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'Major moment in MS research' as new Octopus trial starts

"I was playing a game of ultimate frisbee and got fuzzy vision in one eye - a bit like looking through a steamed-up windscreen."

Ailsa Guidi was 22 at the time, studying at University of Manchester.

"The doctor said it was optic neuritis, so I had steroid treatment, and the blurring went away. So I got on with being a student."

Two years later, in 1999, her vision went fuzzy again. This time, her GP was concerned that it might indicate something more serious.

On a Friday evening, Ailsa went alone for her first MRI brain scan with the neurologist who would give her a life-changing diagnosis.

"He told me: 'you've got very mild multiple sclerosis'. At the time I knew some people who had MS and needed to use a wheelchair. My eyes filled up with tears and the neurologist asked me 'why are you crying? I've just told you it's very mild'," Ailsa remembers.

"But I was 24, all my friends were meeting up at the pub that evening, and so for me, it was a really big thing to take in. Even if having milder MS was good, as the neurologist saw it, for me being diagnosed with MS was not."

Ailsa began treatment, and tried not to let the diagnosis change her life too much.

"At the time, I found it quite hard to talk to friends about it because they were either so worried about me that I ended up telling them I was totally fine, or they just didn't know very much about MS," Ailsa recalls.

She saw in the millennium in Barcelona with her boyfriend Robert, who was studying at the same university. Later they married, and in 2005 had their first child.

MS is a neurodegenerative disease, in which the immune system mistakenly attacks the fatty myelin sheath that protects the nerves in a similar way to insulation around electric wires. As that protection is gnawed away, the nerves can eventually stop being able to send the signals that help us to walk, talk, think clearly or use our hands normally.

'A major moment in MS research'

Ailsa, now 47, is taking part in a groundbreaking new trial, which is looking into whether existing drugs can be repurposed to help slow MS progression.

The way it is designed means several drugs can be tried at the same time, and more can be added or dropped as results emerge.

The Octopus trial - so-called because it is a multi-arm, multi-stage trial - is being run by Prof Jeremy Chataway, from the National Hospital for Neurology and Neurosurgery UCLH in London, with £13m in funding from the UK's MS Society.

A similar trial design has been used to test drugs for prostate cancer and Covid.

Existing trial patients who prove to be on ineffective drugs can swap to a new arm, and are allowed to continue any other MS disease-modifying drugs they may already be taking.

The first two trial medications are high-dose metformin - a diabetes drug that may help regenerate myelin - and a version of high-dose alpha-lipoic acid, which is a food supplement that acts as an anti-oxidant. It has already been approved in Germany for treating neuropathy - weakness, pain, numbness or tingling in damaged nerves.

The trial team spent several years whittling down 100 potential drugs, and will add more as other strong contenders emerge.

"We are at the start of a long journey," says Prof Chataway. "There are now many treatments for relapsing-remitting MS, but far less available for progressive MS. This trial structure is like a machine for testing drugs for progressive MS. We hope to make it an everlasting machine - at least until we have achieved what we want in controlling and ultimately reversing progression in this difficult stage of MS."

He thinks MS patients should eventually be able to take disease-modifying drugs to deal with the inflammatory component of MS and add on any remyelinating drugs that prove to help repair or even stop nerve damage.

"This is a major moment in MS research," Prof Chataway believes. "Octopus has the potential to change the clinical trials landscape around the world, and we won't stop until we have the treatments that transform the lives of everyone with MS."

The first 375 patients are already being recruited for stage one of the trial, with stage two due to bring the total up to about 1,000.

This month, Ailsa became one of the first people to be accepted on to the trial, which is aiming to recruit at another 30 centres around the UK as they are approved.

After a brain scan, blood tests and a thorough neurological examination, she has now received her first dose of trial medication.

Ailsa knows that she may be on the placebo arm getting no real treatment, but she hopes the Octopus trial will help doctors find ways of slowing or halting MS progression, and perhaps even repair some of the damage.

"I've got difficulties walking but I can live with that. I just don't want to get any worse."

'Biggest impact is what MS takes away from you'

Ailsa took medical retirement at 33 when it became clear that she could not manage her MS fatigue while working and taking care of their three children while Robert was working full-time.

Robert, also 47, says MS has had a more noticeable impact on them as a family as the illness has progressed.

"At the beginning, things were fairly normal. But now we have to plan a bit more, and take the right equipment. It limits the scope of what you can do, so sport or dancing aren't options any more. The biggest impact is the things that MS takes away from you," he says.

"Ailsa and I are a very close partnership and I think we're both positive people. Everyone has their own struggles in life, so you've just got to get on with it and enjoy life as much as you can."

Why the immune system goes rogue in this way for about three million people worldwide has long been debated. A Harvard University study in 2022 showed compelling evidence that the Epstein-Barr virus that causes glandular fever triggers the process. More research is taking place in the hope that one day, MS can be prevented.

As Ailsa's symptoms progressed, she went from using a single stick or crutch for balance, to a walker, and now a wheelchair, trike or mobility scooter for longer distances, such as when walking the family labrador with Rob or the children.

"I think it's important to be really open with the children, so they understand MS and the impact in their own way," she says.

"And obviously the impact changes. When the children were small, they understood that it may mean you can't join in the mums' race at school, or you might have to do it on your trike. And as the children grow older, they might have to help push my wheelchair when I take them shopping."

In February 2022, Ailsa was given the unwelcome news that she had gone from having relapsing-remitting MS, in which symptoms often improve after a relapse, to having secondary progressive MS, when symptoms no longer clear up after years of cumulative nerve damage.

About 130,000 people in the UK live with MS, and of those, tens of thousands - like Ailsa and me - live with a progressive form of the disease.

Under the current National Institute for Health and Care Excellence guidelines, only two drugs - Siponimod and Extavia - are approved for secondary progressive MS, and not everyone will qualify for them.

Ailsa discovered this spring that she does not meet the criteria for Siponimod.

