anti-CD20 monoclonal antibody. The dosing regimen evaluated in the two trials entailed a Day 1 intravenous infusion of 150 mg over four hours and a Day 15 infusion of 450 mg over one hour, followed by a 450-mg dose administered by one-hour infusion every six months. More than 1,090 people with relapsing forms of MS enrolled in the trials.

TG Therapeutics announced that it planned to provide more results from the studies – which also looked at MRI measures of disease activity, confirmed disability progression, and safety endpoints – in the first months of 2021. The company added that it was targeting mid-year 2021 for submission of a Biologics License Application seeking FDA approval of ublituximab monotherapy for treatment of relapsing MS.

Biotin for progressive MS: Only modest benefit vs. placebo in Phase III trial

High-dose biotin is a pharmaceutical-grade form of vitamin B7 that long has intrigued investigators searching for interventions to halt the neurodegeneration that drives progressive forms of MS. Unfortunately, the results of a large Phase III trial evaluating MD1003, a high-dose biotin from MedDay Pharmaceuticals, suggest that researchers will need to turn their attention to other potential therapies.

The SPI2 study was a randomized, double-blind, placebo-controlled trial involving 642 adults enrolled at 90 sites in 13 countries. All participants had a diagnosis of primary or secondary-progressive MS. They were randomly assigned in a 1:1 ratio to receive either 100 mg of oral biotin three times each day or placebo. The study’s primary efficacy endpoint looked at the proportion of study subjects in each group who had confirmed improvement from baseline in the Expanded Disability Status Scale (EDSS) or in a timed 25-foot walk (T25W) at month 12, with confirmatory results at month 15.⁴

Twelve percent of the study participants receiving MD1003 met that primary endpoint, as did 9% of the people in the placebo group. Meanwhile, 26% of people in each group experienced at least one serious treatment-emergent adverse event. Further, the researchers noted, MD1003 affected the accuracy of laboratory tests that make use of certain antibodies.

Publishing their findings in Lancet Neurology in December, the study’s authors concluded, “MD1003 did not significantly improve disability or walking speed in patients with progressive multiple sclerosis and thus, in addition to the potential of MD1003 for deleterious health consequences from interference of laboratory tests, MD1003 cannot be recommended for treatment of multiple sclerosis.”

Two Phase III studies seeking to enroll participants with progressive MS

While last month’s news on high-dose biotin was disappointing for people living with progressive MS, there are several hopeful developments on the horizon. They include the roll-out of two Phase III trials – HERCULES and PERSEUS – evaluating tolebrutinib (SAR442168) in non-relapsing secondary-progressive MS and primary-progressive MS, respectively.

Tolebrutinib is an oral medication that selectively inhibits Bruton’s tyrosine kinase (BTK). BTK is an enzyme that affects the activity and survival of B cells, which have been implicated in the development of MS.

The HERCULES trial will enroll 1,290 adults with non-relapsing secondary-progressive MS. Those study subjects will receive either a daily oral dose of tolebrutinib or placebo. PERSEUS will enroll 990 adults with primary-progressive MS, who also will receive either an oral dose of tolebrutinib or placebo each day. Participants will be assigned to receive the investigational medication in a randomized fashion; investigators will not choose or know which people are taking the medication and which are receiving placebo. The studies will examine impact on disability progression, cognitive function, MRI measures of disease activity, and quality of life, and also will assess the safety of the medication. ^5,6

The studies are sponsored by Sanofi Genzyme. Several MS centers across the country are enrolling patients in the trials. Further information is available by visiting the clinicaltrials.gov website and using the study identification code NCT04411641 for the HERCULES trial and searching with the identification code NCT04458051 for the PERSEUS trial. People considering participating in one of the studies also can contact their MS clinician.

