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“She’s just highly strung or emotional” – how female brain injuries are going undetected

Mounting evidence shows that women are more likely to sustain concussions than men – but official medical bodies are not responding…

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Various studies suggest that women and girls sustain more concussions, at a higher rate than their male counterparts in the same sports.

A recent National Collegiate Athletic Association (NCAA) Injury Surveillance Program study, for example, shows the rate of concussion per 1000 athlete-exposures in football is 6.3 in females versus 3.4 in males. Similar differences were noted in basketball (6.0 in females versus 3.9 in males) and baseball/softball (3.3 versus 0.9).

Women are also known to experience more severe symptoms, and take longer to recover.

A study published in 2017 (Neidecker et al) compared the medical records of 110 male athletes and 102 female athletes, all of whom had endured a single sports-related concussion. Female athletes had symptoms for an average of 28 days, versus 11 in males.

In fact, multiple research studies have found in sports with similar rules between females and males, that rates of concussion are higher in women (Gessel, Fields, Collins, Dick, & Comstock, 2007; Hootman, Dick, & Agel, 2007; A E Lincoln et al., 2012).

But in-depth research specifically on the female brain injury experience is limited. Meanwhile, no female-specific brain injury guidelines exist in the sporting, military or healthcare arenas. Protocols and educational resources are also in short supply.

“I think some of it is misogyny,” says Katherine Price Snedaker, founder of Pink Concussions, the world’s first non-profit organisation for women and girls living with a brain injury.

Katherine was a social worker helping children with concussion when she started to notice differences between how parents of boys and girls responded to injuries.

“The girls’ parents were calling me weeks or months after the incident, yet with the boys’ parents it was within hours or days. I just kept seeing this pattern,” she says.

Katherine, who has three sons, initially put this down to bad parenting; but now blames widespread lack of awareness about female brain injury.

“If you don’t know what a concussion is, you’re going to be less likely to get the help in the time that it takes.

“People might have some of these symptoms, like headaches and nausea, anyway. If you don’t know what you’re feeling, you can’t know what to look for.”


Katherine (pictured above spreading the word about Pink Concussions) began looking for research on the differences between brain injuries in males and females, and while there was information out there, it was always in the small print, never the focus of the study itself.

She wanted to create a platform that would bring all of this information together, and so Pink Concussions was born.

That was in 2013 and, two years later, the organisation had enough support behind it to become an official non-profit.

Since then it has held seven international medical summits and scientific conferences and built up an advisory board of over 80 experts from around the world.

It also routinely works with major US health organisations, including the Centre for Disease Control and Prevention and NIH (National Institutes of Health); and provides support groups for more than 4,000 women and caregivers.

“My greatest goal is to work with the UN. We’re a small organisation and we’re all volunteers. The annual number of donations we take in is probably smaller than most school sports teams do, but we’re the only ones who do what we do.”

Pink Concussions is working to close the gap in research and awareness of female brain injury, through education, training and support. It also conducts its own research studies, exploring both sex and gender differences in brain injury.

As noted on its website, scientific research shows that female and male brains differ in more than 100 ways in structure, activity, chemistry, and blood flow.

Other potentially relevant sex differences include hormone levels, neck strength and head size.

Differences in gender – a social construct which is often but not always concordant with biological sex – include what Pink Concussions calls the “controversial explanation” that women are perceived as being more likely to report injuries.

Statistically, there are higher numbers of brain injuries in men than women, which goes someway to explaining why the vast majority of research has been studied from a male perspective.

It is increasingly evidenced, however, that women have more symptoms, feel them more intensely, take longer to recover and are more likely to experience post-concussion syndrome.

The lack of knowledge and awareness of female brain injuries, among women themselves, and in wider society, can have serious consequences.

If a woman’s recovery speed or symptoms don’t match expectations, this can lead to doubt, isolation and anxiety, beyond any she may already be experiencing, says Katherine. Women are therefore not prepared to cope with their injury.

“I think for many years, people just said it’s because women aren’t as tough as men. Women are weaker and complain more.

I’ve seen some really great sports doctors say ‘oh, she’s just highly strung, or she’s just emotional’.”

It’s only very recently that researchers have started to study brain injury specifically in women, after years of men doing research on men, says Katherine.

“In brain injury, it’s been men doing research on men or male animals. When they use female animals it’s messy. If a lab rat goes through its menstrual cycle every six days, that really throws off results, so it’s pretty uniform that they don’t do research on female animals.”

Also, the majority of brain injury research has been conducted on athletes, and the sports with the highest risk of concussion, such as American football, rugby and boxing, are male-dominated.

“If you want to see a bunch of guys with a brain injury where do you go? The (American) football field. Football has always worked out well in providing men to be studied.

“The researchers need them as lab rats as much as they want the researchers. The two are  entrenched in each other.”