"That was a new thing to deal with, because facing progressive MS feels quite different when you run out of disease-modifying drug options. It means that your life has changed in quite significant ways."

'Ability to revolutionise treatment'

Dr Emma Gray, assistant director of research at the MS Society, says the Octopus trial should significantly speed up how quickly treatments can be tested.

"We wanted the trial to be as inclusive as we could, including people up to the age of 70 and those who can't walk, because we often hear from people with more advanced MS that they can't access other studies. My hope is that with Octopus, we have created a world-first platform trial that has the ability to revolutionise the treatment of people with progressive forms of MS - and that this really does change the landscape for MS for good."

For people like Ailsa - and me - with more advanced MS, this trial does offer hope.

I am currently on the same hospital's MS-STAT2 simvastatin trial, testing whether a high-dose statin can limit brain atrophy in MS. That trial is now drawing to a close.

If such repurposed drugs are shown to be effective, that could help thousands of people with progressive MS who otherwise risk being told there is nothing more their doctor can do.

Selma Blair: 'Multiple sclerosis took my career down'

'it changed my whole life plan' - nielsen on ms relapse.

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• Published: 13 January 2023

Neurodegenerative disease

A neural stem-cell treatment for progressive multiple sclerosis

• Valentina Fossati   ORCID: orcid.org/0000-0003-1825-9371 1 ,
• Luca Peruzzotti-Jametti   ORCID: orcid.org/0000-0002-9396-5607 2 &
• Stefano Pluchino   ORCID: orcid.org/0000-0002-6267-9472 2  

Nature Medicine volume  29 ,  pages 27–28 ( 2023 ) Cite this article

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• Multiple sclerosis
• Stem cells in the nervous system

A phase 1 trial using an allogeneic stem-cell-based therapy in people with progressive multiple sclerosis (MS) shows the feasibility and tolerability of the approach; rigorous evaluation of this and other regenerative strategies for MS is now urgently needed.

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Fossati, V., Peruzzotti-Jametti, L. & Pluchino, S. A neural stem-cell treatment for progressive multiple sclerosis. Nat Med 29 , 27–28 (2023). https://doi.org/10.1038/s41591-022-02164-9

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Is a Cure for MS on the Horizon?

• New Treatments
• FDA Approvals
• Latest Research

Lifestyle Changes

Frequently asked questions.

There is not yet a cure for multiple sclerosis (MS) , and the condition isn't fully understood. But there have been significant advancements in treatment , some of which successfully slow the progression of the disease in many people.

Several new medications have been approved in recent years that slow the course of the disease and reduce symptoms and relapses. Other potential treatments are in trials, including stem cell therapies. And researchers are making progress in understanding the risk factors and causes of MS.

Read on to find out more about the latest research on MS, including the efforts to find a cure for the condition.

sinology / Getty Images

Latest Treatments

Experimental therapies are being explored, as MS treatments and various clinical trials have shown promise. One medication, ibudilast, completed a phase 2 clinical trial in 2018 that showed it can slow the progression of the disease.

Ibudilast is an anti-inflammatory medication that works by reducing inflammation in the body and decreasing the action of a specific enzyme known as phosphodiesterase. Phosphodiesterase breaks down certain organic molecules and, in the process, relaxes muscles and enhances blood flow.

Studies found that while not able to prevent the development of new MS lesions, ibudilast was able to reduce brain atrophy over time compared to a placebo.

The medication can also inhibit certain actions of the immune system that are believed to be behind the nerve cell damage that occurs in the brains of people with MS.

There have also been recent advancements in the use of stem cell therapy for MS. Stem cells are the cells that all other cells in the body are generated from. These cells help the body essentially repair itself.

In 2020, a clinical trial followed patients for one year. In that time:

• About 60% of the patients treated with intrathecal (injected into their spinal fluid) mesenchymal stem cell therapy had no evidence of disease.
• About 40% of the patients treated with intravenous (given in a vein) mesenchymal stem cell therapy had no evidence of disease.
• About 10% of patients in the control group (that did not get a real treatment) had no evidence of disease.

New FDA Approvals

One of the main treatments used to help manage the symptoms and progression of MS is disease-modifying therapies (DMTs). These medications are designed to change the course of MS progression, which ultimately helps reduce its symptoms.

Several new DMT therapies have been approved by the Food and Drug Administration (FDA) to treat and manage MS, including:

• Fingolimod (Gilenya) : First used to treat MS in adults, Gilenya became the first DMT therapy approved by the FDA for use in children with pediatric MS in 2018.  
• Diroximel fumarate (Vumerity) : This medication is similar to an older type of DMT known as Tecfidera. It was approved for use in 2019 after it was shown to possess the same medicinal benefits with fewer side effects.
• Ozanimod (Zeposia) : This medication has been approved to treat three types of MS: clinically isolated syndrome, relapsing-remitting MS , and active secondary progression MS . It received FDA approval in March 2020.
• Ofatumumab, Novartis (Kesimpta) : This injectable medication was approved in 2020 after it demonstrated the ability to reduce MS symptom relapses more effectively than previously used DMTs. It was also shown to reduce disease activity in the brains of people with MS, as seen with scans taken by an MRI machine.
• Ponesimod (Ponvory) : In March 2021, the FDA approved this medication after it was shown to help reduce MS symptom relapses by more than 30%.

Two other oral DMTs were approved in 2019: siponimod (Mayzent) and cladribine (Mavenclad). Both of these treatments were shown to reduce the relapse rate of people with MS.

Cladribine was the first oral medication approved for use as a short-course oral DMT, which means that it is taken for a shorter duration of time. Specifically, people with MS take cladribine in two short-term courses that are one year apart.

Recent Research

Another type of stem cell therapy that is being investigated for MS is called hematopoietic stem cell transplantation (AHSCT). The main goal of this type of therapy is to reset the immune system by using chemotherapy to get rid of harmful immune cells that are causing damage and replace them with healthy immune cells (that were harvested prior to chemotherapy) that can reconstitute the immune system.

This method of treating MS is being explored in clinical trials.