Examining the impact of another BTK inhibitor across the MS spectrum

As recruitment progresses for the HERCULES and PERSEUS trials of Sanofi Genzyme’s tolebrutinib in progressive MS, Roche is rolling out a Phase III program to assess the efficacy and safety of its oral Bruton’s tyrosine kinase (BTK) inhibitor, fenebrutinib, in both relapsing and primary-progressive MS. ^7,8

The investigational medication is described by researchers as having a dual mechanism of action that “targets acute and chronic aspects of MS by decreasing B-cell activation and limiting myeloid proinflammatory responses.”⁸

Fenebrutinib will be evaluated in two identical trials in relapsing MS and in another trial enrolling people with primary-progressive MS (PPMS). All three trials will have a primary endpoint of 12-week composite Confirmed Disability Progression. The two relapsing MS trials will include a co-primary endpoint examining the annualized relapse rate.⁸

Investigators hope to enroll 734 people in each of the relapsing MS trials, which will be known as FENhance 1 and FENhance 2. Patients in those trials will be randomized to receive either fenebrutinib or Aubagio^® (teriflunomide). Target enrollment for the PPMS trial, called FENtrepid, is 946 patients. Those study participants will be randomized to receive either fenebrutinib or Ocrevus^® (ocrelizumab).^8,7

Further information on the studies is available at clinicaltrials.gov.

Very early – but very intriguing – news on targeting MS with a vaccine

Can a vaccine reduce the severity of MS by prompting the immune system to tolerate rather than attack the myelin sheath that protects nerve fibers?

Researchers in Germany this month took a mouse-sized but potentially huge step toward answering that question in the affirmative.

Writing in the January 8, 2021 issue of the journal Science, those investigators reported on their experience with administering a messenger RNA vaccine to mice with experimental autoimmune encephalomyelitis (EAE), a condition similar to MS.⁹ The scientists injected the mice with nanoparticle-formulated messenger RNA that had been altered in a way designed to suppress autoimmune destruction of a substance akin to myelin. The vaccine employed a technology like the one used to produce the COVID-19 vaccines developed by Pfizer/BioNTech and Moderna. Unlike those vaccines, however, this one is intended to treat rather than prevent disease.

In vaccinated mice who had shown early signs of significant movement problems, “further disease progression could be prevented, and motor functions were restored,” the researchers noted. They added, “Demyelination of the spinal cord was also considerably reduced” relative to the extent of myelin damage seen in unvaccinated mice with EAE.

There is, of course, a tremendous difference between obtaining favorable results in mice and being able to replicate those outcomes in people. Many a treatment that looked extremely promising in an animal-model study fell short in human trials – or did not even progress to the point of a Phase I study. Much more research, over the course of years, will be needed to assess whether the vaccine the German research team developed is safe and effective in people with MS. In the interim, however, those scientists say that their findings highlight new possibilities in the fight against MS. In the conclusion of their paper, they noted, “Tailoring the treatment for the disease-causing antigens of individual patients is conceivable, similar to that which has been successfully executed in the setting of personalized cancer vaccines.”

Welcome news on COVID-19 for people with MS

Having multiple sclerosis does not appear to increase the risk that a person who contracts COVID-19 will have a more-severe infection or die from the virus, according to research recently reported by Spanish investigators.¹⁰

The researchers followed 41 people with MS diagnosed with COVID-19. Twenty-one of the patients were women. The average age of the people studied was 39.4 years. Thirty-eight had relapsing-remitting MS, while three had progressive MS. Thirty-nine were taking a disease-modifying therapy (DMT). Three had other serious health conditions.

While 17% of the patients were admitted to the hospital, none required admission to the intensive care unit, and none died. The patients who were admitted tended to be older than the average age of the group and to have higher Expanded Disability Status Scale (EDSS) scores, but those differences were not statistically significant. Seven of the patients reported that their MS worsened while they were battling the coronavirus, and DMT use was stopped or delayed in 10 of the patients with COVID-19.

The investigators concluded, “From our experience, the SARS-CoV-2 infection does not seem to entail a more aggressive form of the disease in this group of patients [people with MS].”

Categorizing the different ways MS affects cognition

A team of Italian and Portuguese researchers has proposed a five-phenotype approach to categorizing the impact MS has on cognitive function. They add that determining which phenotype applies to a particular patient can help clinicians make treatment decisions and individualize cognitive-rehabilitation strategies.

The investigators base their approach on findings from neurological examinations and cognitive testing of more than 1,200 people with MS and 196 healthy controls. A subset of patients also underwent magnetic resonance imaging (MRI) of the brain. The study, which involved people receiving care at eight MS centers in Italy, ran from 2010 through October 2019.¹¹

The five phenotypes the researchers identified are:

• Preserved cognition, seen in 19.4% of the patients studied
• Mild verbal memory/semantic fluency, 29.9% of patients
• Mild-multidomain, 19.5% of patients
• Severe-executive/attention, 13.8% of patients
• Severe-multidomain, 17.5% of patients

The researchers added that people with preserved cognition or mild problems with verbal memory/semantic fluency tended to be younger than patients with other phenotypes, and to have had a shorter duration of disease.