But a study by the American Medical Society for Sports Medicine found that women are 12 per cent more likely to sustain a concussion than men in matched sports. Yet unlike in the men’s game, often these are not noticed or reported to medical professionals at the time of injury.

“Usually women’s sports are underfunded, and traditionally they have fewer medical staff on the pitch or the field.”

But it’s not just the sporting world which is neglecting to address the issue in women. In the military, safety and training equipment is often designed for men, says Katherine, and women are less likely to speak out about an injury for fear of being judged as “not tough enough”.

“Women are trying to operate and train on equipment that’s not necessarily made for them. A woman who might be the only female in her platoon, may be less likely to come forward if she’s injured, because she doesn’t want to be the one being pointed out,” she says.

Beyond the sporting world, those keen to study female concussion and chronic traumatic encephalopathy (CTE), would find a high volume of cases among domestic violence survivors, research suggest.

Blows to the head, face and neck combined with asphyxiation from strangulation, common in intimate partner violence (IPV), can lead to many women living with undiagnosed brain injuries.

In one of the first research studies into traumatic brain injury (TBI) in survivors of intimate partner violence, Pink Concussions board member Dr Eve Valera found that three quarters of the women she interviewed had sustained at least one mild TBI from their partners.

Eve, an assistant professor in psychiatry at Harvard Medical School, is now working on a new study, replicating many of those which have been conducted on male athletes, exploring the long-term effects of these brain injuries for women.

“If we’re talking about neurodegeneration in women we really know nothing. I call it an international public health epidemic. We have all these resources and money and studies on male athletes and there’s nothing like that with respect to women experiencing IPV.

“There’s a disjoint between what people are learning from sports or military data, where we see most repetitive head injury research, and what a woman may think is going on with her.

“There’s an awareness that playing football can lead to injuries that can have long-term neurodegenerative consequences but for the most part, there’s no public awareness that, if you’ve been in a physically abusive situation and you’re getting these types of blows to the head, you may have a long-term neurodegenerative disease.”

The lack of studies for women often means that survivors who do wish to speak up about their injuries find they have nowhere to turn. Eve has been contacted by women who have been turned away by researchers who cannot study them because of their sex.

“These women are left with no one. They call me and they’re desperate,” she says. “Where as male athletes feel like they have a place to go if they’re concerned about CTE, if you are an IPV survivor you don’t have anywhere to turn.”

Pink Concussions launched its campaign the ‘Pink Brain Pledge’ for this very reason. By partnering with several brain banks around the world, it is encouraging women to ‘take the Pink Brain Pledge’ and donate their brain to science. So far, 450 women have done just that.

“Any woman can pledge her brain for our programme. As much as we need women with brain injuries, we also need women without, for controls.”

Katherine believes studying these brains could lead to huge developments in brain injury research – and the key could be in looking at how hormone levels affect outcomes.

“We’ve proven the same thing over and over again, that there are differences. Now we’re trying to push the research to the next point. Let’s figure out why these things are happening.

“We look at what hormones people were born with, what hormones they are taking, and if you were born male, and you’re taking female hormones, how does that affect things?

“If hormones can control the outcome, then how can we take that and make an antidote or something that’s preventative or at least lowers your rate? We’re not there yet, but that’s my hope.”

This is not just a women’s issue. While females remain at the heart of Pink Concussions, the work the organisation is doing could help to improve education and medical care for all those living with a brain injury.

“Slowly we’re spreading out and women are learning more about brain injury. But I’m hoping that the gains we make in female brain injury we can apply to men too.”

For more information visit https://www.pinkconcussions.org

(Photos provided by the Schulich School of Medicine & Dentistry, Western University, Canada.)


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City dwellers “more likely to die in hospital” after stroke – US study

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Compared to those living in urban areas, stroke patients treated at rural hospitals were one third less likely to undergo a procedure to remove a blood clot that caused the stroke and were more likely to die of stroke before leaving the hospital.

Researchers examined national data on almost 800,000 adults hospitalised after a stroke between 2012 and 2017.

In their paper, published in the American Stroke Association’s Stroke journal, the researchers warn that this urban-rural divide may be getting worse. This gap, the paper states, could be caused by the slower take-up of newer treatments and technologies, and because rural hospitals are less well-resourced and have poorer access to specialist care. Rural hospitals may also be more likely to lack specialised clinical support, such as dedicated stroke units.

Other causes for poorer stroke care could be a lack of clinical expertise in urban areas, due to difficulties attracting and retaining experienced staff, and poorer access to emergency services and longer responses to emergency calls due to distance.

“The lack of access to specialists is often a limiting factor in adequate care for rural stroke patients, and in this case, that could mean a neurologist to guide the initial care, an interventional neurologist or radiologist to do a procedure, or having a neurosurgeon available for backup in case of any complications,” said Gmerice Hammond, author of the study and a cardiology fellow at Washington University School of Medicine.