BEAT-MS Trial

The study is referred to as BEAT-MS, and the participants chosen for the trial will be assigned a specific treatment plan—either AHSCT or another effective treatment called best available therapy (BAT). Once the study begins, each participant will be treated and monitored for six years.

Risk Factors

Research on the risk factors associated with the development of the disease is also underway. While some risk factors are known, others have yet to be discovered.

Some unproven theories that medical researchers have theorized might play a role in the onset of MS include:

• Environmental allergies
• Exposure to house pets
• Heavy metal toxicity
• Exposure to organic chemicals

Viruses and MS

According to the National Multiple Sclerosis Society, researchers are also looking at the possible role of viruses in a person’s risk of developing MS. Several viruses are being investigated, including:

• Epstein-Barr virus
• Human herpes virus 6
• Varicella-zoster virus
• Cytomegalovirus
• John Cunningham virus
• Human endogenous retroviruses

Sex Differences

Research has shown that women are more likely than men to develop MS. However, studies have also found that the type of MS that is more common also varies between the sexes.

While women are more at risk for the disease overall, men are more often diagnosed with a specific type of MS known as primary progressive MS. Men with MS are also more likely to experience a faster disease progression and cognitive impairment than women.  

Finding out why these sex-related disparities exist would help medical researchers develop an optimal treatment for everyone with MS.

Genetic Research

Genetics may play a role in why some people develop MS but others do not. The role of genetic variants in MS is another key research area. A study published in 2018 added four new genes to the more than 200 genetic variants already associated with MS.

Genetic Research and MS

Understanding which genes might increase a person’s risk of developing MS would give medical researchers the information they need to create clinical tools that could help providers treat and possibly prevent MS.

Research has shown that there are several lifestyle factors associated with developing MS. For example, smoking cigarettes, being overweight as a child, and having low levels of vitamin D have all been identified as potential triggers for the disease.

Understanding how other lifestyle influences might affect MS risk could assist researchers in identifying new ways to treat and prevent the disease.

Diet and Gut Health

Diet and chronic disease often go hand in hand. “Gut microbiome” is the term used to describe the collection of living organisms that inhabit the intestines.

The gut microbiome has been a main area of interest for MS researchers. Studies have found that there might be a connection between the state of a person’s gut microbiome and their risk for developing MS.

A study published in 2020 showed that the diversity of the organisms in the guts of people with MS and people without MS were not significantly different. However, there were marked dissimilarities which the researchers said mean that a more long-term and extensive review of MS and the gut microbiome’s possible role in its development is needed.

MS treatments and management techniques have come a long way. The latest advancements in DMTs have given people with MS more options than ever, some providing even fewer side effects than older treatments.

Aside from oral and injectable DMTs—typically the first-line therapies for MS—other experimental treatments such as stem cell therapy have been showing great promise in helping people with MS manage the disease.

The more educated medical researchers become about the potential genetic risk factors and lifestyle choices that may play a role in the development of MS, as well as what causes the disease in the first place, the more equipped they will be to find better treatments.

A Word From Verywell 

As of yet, no cure for MS has been found. However, the major advancements in treatments and the new information that has been learned about the potential causes and risk factors are showing great promise at helping slow or completely halt disease progression in people who do develop MS.

For people with MS experiencing disease progression and worsening of symptoms, the latest FDA-approved treatments might help reduce relapses, which in turn can improve their quality of life.

It’s hard to give an exact timeline for when scientists will find a cure for MS, but new treatments and potential causes (like genetic links) are being explored right now.

Research on MS is exciting and covers a lot of ground. New medications and experimental treatments such as stem cell therapy are being thoroughly investigated. Researchers are also looking at why the disease develops in the first place, which could help them find a way to prevent it.

There is no way to completely halt MS progression, but there are treatments that have been shown to significantly slow it. A type of stem cell therapy known as mesenchymal stem cell therapy is getting close to becoming a treatment that could completely halt MS progression, but more research is needed.

Fox RJ, Coffey CS, Conwit R, et al. Phase 2 trial of ibudilast in progressive multiple sclerosis . N Engl J Med. 2018;379(9):846-855. doi:10.1056/NEJMoa1803583

Petrou P, Kassis I, Levin N, et al. Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis . Brain. 2020;143(12):3574-3588. doi:10.1093/brain/awaa333

Food and Drug Administration. FDA expands approval of Gilenya to treat multiple sclerosis in pediatric patients .

National Multiple Sclerosis Society. FDA approves oral Vumerity™️ (diroximel, fumarate), similar to Tecfidera®, for relapsing MS .

National Multiple Sclerosis Society. UPDATE: FDA-approved oral Zeposia® (ozanimod) for relapsing forms of MS now available for prescription .

National Multiple Sclerosis Society. FDA approves Kesimpta® (ofatumumab), similar to Ocrevus®, for relapsing MS .

Kappos L, Fox RJ, Burcklen M, et al. Ponesimod compared with teriflunomide in patients with relapsing multiple sclerosis in the active-comparator phase 3 OPTIMUM study: a randomized clinical trial . JAMA Neurol. 2021;78(5):558-567. doi:10.1001/jamaneurol.2021.0405

Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study . Lancet. 2018;391(10127):1263-1273. doi:10.1016/S0140-6736(18)30475-6

Deeks ED. Cladribine tablets: a review in relapsing MS . CNS Drugs. 2018;32(8):785-796. doi:10.1007/s40263-018-0562-0

Immune Tolerance Network. About BEAT-MS .

National Multiple Sclerosis Society. What causes MS?

