MS risk higher for people living in urban areas, new research reveals

In Italy, a study has found that air pollution could be a risk factor for the development of MS.

The research, which was presented at the European Academy of Neurology (EAN) Virtual Congress, detected a reduced risk for MS in individuals residing in rural areas that have lower levels of air pollutants known as particulate matter (PM). It showed that the MS risk, adjusted for urbanisation and deprivation, was 29% higher among those residing in more urbanised areas.

The study sample included over 900 MS patients within the region, and MS rates were found to have risen 10-fold in the past 50 years, from 16 cases per 100,000 inhabitants in 1974 to almost 170 cases per 100,000 people today. Whilst the huge increase can partly be explained by increased survival for MS patients, this sharp increase could also be explained by greater exposure to risk factors.

The analysis was conducted in the winter, as this is the season with the highest pollutant concentrations, in the north-western Italian region of Lombardy, home to over 547,000 people.

Commenting on the findings at the EAN Virtual Congress, lead researcher Professor Roberto Bergamaschi explained, “It is well recognised that immune diseases such as MS are associated with multiple factors, both genetic and environmental.

“Some environmental factors, such as vitamin D levels and smoking habits, have been extensively studied, yet few studies have focused on air pollutants. We believe that air pollution interacts through several mechanisms in the development of MS and the results of this study strengthen that hypothesis.”

The term particulate matter (PM) is used to describe a mixture of solid particles and droplets in the air and is divided into two categories. PM10 includes particles with a diameter of 10 micrometres of smaller and PM2.5 which have a diameter of 2.5 micrometres or smaller.

Both PM10 and PM2.5 are major pollutants and are known to be linked to various health conditions, such as heart and lung disease, cancer, and respiratory issues. According to the World Health Organisation, 4.2 million deaths occur every year because of exposure to ambient (outdoor) air pollution.

Three different areas were compared within the study region based on their levels of urbanisation, of which two areas were found to be above the European Commission threshold of air pollution.

Professor Bergamaschi added: “In the higher risk areas, we are now carrying out specific analytical studies to examine multiple environmental factors possibly related to the heterogeneous distribution of MS risk.”

The number of people living with MS around the world is growing, with more than 700,000 sufferers across Europe alone. The vast majority (85%) of patients present with relapsing remitting MS, characterised by unpredictable, self-limited episodes of the central nervous system. Whilst MS can be diagnosed at any age, it frequently occurs between the ages of 20-40 and is more frequent in women. Symptoms can change in severity daily and include fatigue, walking difficulty, numbness, pain and muscle spasms.

Novartis builds case for MS drug ofatumumab as FDA decision looms

Swiss drug maker Novartis has reported new data with its MS drug ofatumumab showing that it can suppress disease activity for up to two years, as it waits for an FDA decision on the drug in June.

New results from the firm’s clinical trials programme for ofatumumab (OMB157) showed that 47% of patients with relapsing MS had no evidence of disease activity (NEDA) in the first year after treatment, rising to almost 88% in the second year.

Ofatumumab – a CD20-targeting antibody – is already used as an intravenous treatment for chronic lymphocytic leukaemia (CLL) under the Arzerra brand name but has seen its use in that indication lowered due to increased competition.

Novartis believes the subcutaneous version of the drug can make sales of over $1billion per year as an MS therapy, and challenge other new therapies like Roche’s fast-growing Ocrevus (ocrelizumab), which also targets CD20 and brought in CHF 3.7 billion ($3.8 billion) in only its second full year on the market.

If approved, ofatumumab would become the first B-cell-targeting therapy for relapsing forms of MS that can be self-administered by patients at home once a month. A verdict is also due from the European Medicines Agency (EMA) in the first half of 2021.

Earlier results from a pair of phase 3 trials – ASCLEPIOS 1 and 2 – showed that the antibody was more effective at cutting relapses than Sanofi’s once-daily oral MS drug Aubagio (teriflunomide), reducing the rate by 50.5% and 58.5% respectively in the two studies.

The new findings were presented at the virtual European Academy of Neurology (EAN) congress, and showed that Aubagio was also less effective at banishing disease activity. In the first year 34.5% of patients on Sanofi’s drug achieved NEDA, rising to 48.2% in year two.

ASCLEPIOS clinical investigator Prof Ludwig Kappos of University Hospital Basel said: “Achieving no evidence of disease activity is widely recognised as an important treatment goal for MS therapies.”

If approved, ofatumumab won’t have the same breadth of approved indications as Ocrevus, as Roche’s drug can be used in both relapsing and primary progressive forms of MS.

There’s also a big difference between the two drugs when it comes to their dosing. Patients will have to decide whether they prefer to self-inject ofatumumab once a month or visit a clinic for an intravenous infusion of Ocrevus every six months.

The Covid-19 pandemic could be a lift for Novartis on the dosing issue, given the reduced access to healthcare services, although lockdowns are now beginning to be lifted.