Preventing misdiagnosis of MS based on MRI findings: A helpful, hopeful sign

Misinterpretation of magnetic resonance imaging (MRI) findings is a common cause of MS misdiagnosis. Now, research indicates that identifying a vein in or near the middle of white matter lesions on MRI sequences – the so-called “central vein sign,” or CVS – can help distinguish between MS and other conditions.¹²

Investigators performed magnetic resonance imaging on 30 people, 15 of whom had confirmed MS and 15 of whom had been misdiagnosed with MS.

The number of brain lesions per patient shown on the imaging did not differ significantly between the two patient groups. However, the number of lesions marked by a central vein sign did differ, with the CVS present in an average of 0.93 lesions in the people who had been misdiagnosed with MS and in an average of 6.3 lesions among the subjects who actually have MS. Employing a lesion-threshold criterion developed from the analysis enabled CVS-based identification of 79% percent of patients who actually have MS and allowed correct identification of 87% of the patients previously misdiagnosed with MS.

The investigators said that their findings provide cause to incorporate the CVS into the diagnostic evaluation of possible MS to increase accuracy and reduce misdiagnosis.

References

¹ Genentech. FDA approves Genentech’s Ocrevus (ocrelizumab) shorter 2-hour infusion for relapsing and primary progressive multiple sclerosis. December 14, 2020. Available at https://www.gene.com/media/press-releases/14890/2020-12-14/fda-approves-genentechs-ocrevus-ocrelizu. Accessed January 11, 2021.

² Hartung H-P. Ocrelizumab shorter infusion: Primary results from the ENSEMBLE PLUS substudy in patients with MS. Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e807. DOI: 10.1212/NXI.0000000000000807.

³ TG Therapeutics. TG Therapeutics announces positive topline results from the ULTIMATE I & II phase 3 studies evaluating ublituximab monotherapy for the treatment of patients with multiple sclerosis. December 10, 2020. Available at https://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-announces-positive-topline-results-ultimate-i-ii. Accessed January 8, 2021.

⁴ Cree BAC, Cutter G, Wolinsky JS, et al. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomized, double blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2020;12:988-997.

⁵ National Library of Medicine. NCT04411641. Nonrelapsing secondary progressive multiple sclerosis (NRSPMS) study of Bruton’s tyrosine kinase (BTK) inhibitor SAR442168 (HERCULES). Available at https://clinicaltrials.gov/ct2/show/NCT04411641. Accessed January 12, 2021.

⁶ National Library of Medicine. NCT04458051. Primary progressive multiple sclerosis (PPMS) study of Bruton’s tyrosine kinase (BTK) inhibitor SAR442168 (PERSEUS) (PERSEUS). Available at https://clinicaltrials.gov/ct2/show/NCT04458051. Accessed January 12, 2021.

⁷ Roche. Roche expands its multiple sclerosis portfolio with investigational BTK inhibitor fenebrutinib and initiates novel clinical trials for OCREVUS (ocrelizumab). September 9, 2020. Available at https://www.roche.com/media/releases/med-cor-2020-09-09.htm/. Accessed January 12, 2021.

⁸ Gheen M, et al. Examination of fenebrutinib, a highly selective BTKi, on disease progression of multiple sclerosis. ECTRIMS 2020 [P0211].

⁹ Krienke C, Kolb L, Diken E, et al. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science. 2021;371:145-153.

¹⁰ Meca-Lallana V, et al. Experience in multiple sclerosis patients with SARS CoV-2 infection. ECTRIMS 2020 [P0079].

¹¹ DeMeo E, Portaccio E, Giorgio A, et al. Identifying the distinct cognitive phenotypes in multiple sclerosis. JAMA Neurology. Published online January 4, 2021. doi:10.1001/jamaneurol.2020.4920.

¹² Kaisey M, et al. Preventing multiple sclerosis misdiagnosis using the “central vein sign”: A real-world study. ECTRIMS 2020 [P0135].

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