Tarlinton RE, Martynova E, Rizvanov AA, Khaiboullina S, Verma S. Role of viruses in the pathogenesis of multiple sclerosis . Viruses. 2020;12(6):643. doi:10.3390/v12060643

Eccles A. Delayed diagnosis of multiple sclerosis in males: may account for and dispel common understandings of different MS ‘types’ . Br J Gen Pract. 2019;69(680):148-149. doi:10.3399/bjgp19X701729

Airas L. Hormonal and gender-related immune changes in multiple sclerosis . Acta Neurol Scand. 2015;132(199):62-70. doi:10.1111/ane.12433

International Multiple Sclerosis Genetics Consortium. Low-frequency and rare-coding variation contributes to multiple sclerosis risk . Cell. 2018;175(6):1679-1687.e7. doi:10.1016/j.cell.2018.09.049

Jakimovski D, Guan Y, Ramanathan M, et al. Lifestyle-based modifiable risk factors in multiple sclerosis: review of experimental and clinical findings . Neurodegener Dis Manag. 2019;9(3):149-172. doi:10.2217/nmt-2018-0046

Mirza A, Forbes JD, Zhu F, et al. The multiple sclerosis gut microbiota: a systematic review . Mult Scler Relat Disord. 2020;37:101427. doi:10.1016/j.msard.2019.101427

By Angelica Bottaro Bottaro has a Bachelor of Science in Psychology and an Advanced Diploma in Journalism. She is based in Canada.

Title: Inside the Brain: How New Research Could Revolutionize MS Treatment

This story is a part of our “Ask a Professor” series, in which Georgetown faculty break down complex issues and contribute to trending conversations, from the latest pop culture hits to research breakthroughs and critical global events shaping our world.

A new development in a Georgetown lab could revolutionize the treatment for patients with late-stage multiple sclerosis and slow the progression of the disease.

Jeffrey Huang , a provost’s distinguished associate professor in the College of Arts & Sciences’ Department of Biology , and his team have developed a novel drug application that reversed the effects of late-stage MS in mice. The drug is now being planned for a clinical trial on people with MS. 

“Our team is ecstatic to move to clinical trials,” said Huang, who is also the deputy director of the Center  for Cell Reprogramming . “Based on our success in animal trials, we believe our drug will help stabilize patients with the disease, reducing not only the number of relapses, but their severity as well.”

The Mechanics of Multiple Sclerosis

Multiple sclerosis, often abbreviated to MS, is an autoimmune disease that affects some 2.8 million people worldwide. MS causes the body to attack the protective coverings that surround nerve cells in the brain, called myelin.

“Myelin is like the insulation around copper wires, which are your nerves,” explained Huang. “In order for nerve cells to communicate, they rely on myelin. If there’s any damage to that insulation then that high-speed communication is severely impaired.”

As inflammation destroys myelin in the brain and spine and interrupts nerve-cell communication, patients can experience a litany of adverse health effects, including muscle spasms, loss of balance and ambulatory dysfunction. Typically, when myelin is damaged, the body is able to regenerate that protective layer fairly quickly. 

“In the initial stages of MS, the body is still able to remyelinate after a flare-up, but those natural repair systems stop functioning as effectively after someone has been living with MS for a significant amount of time,” said Huang.  

This new approach is distinct from available therapies for patients with MS. Current drugs on the market target the immune cells in the blood, primarily B cells and T cells, rather than those in the brain. And those drugs drop in efficiency as the disease progresses. Huang is applying an existing drug to MG for the first time, which he believes will be a game changer. 

A Novel Therapy for Myelin Regeneration

Huang’s approach to myelin regeneration begins by looking at the root mechanics of remyelination. That process starts with the resident immune cells in the brain and spine called microglia. Microglia are like an all-star pit crew for the brain: They clean up damage after it occurs and ensure the brain is ready to keep racing. In late-stage MS, microglia become inflamed and aggressive and have trouble communicating with the cells that spur remyelination. 

“Following injury, these cells go from Bruce Banner to The Incredible Hulk, and continue to cause damage to myelin and nerve fibers in the brain and spinal cord,” said Huang. “Our drug is able to reverse its phenotype back into Bruce Banner, who can return to doing nice things in the brain.”

Huang and his team’s revolutionary method turns microglia back into its healthy, homeostatic state – and it’s already seen success.

They successfully achieved remyelination in animals such as mice by stimulating the microglia, which then starts a chain reaction in the brain and spinal cord that MS impedes. For people with late-state MS, then, this drug could revolutionize their treatment, giving patients more healthy years with increased independence. 

The next steps are clinical trials in humans, which will be conducted by a pharmaceutical company working alongside the Huang team. In addition to the Huang lab , Georgetown is also home to the Center for Brain Plasticity and Recovery and   Center for Neural Injury and Recovery , which studies neural plasticity, injury and recovery. 

“The goal is to be able to stop the disease from progressing using our drug,” said Huang. 

Ask a Professor

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What’s New in MS Research – September 2023

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

In this Article

For first time, ms therapies included on who list of essential medicines.

In another first, the FDA approves 
a biosimilar for relapsing forms of MS

Phase I study looks at ANK-700, an experimental “inverse vaccine” for MS

Ibudilast shows favorable effect on measure linked to disability progression in progressive ms, encouraging news on ocrevus ® for people with primary-progressive ms.

Aubagio ® Cuts risk of first demyelinating event in people with radiologically isolated syndrome

Multi-protein blood test offers insights into MS disease activity

Predicting non-relapsing progression following anti-cd20 therapy for ms, study shows no link between vaccination and hospitalization for ms flare-ups, pinpointing a way to relieve fatigue in ms study shows short-term benefits of acupuncture, cannabinoid-based mouth spray relieves ms spasticity in two trials, for more information.

This edition of “What’s New in MS Research” opens with a pair of “firsts:” the first listing of multiple sclerosis (MS) therapies on the World Health Organization’s List of Essential Medicines and the first United States Food and Drug Administration (FDA) approval of a biosimilar therapy for the long-term treatment of MS.

Those developments reflect an increasing awareness among public health officials internationally and in the United States that it is critical for people with MS to have access to the therapies that can make a real difference in their lives.

The other items in this iteration of “What’s New in MS Research” highlight the many avenues of inquiry researchers are pursuing to develop, assess, and optimally employ disease-modifying therapies (DMTs), other MS-focused treatments, and additional interventions to promote the overall health and well-being of people living with multiple sclerosis.