“Clinicians need to work to improve access to high-quality stroke care for individuals in rural areas. That means partnerships between hospitals for rapid transfer, as well as telehealth when appropriate. And clinical leaders and policymakers should prioritize improving access, care and outcomes for stroke in rural communities.”

The study had some limitations, including a lack of data on the severity of patients’ strokes, or factors that would determine whether a patient received advanced therapies, sich as the size of the clot and where it is located.

Karen Joynt Maddox, senior author of the study and assistant professor of medicine at Washington University School of Medicine, calls the differences in care, and the lack of improvement over the five-year period, ‘striking’.

“Future studies using more detailed clinical data will be important to follow up on our findings and to determine why patients in rural areas aren’t receiving advanced therapies. Is it because their stroke severity is different? Or because delays in getting to the hospital meant they weren’t eligible by the time they arrived?

“Those questions can’t be answered with administrative data, but they’re very important to look into so that we can develop effective solutions.”

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Legal

Capacity for decisions in life and love: part 1

Under Article 8 of the Human Rights Act we all have a right to enjoy a private and family life. The need for relationships and intimacy is an essential part of most of our lives but for individuals living with an acquired brain injury, this can be far more complex, as Georgina Moorhead of Irwin Mitchell explains.

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Dating and Sexual Relationships

The law states that people have capacity to engage in sexual relationships if they understand the physical context. In other words, they should understand the basic mechanics of the acts involved, the risk of pregnancy or sexually transmitted disease and the ability of either party to say no at any stage.

In the context of serious injury litigation, we commonly encounter Claimants who have a strong desire for romantic relationships.

Unfortunately, the cognitive issues they face, which often include difficulty concentrating, poor memory, poor language skills and reduced problem- solving abilities, in addition to disinhibition, impulsivity and impaired reading of social cues, can present significant challenges in both dating and forming romantic relationships.

Cognitive impairments can also impact an individual’s ability to fully comprehend issues such as safe sex and consent.

For professionals involved in such cases, it is crucial to respond by sourcing appropriate support in order to maximise an individual’s capacity to engage in dating safely, whether in person or online.

I recently represented a young man affected by many of these issues. He had a strong desire to be in a relationship but exhibited impulsive behaviour which frequently overrode his ability to exercise caution or appropriate dating behaviour.

His lack of capacity manifested in him having difficulty understanding and utilising appropriate online communication, inappropriate and excessive use of dating sites and accessing inappropriate websites. He was also unable to consistently read social cues and adapt his behaviour/ make decisions accordingly. For all these reasons, the Claimant was considered to be at risk online.

We therefore arranged a specific capacity assessment, following which protective measures were introduced and input was arranged to help monitor and manage my client’s risk from online activity.

He also benefited from input from brain injury specialist support workers with whom he was able to openly discuss his online activity and increase his understanding of the need for him to exercise caution. Ultimately, he had capacity to date and enter romantic relationships but there was a very clear need for support to enable him to do so safely.

In this case, I worked closely with Irwin Mitchell’s Court of Protection team, who appointed a property and financial Deputy for my client.

Katie Strong, a partner in Irwin Mitchell’s Court of Protection team explains that: “Capacity is decision specific and so over time, the level of support and supervision will be kept under review and reduced in the event my client regains capacity in this area.  As well as the specialist support team, we have instructed a neuropsychologist to monitor the client’s capacity and provide support to him as well as his support team in managing the risks.”  

Considerations in Litigation

We are all familiar with the presumption of capacity under the Mental Capacity Act 2005. In serious injury litigation involving brain injured individuals in particular, complex issues often arise when we are acting for clients who have been placed in a vulnerable position (through no fault of their own) and their ability to make reasoned, informed decisions simultaneously reduced.

Such cases inevitably prompt legal professionals to think ‘outside the box’. For example, does an individual require subscriptions for dating agency sites, psychological support or professional IT support to assist in the management of online risk? Does the Case Manager need to act as an intermediary with dating agencies? Is there a role for support workers? There is no ‘one size fits all’ approach and, as always, cases should mould around the individual involved and their particular circumstances.

For example, if a client demonstrates a desire to be in a long- term relationship and to have children, the legal team should consider obtaining expert evidence which addresses the need for any future support that may be required with childcare, both in the context of a successful relationship and relationship breakdown.

An assessment of how well they may manage the end of a relationship and cope with the emotional and psychological challenge may also impact their future care needs, and we may need to prompt our care experts to include additional future contingency care during such periods.

Ultimately, the Courts have consistently held that the requisite standard for capacity to consent to sexual relationships and marriage is deliberately not a high one. We cannot prevent our clients from making decisions we consider to be unwise but we do have several tools at our disposal to protect and support whatever capacity they do have. Our role is to ensure that our client is able to maximise their independence so far as possible.

Read part 2 of this article series – exploring issues regarding capacity to cohabit and marry in more depth.

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MS update

A round up of the latest developments in Multiple Sclerosis (MS) research.

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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.

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