Novartis Pharma president Marie-France Tschudin said last month that “now more than ever, bringing a B-cell therapy that’s highly efficacious and administered at home is highly attractive.”

“Our goal is that when patients come back, we’ll make it easy for them to start on ofatumumab,” she added.

Novartis acquired the drug from GlaxoSmithKline and Genmab in 2015 in a $1 billion deal.

Higher blood NfL levels indicate worse disability over time in MS, study suggests

A large population study in Sweden has suggested that higher blood levels of the neurofilament light chain (NfL) protein at diagnosis are predictive of worse disability over time in people with multiple sclerosis.

The study, “Plasma neurofilament light levels are associated with the risk of disability in multiple sclerosis,” was published in the journal Neurology.

NfL levels are commonly used as a marker for nervous system injury, with NfL protein released when neurons become damaged.

Previous research has suggested NfL as a prognostic biomarker in MS, however, most of these studies measured NfL levels in cerebrospinal fluid (CSF), the fluid that surrounds the brain and spinal cord, which is not feasible as a routine clinical test due to its invasive nature.

Other studies have shown that NfL levels in blood are closely related to levels in CSF, raising the possibility that blood NfL levels could have prognostic value in MS. However, whether these levels can predict long-term outcomes in MS has not been extensively evaluated.

“In a disease like MS that is so unpredictable and varies so much from one person to the next, having a non-invasive blood test like this could be very valuable, especially since treatments are most effective in the earliest stages of the disease,” Ali Manouchehrinia, PhD, of the Karolinska Institutet, Sweden, and a study co-author, said.

To address blood NfL as potential marker of likely disability worsening over time (a prognostic marker), researchers measured blood NfL levels in 4,385 people with MS, including 3,664 with relapsing-remitting MS (RRMS), 511 with secondary progressive MS (SPMS), and 129 with primary progressive MS (PPMS). The remaining 81 individuals did not have their MS type recorded in the data analysed.

For comparison, NfL levels were measured in a control group of 1,026 non-MS people of similar age and sex to the MS group.

Results showed that blood NfL levels varied significantly with age in all groups. After adjusting for this, NfL levels were significantly higher in all MS groups than in controls — the median NfL levels were 8.5 picograms (pg)/mL in controls, and 17.1 pg/mL in RRMS patients, 18.4 pg/mL in those with SPMS, and 14.7 pg/mL in PPMS patients.

Researchers then calculated whether higher NfL levels were predictive of worsening disability, as assessed by reaching various benchmarks on the Expanded Disability Status Scale (EDSS) during a median of five years of follow-up.

High NfL blood levels were defined based on the values measured in controls, and multiple cut-off values were also assessed. The statistical models used for these calculations were adjusted taking into account other relevant factors, including sex, age, disease duration, and MS treatment.

Overall, high NfL levels were significantly predictive of sustained EDSS worsening (greater disability). Depending on the cut-off used, the risk of disability worsening rose by 40% to 65% in people with high blood NfL levels, compared to those with lower levels.

High NfL levels were also significantly associated with a risk of reaching an EDSS score of 3.0, indicating moderate disability without walking impairment. Similar results were found for reaching an EDSS score of 4.0, indicating significant disability with mild walking impairment.

At some cut-offs, high NfL was significantly associated with a risk of reaching an EDSS score of 6.o (corresponding to needing an aid to walk 100 meters, about 330 feet). As findings weren’t entirely significant, a definitive conclusion cannot be drawn from this data and future studies will be needed to help clarify whether blood NfL levels can predict more severe disability, the researchers noted.

Similarly, high NfL levels were significantly predictive of progression from RRMS to SPMS at some cut-offs, but not at others, making it difficult to draw reliable conclusions and again highlighting a need for further research.

Taken together, the “findings suggest that [blood] NfL measurement can usefully provide additional predictive power in the form of an easily accessible and easy-to-measure biomarker for monitoring of disease activity and potentially treatment response in MS,” researchers wrote.

Nonetheless, “more research is needed before a blood test could be used routinely in the clinical setting, but our results are encouraging,” Manouchehrinia concluded.

Preliminary research on Covid-19 in people with MS offers some reassurance

One area that has caused concern most recently for those in the MS community is the impact of Covid-19. However, preliminary results from Italy has shown that people with MS who contracted the virus did no worse than the general population.

Researchers in the country have been collecting data to understand the relationship between MS and Covid-19, whether having the condition increases the risk of a more severe impact of the virus, and whether taking disease modifying drugs may add any extra risk.

The Italian Multiple Sclerosis Society (AISM), the Italian Multiple Sclerosis Foundation (FISM), and the Multiple Sclerosis Study Group of the Italian Neurological Society set up an online platform to record and collect data about those with MS in Italy who have been diagnosed with Covid-19 or have developed symptoms (suspected Covid-19). MS neurologists across Italy were asked to input data and share patient outcomes.

Early results from the data collected so far have now been published. Preliminary data includes 232 people with MS, 57 of which have tested positive for Covid-19 and 175 who have suspected Covid-19. Of the 232 people studied, 211 were taking a disease modifying drug.