The World Health Organization (WHO) in July 2023 added three disease-modifying therapies (DMTs) for multiple sclerosis to its list of “Essential Medicines,” marking the first time that MS treatments have been included on the roster. 1

The DMTs added to the list are Mavenclad ® (cladribine); glatiramer acetate, which is marketed as Copaxone ® and in a generic formulation; and rituximab, which is marketed in the United States as Rituxan ® . While Rituxan has many FDA-approved uses in cancer and other conditions, it is not approved in the United States for the treatment of MS.

The WHO said that it chose those medications for its list because all three have been shown to delay or prevent progression of MS and because they have different routes of administration, prices, and roles in treating the disease. Mavenclad is provided as tablets taken by mouth, while glatiramer acetate is given by injection, and rituximab is administered by intravenous infusion. In a press release, the organization explained that adding MS therapies to its list “is aimed at facilitating improved access to treatment for people living with MS around the world. The decision to support off-label use of ritixumab is supported by strong evidence of its efficacy and safety for this indication.”

The MS Coalition (MSC), a network of nine member organizations that include MSAA, applauds the WHO’s inclusion of MS disease-modifying treatments (DMTs) on the Essential Medicines List (EML) as part of its commitment to brain health. As the MSC notes, “This decision is an important step to increasing worldwide access to life-changing medications. Affordable access to DMTs is essential for all people with MS and aligns with the Coalition’s mission to improve the quality of life for those affected by MS. While there are far more DMTs available in some parts of the world, the inclusion of these DMTs on the EML list represents a giant step forward towards equitable access around the world.”

In addition, MSAA would like to recognize the MS International Federation (MSIF) for their vital role in advocating for this urgently needed inclusion of MS disease-modifying treatments (DMTs) on the WHO Essential Medicines List. Headquartered in London, the MSIF is a unique global network of 48 MS organizations as well as members of the MS community – including people with MS, volunteers, and staff in many countries. In collaboration with other health groups, the MSIF applied for the inclusion of MS medications in December 2022, following several years of work toward this goal by experts from around the world.

Beyond the specific therapies the WHO chose to place on the list, this first-ever inclusion of DMTs represents an important precedent for MS medications as a whole and recognition of the need to provide people with MS with ready access to therapies.

In another first, the FDA approves a biosimilar for relapsing forms of MS

In August 2023 the Food and Drug Administration (FDA) approved Tyruko ® (natalizumab-sztn), making that medication the first biosimilar to be approved for the long-term treatment of MS. 2

Marketed by Sandoz, Tyruko is a biosimilar to Tysabri ® (natalizumab), a disease-modifying therapy for MS that was approved in 2004 and is given via IV infusion every four weeks. The advantages of having generic, biologic, and biosimilar products available often include greater accessibility to the medication, potential savings, and continued product development through competition.

According to the FDA, “Biological products include medications for treating many serious illnesses and chronic health conditions, including MS. A biosimilar is a biological product that is highly similar to, and has no clinically meaningful differences from, a biological product already approved by the FDA (also called the reference product). This means patients can expect the same safety and effectiveness from the biosimilar as they would the reference product.”

As with Tysabri, Tyruko is approved to treat relapsing forms of MS, which include clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and active secondary-progressive MS (SPMS). Because it is a biosimilar, Tyruko is given at the same dosage and via the same administration as Tysabri, while also carrying the same benefits and risks.

Tysabri’s benefits – when compared to placebo over a two-year period – include a 67% decrease in the number of relapses, a 92% reduction in lesions, and a reduction in disability progression (42% reduction over three months and 54% reduction over six months). Common side effects include headache and fatigue, infections such as upper respiratory tract infection (URTI) and urinary tract infection (UTI), as well as infusion reactions.

Tysabri is a monoclonal antibody that acts against a molecule involved in the activation and function of lymphocytes, which are immune system cells produced to fight infection and disease. It also acts against the passage of lymphocytes into the central nervous system (CNS). Tysabri increases the risk of progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal brain infection caused by the JC virus. Given that natalizumab products increase the risk of PML, all such medications are required to have dedicated Risk Evaluation and Mitigation Strategy (REMS) programs.

With MS, the immune system becomes misdirected and attacks the myelin and the nerves of the central nervous system (CNS). Following successful results in a study of mouse models with experimental autoimmune encephalitis (EAE), an induced illness that causes MS-like symptoms and damage, ANK-700 is currently being tested in humans for safety. This experimental treatment is often referred to as an “inverse vaccine,” which means that rather than train the immune system to attack specific targets such as those that cause infection, ANK-700 is designed to train the immune system to be tolerant of specific targets: in this case, the body’s own myelin.

With regard to the mouse models, researchers found that both for those with a relapsing form of EAE or a progressive form, a research candidate with the same type of “inverse vaccine” design was able to stop the immune system’s attack on myelin. The nerves of the treated mice were able to regain function and the MS-like symptoms were reversed.

According to an article published online by Multiple Sclerosis News Today, “Scientists previously discovered immune tolerance against a target could be achieved by tagging the target with a sugar molecule called N-acetylgalactosamine or pGal. This molecule prompts the target to be taken up by regulatory immune cells that activate tolerance processes in other immune cells.” 3

A press release from the University of Chicago’s Pritzker School of Molecular Engineering (PME) explains that this new type of vaccine developed by their researchers “has shown in the lab setting that it can completely reverse autoimmune diseases like multiple sclerosis and type 1 diabetes — all without shutting down the rest of the immune system.” 4

Readers should note that initially, many experimental treatments for MS show positive results in animal studies, but only a small fraction of these treatments advance to human studies and ultimately show both safety and efficacy. While ANK-700 still has a long road of studies ahead to see how it may affect disease activity in individuals with MS, these types of experimental treatments are exciting to hear about and provide much hope for the future. This study was funded by ANK-700’s developer, Anokion, and details were published on September 7, 2023 in Nature Biomedical Engineering. 5

The anti-inflammatory medication ibudilast preserved the integrity of brain tissue in people with progressive forms of MS in a Phase II clinical trial, researchers reported. 6

Ibudilast is an oral medication used to treat asthma in Japan and South Korea. The biopharmaceutical company MediciNova is evaluating the therapy for potential roles in progressive forms of MS, amyotrophic lateral sclerosis (ALS), and other conditions.

Researchers analyzed data from the SPRINT-MS trial to evaluate the impact of ibudilast on tissue integrity and volume in the thalamus, a small, grey matter structure of the brain that relays motor and sensory signals to other regions of the brain.

In the trial, 255 people with progressive MS were assigned in a random fashion to receive either ibudilast or placebo. Investigators then used magnetic resonance imaging (MRI) to assess the thalamic magnetization transfer ratio (MTR), which is a measure of tissue integrity and demyelination, and thalamic volume (TV) over 96 weeks.

Relative to placebo, ibudilast had a more favorable impact on thalamic MTR. Noting that thalamic MTR is associated with confirmed disability progression, the researchers said that this finding suggested “a clinically relevant effect on thalamic tissue integrity.” However, ibudilast was not shown to have an effect on thalamic volume, which the investigators said suggested “that thalamic atrophy is more closely associated with global inflammatory activity than local tissue integrity.”

The findings follow publication of the SPRINT-MS trial’s main results in The New England Journal of Medicine in 2018. 7 The study found that, relative to placebo, ibudilast cut the rate of brain atrophy – the trial’s primary endpoint – roughly in half over 96 weeks. This latest analysis builds on that welcome news and provides further hope that the years ahead will see an expansion of the treatment choices available for people with primary-progressive and secondary-progressive MS.

In 2017, Ocrevus ® (ocrelizumab) became the first disease-modifying therapy approved by the Food and Drug Administration (FDA) for the treatment of primary-progressive multiple sclerosis (PPMS). The FDA’s approval was based on the results of the Phase III ORATORIO trial, which found that people with PPMS who received Ocrevus had lower rates of disease progression than study participants who received placebo. 8

The approval represented a great advance for people with PPMS (while several investigational medications currently are being evaluated in PPMS, Ocrevus remains the only FDA-approved therapy for the condition). However, ORATORIO limited its assessment of Ocrevus in people with PPMS to those who were 18 to 55 years of age, who had an Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5, and who met other requirements. Because of those criteria, patients and clinicians have not had data on the efficacy and safety of the medication in people older or younger than the study population or in those with an EDSS score lower or higher than the range included in the trial. (The EDSS runs from 0 to 10, with a higher score indicating greater disability.)

A group of Italian researchers recently helped fill in that evidence gap by conducting a retrospective study that compared outcomes in people with PPMS who did, and did not, meet the age and EDSS criteria used in ORATORIO. 9 The study focused on 589 people who were treated with Ocrevus between May 2017 and June 2022. Of the total, 149 met the ORATORIO criteria and 440 did not.

The researchers found that people in both groups had a similar probability of experiencing clinical progression over time. For example, the cumulative probability of clinical worsening by two points or more on the EDSS scale over 12 months was 3.4% in both groups. Over 24 months, that probability was 5.4% in the ORATORIO group and 5.0% in the non-ORATORIO group. Interestingly, no significant differences in 12-month and 24-month clinically worsening were noted based on baseline EDSS score. People aged 56 to 65 years fared similarly to those aged 18 to 55 in terms of clinical status, but those aged 66 years and older were more likely than the ORATORIO group to experience clinical worsening over one or two years. Of course, this finding could reflect the interplay between the MS disease process and aging. Meanwhile, having had PPMS for more than 10 to 15 years did not appear to limit the impact of Ocrevus.

One of the key strategies in the fight against MS has been to determine the effectiveness and safety profile of a medication in a specific group of people and then explore whether that therapy also has a role in treating a broader population. This study by Italian researchers is both a classic example of that strategy succeeding and heartening news to many people living with PPMS.

The researchers studied 35 patients to explore how unmet needs, quality of life, and depression in older people with MS and in people with advanced MS differed from those of younger people with MS who were fully independent. Twenty-one people participating in the study were aged 64 or younger and did not require assistance with daily activities. These people served as the control group against which older people and those with an Expanded Disability Status Scale score of 7 or higher, indicating advanced MS, were compared.

While researchers noted that the better mental QoL among older people with MS relative to younger people was surprising, they did not offer potential explanations for the finding. They did say, however, that they plan to conduct future studies to look deeper into these results and to better understand the needs of older people with MS and people with advanced MS.

Aubagio ® cuts risk of first demyelinating event in people with radiologically isolated syndrome

People with radiologically isolated syndrome (RIS) who took the disease-modifying therapy Aubagio ® (teriflunomide) saw their risk for a first clinical demyelinating event reduced by 72% relative to people with RIS who received placebo in a 96-week study. 10

The phase III randomized clinical trial was conducted from September 2017 to October 2019 at MS referral centers in France, Switzerland, and Turkey. The study involved 89 people, all of whom met the criteria for RIS, which the study’s authors noted is the earliest detectable preclinical phase of MS.

A person is classified as having RIS when magnetic resonance imaging (MRI) scans find white matter abnormalities consistent with MS in the brain or spinal cord even though the person has no clinical signs or symptoms of the disease. RIS often is identified when a person has an MRI for another reason, such as to evaluate the brain after a car accident or fall. Epidemiological studies indicate that as many as half of people with RIS will go on to be diagnosed with clinically definite MS over the following 10 years.

The study’s participants had an average age of 37.8 years. Seventy-one percent were female. Forty-five of the participants received 14 mg daily of Aubagio while the other 44 participants received a placebo. Nine people in each group stopped participating in the study for reasons that included adverse events, withdrawal of consent, lack of follow-up information, and pregnancy.

Researchers found that the unadjusted risk for a first clinical event in people receiving Aubagio was 63% lower than the risk for people in the placebo group. After adjusting for differences in the two groups in accord with standard statistical protocols, the people receiving Aubagio had a 72% lower risk relative to the placebo group.