The data recorded the severity of Covid-19 in these 232 people:

  • 223 (96%) had a mild infection
  • 4 (2%) had a severe infection
  • 6 (3%) had a critical infection

Of those who were critical, one person recovered, and five died. The people who died tended to be older (50+) and had other health conditions.

It’s too early to say from this data whether DMDs make a difference to Covid-19 recovery, but it does not suggest that the current DMD advice should be changed.

Although this research is preliminary and the numbers are fairly small, these results are reassuring for people with MS, suggesting that having MS doesn’t increase your likelihood of a more severe Covid-19 infection and the majority are likely to have a mild infection, the same as the general population.

Evobrutinib lowers MS relapse rates over 2 years of use, trial data shows

Trial data has shown that the investigational oral medication evobrutinib leads to a sustained reduction in relapse rates in people with relapsing MS.

These findings were presented in a poster at the 2020 congress of the European Academy of Neurology (EAN), which was held virtually due to the COVID-19 pandemic.

The study, “Efficacy and Safety of the Bruton’s Tyrosine Kinase Inhibitor (BTKI) Evobrutinib in Relapsing Multiple Sclerosis Over 108 weeks: Open-label Extension to a Phase II Study,” was sponsored by Merck KGaA, the company developing evobrutinib.

Evobrutinib works by blocking the activity of Bruton’s tyrosine kinase (BTK), a protein that is important for the activation of certain types of immune cells — like B-cells — that drive inflammation which damages the nervous system in MS.

Its efficacy and safety were evaluated in a Phase 2 clinical trial (NCT02975349) that enrolled 267 people with relapsing MS, which includes relapsing-remitting MS (RRMS) and active secondary progressive MS (SPMS).

In the initial trial, which lasted 48 weeks, participants were randomly assigned to one of five groups: three groups were given evobrutinib at different doses (25 mg once daily, 75 mg once daily, or 75 mg twice daily); a fourth was given a placebo; and the fifth was given Tecfidera (dimethyl fumarate), an approved oral therapy by Biogen.

Results from this part of the trial showed that evobrutinib, at 75 mg twice daily (highest dose tested), significantly reduced the annualised relapse rate compared to placebo – 0.11 vs. 0.37 relapses/year – with 79% of participants on this dose group remaining relapse-free after 48 weeks.

Participants were then invited to enrol in an open-label extension study (OLE), where all received the active treatment at the dose determined to be the most effective and safe: in this case, evobrutinib at 75 mg twice daily.

Data presented at EAN comes from an analysis of 213 patients who completed at least 60 weeks of treatment in the OLE study.

For those initially randomised to evobrutinib at 75 mg twice daily, this represents a total of 108 weeks (just over two years) of treatment. In these 44 patients, the annualised relapse rate observed after 48 weeks (0.11 relapses/year) was consistent with that seen at 108 weeks (0.12 relapses/year).

Luciano Rossetti, head of global research and development for EMD Serono, said: ““These data demonstrate evobrutinib has a sustained high impact on annualised relapse rate over 108 weeks.”

Notably, the relapse rate for this highest dose of evobrutinib was lower than for all other tested doses of evobrutinib, suggesting that this dosing schedule is best for preventing relapses.

Mathematical modelling suggested that the efficacy of this highest dose is likely attributable to the percentage of BTK molecules that are physically inhibited by evobrutinib, a process referred to as “BTK occupancy.”

“The largest and most sustained reduction in [annualized relapse rate] was achieved when BTK occupancy was [greater than] 95%, observed in nearly all [98%] patients receiving [75 mg evobrutinib twice daily],” the researchers wrote.

No new safety concerns were observed in the OLE study. The most common side effect of evobrutinib’s use was nasopharyngitis (more commonly known as a cold).

In the initial trial, some participants experienced an increase in blood markers of liver damage, but these increases were only observed in the main study and were not found in the OLE.

“We are encouraged by evobrutinib’s breadth of consistent safety data, including no increase of serious infections in more than 1,200 patients [treated across all clinical studies of evobrutinib in MS and other conditions] up to two years,” Rossetti said.

Xavier Montalban, MD, PhD, with Vall d’Hebron University Hospital in Spain, and a trial investigator added: “The 108-week efficacy and safety data for evobrutinib through the double-blind and the OLE period are very robust.

“This, combined with the high selectivity of evobrutinib, suggests that evobrutinib may offer a promising approach to MS treatment.”

Evobrutinib is being further evaluated in two Phase 3 clinical trials, EVOLUTION RMS 1 (NCT04338022) and EVOLUTION RMS 2 (NCT04338061).

More than 1,800 people with relapsing MS will be enrolled and randomised to receive either evobrutinib or Sanofi‘s Aubagio (teriflunomide), or a placebo.

This reflects a change to the trials’ original protocol, which called for evobrutinib to be compared with Biogen’s Avonex (interferon beta-1a).

These trials, which are not yet recruiting participants, are expected to conclude in 2023.