The safety profile of Aubagio in the study was consistent with that seen in earlier studies of the oral DMT, which is approved by the FDA for treatment of relapsing forms of MS.

Learning that an MRI scan obtained for an unrelated reason shows evidence of a potential precursor to MS is disturbing enough, but the anxiety can be compounded by the fact that there currently is no FDA-approved therapy for RIS. This study, and others evaluating different DMTs for their potential use in RIS, provides hope that people diagnosed with the syndrome may have effective, evidence-based treatment options in the future.

Clinicians may one day be able to use a multi-protein blood test to assess disease activity in a person with MS, including determining the likelihood of active inflammation in central nervous system lesions.

A team of researchers recently reported on their assessment of the MS Disease Activity (MSDA) test, which analyzes 18 proteins found in the blood. 11 The researchers drew on blood samples, imaging results, and clinical data from 426 people with MS to develop an algorithm and establish performance specifications for the test.

The researchers then evaluated the test and its algorithm in a separate group of 188 people with MS. As part of that process, they compared the MSDA with the single-protein biomarker that they found to have the highest performance for different disease activity endpoints. Blood levels of that protein, neurofilament light chain (NfL), have been shown in a number of studies to help predict disease course in MS. (See related item below, “Predicting non-relapsing progression following anti-CD20 therapy for MS.”)

In “testing the test,” the investigators found that MSDA scores aligned well with overall disease activity and the presence of gadolinium-enhancing lesions on magnetic resonance imaging. (Gadolinium enhancement typically signifies inflammatory activity within an MS lesion.) For example, the odds of having one or more gadolinium-enhancing with a moderate/high disease activity (DA) score were 4.49 times those of a low DA score, the investigators reported. Further, the odds of having two or more such lesions with a high DA score were 21 times those of a low/moderate score. The researchers noted that the MSDA outperformed NfL in terms of identifying active versus stable MS as defined by a mix of imaging and clinical evidence.

The investigators wrote, “With the successful clinical validation of the MSDA Test, we envision several potential uses in the future, including a routine surveillance test to better monitor disease activity and progression (e.g., distinguish inflammation from silent disease progression), especially in patients considered to have stable disease, and to track new/worsening symptoms, as well as an evaluation test of treatment response, or in consideration of alternative treatment options.”

The MSDA is not yet available for use in clinical practice. The researchers noted that it would be valuable to further evaluate the test in a larger population and in a real-world setting. There also will be regulatory requirements to address, and payers must agree to provide reimbursement for the test. Nonetheless, the ability to draw on multiple proteins in the blood to assess various aspects of MS disease activity represents a major advance in the effort to evaluate and manage multiple sclerosis in a comprehensive manner.

No news is not always good news when it comes to MS. That’s because disease progression can occur even in the absence of an obvious relapse or less-dramatic evidence of clinical worsening, making it difficult for clinicians and patients to know if a therapy is working or if a new approach may be warranted.

Now, however, researchers analyzing data from studies that led to the FDA’s approval of Ocrevus ® (ocrelizumab) for relapsing and progressive forms of MS have found that blood levels of neurofilament light chain (NfL) can help predict non-relapsing progression following treatment with that therapy, which targets the CD20 protein on the surface of B cells. 12

NfL is a protein found in axons, the segment of a neuron that carries electrical impulses away from the main portion of the nerve cell, facilitating transmission of those impulses from one neuron to another. When axons coated with myelin are injured, they release NfL into the cerebrospinal fluid. From there, the protein enters the blood stream. Most research on NfL has examined its role as a marker of acute events, such as relapses. In this study, however, investigators wanted to see whether NfL levels also could provide insights into more-subtle changes in MS course. They explained, “We used ocrelizumab’s ability to robustly suppress acute disease activity as an opportunity to assess the utility of NfL for monitoring risk for relapse-independent clinical progression following treatment initiation.”

The researchers analyzed baseline and subsequent blood levels of NfL in 1,421 people with relapsing MS and in 596 people with primary-progressive MS, evaluating more than 11,800 blood samples and following patients for as long as nine years.

And what did they find? Researchers found that long-term disability progression can still occur in the absence of observable disease activity, i.e., a relapse or clinical worsening, and elevated blood levels of NfL may predict the risk of such progression. In this study, after administration of Ocrevus, which suppressed relapse activity, patients who had persistently elevated levels of serum NfL at Week 24 and Week 48 were at increased risk of long-term disability progression. Researchers said this heightened risk was seen in both people with relapsing MS and those with primary-progressive MS.

The investigators concluded, “Suppression of relapsing biology with high-efficacy immunotherapy provides a window into the relationship between NfL levels and future non-relapsing progression.” This window can offer an important perspective not only on the management of individual patients but also into strategies for drug development.

People with MS who received one of several different types of vaccines were no more likely to be hospitalized for an MS flare-up in the 60 days after they were vaccinated than they were in the 60 days – or longer – before vaccination.

That was the main finding of a French study that examined records on more than 100,000 people with MS to investigate the common – but not scientifically supported – concern that vaccination may trigger MS flare-ups. 13

Researchers analyzed an average of 8.8 years’ worth of data on the study subjects, 71.8% of whom were female. The people included in the analysis had an average age of 43.9 years. Roughly two-thirds had been diagnosed with MS for at least two years. Seventy percent had used at least one disease-modifying therapy.

Vaccines analyzed in the study included those for influenza, pneumococcal diseases, and diphtheria, tetanus, poliomyelitis, pertussis, and Haemophilus influenzae (the DTPPHi vaccine). All of the vaccines were inactivated, meaning that they did not contain live viral or bacterial material. Vaccines against COVID-19 were not included in the analysis because the period studied ran from January 2007 to December 2017, ending roughly two years before the coronavirus outbreak.

Of the 106,523 people studied, 35,265 – or one-third – were hospitalized for an MS flare-up on at least one occasion over the average 8+ years for which data was available on them. The adjusted odds ratio (aOR) of being hospitalized for an MS flare-up in the 60 days after receiving any one of the vaccines studied was 1.00. This means that a person was no more and no less likely to be hospitalized for an MS flare-up in the 60 days after vaccination than in the comparable period prior to vaccination. (By comparison, an aOR of 1.5 would represent a 50% increase in likelihood of hospitalization and a 2.0 aOR would represent a doubling of risk.)

Turning to specific vaccines, the aOR was 0.95 for the DTPPHi vaccine, 0.98 for the influenza vaccine, and 1.20 for the pneumococcal vaccine, which acts against the bacterium Streptococcus pneumoniae, and which can help prevent some cases of pneumonia, meningitis, and sepsis.

The investigators explained that, to their knowledge, their study is the most extensive research conducted to date on the risk of being hospitalized for an MS flare-up following vaccination. They added that examining this topic is essential because infections are known to increase the risk of MS flare-ups and to exacerbate symptoms, making it imperative that people with MS take steps – such as vaccination – to avoid infection. Further, they noted that “a possible association between vaccination and the onset of MS is the source of a decade-long debate,” adding that the inconclusive evidence and ongoing debate over that separate question “has spurred doubts and potentially detrimental vaccination hesitancy” among people who already have MS.

The researchers added that the strengths of their study included the large number of people in the analysis and the long follow-up period. Despite its size, however, the researchers noted that, “The study cannot completely rule out the existence of a small risk, particularly in the case of the pneumococcal vaccine.” They added, “considering the number of vaccine subtypes available, further studies are needed to confirm these observed results.”

While offering those important caveats, the researchers summed up their findings by noting, “We did not observe an association between the risk of hospitalization for an MS flare-up and vaccination, considered overall or individually, regardless of the age group studied.”

Guidelines from medical societies and multiple sclerosis advocacy organizations identify administration of inactivated vaccines as a key means of protecting the health of people with MS. The guidelines note that an individual should not receive a specific vaccine if he or she has a contraindication to it, and caution against giving vaccines while a person is experiencing an active flare-up of their MS.

With “flu” season fast approaching and an uptick in COVID-19 cases, it is important for people with MS to talk with their clinicians about which vaccines may be appropriate for them and about the risks and benefits associated with each vaccine. This large study hopefully will help to inform that discussion and provide some reassurance in terms of vaccination risk, which, of course, must be balanced against the risk that comes from not being vaccinated.

Four weeks of acupuncture significantly relieved fatigue in an international study of 60 people with relapsing-remitting MS. 14

All of the study participants reported fatigue, were not experiencing an MS exacerbation during the trial, and were given the medication amantadine. (In the United States, amantadine is approved by the FDA to prevent and treat influenza, to treat Parkinson’s disease and related conditions, and to treat movement problems that occur as side effects of certain medications. In other countries it also is used to treat MS-related fatigue, and some clinicians in the U.S. prescribe it “off-label” for that purpose.)

The study subjects were randomized into two groups of 30 people each. People in the first group received acupuncture treatment two to three times a week for a total of 10 sessions over four weeks. They also received 100 mg of amantadine daily, as well as whichever disease-modifying therapy (DMT) they were taking, if any. People in the other group took daily amantadine plus any DMT that had been prescribed for them. The study’s primary endpoint was change from baseline in the Fatigue Severity Score (FSS). The secondary endpoint was change from baseline in the Multiple Sclerosis Quality of Life 54 (MSQOL-54) questionnaire score.

Both groups saw their fatigue reduced over the course of the four-week study, but people in the acupuncture group had a greater reduction in fatigue than their counterparts in the control group. They also had greater improvement in their quality of life, including in both physical and mental status, than those in the control group. All of those differences were statistically significant. No adverse events were reported in either group.

In keeping with the adage that “everything old is new again,” the ancient practice of acupuncture – administered by properly trained and licensed personnel – may offer new hope to the estimated two-thirds of people with MS who experience fatigue.

People experiencing MS-related spasticity who made daily use of an oral spray containing cannabinoids experienced significant improvement in several measures of spasticity over 12 weeks, according to researchers. 15

Those investigators analyzed results of two trials of nabiximols, a spray developed as a treatment for MS spasticity that is approved for use in European Union countries and elsewhere in the world, but which is not approved by the Food and Drug Administration for use in the United States. Nabiximols is a botanical mixture that contains delta-9-tetrahydrocannibinol (THC) and cannabidiol (CBD) from cannabis plants, as well as other non-cannabinoid ingredients.

Measures examined included patients’ daily self-reported scores from 0 to 10 on the Spasticity Numeric Rating Scale (NRS), patients’ daily spasm counts, and clinicians’ assessment of their patients’ spasticity using the modified Ashworth scale (MAS).

Both studies had an initial stage, Part A, in which all patients received nabiximols. Those who had a 20% or greater improvement in their Spasticity NRS score in Part A went on to the second stage, Part B, in which half of the people received nabiximols and half did not. Researchers use this two-step approach so they can first identify people who respond to a medication and then go on to study the impact of the medication relative to placebo only in a population of known responders. This can yield more valuable information on a medication than studying the therapy in a larger population in which the percentages of responders and non-responders are unknown at the outset.

In the first study, 124 people were randomly selected to use nabiximols, plus whatever other spasticity medicines or therapies they were receiving, while 117 people were randomized to receive placebo plus their current treatments, if any. The second study was limited to people who had not obtained adequate relief from two prior anti-spasticity medications and who were on current treatment for the condition. In that study, 53 people were randomized to receive nabiximols and 53 were assigned to the placebo group.

In Part B of both studies, participants receiving nabiximols had more favorable changes from baseline in their daily Spasticity NRS scores than their counterparts in the placebo group. Further, patients receiving nabiximols in the first study had a 19% greater reduction in daily spasms than people on placebo, while that difference stood at 35% in the second study. People receiving nabiximols also had better results in terms of change in spasticity as measured by the modified Ashworth scale, with the greatest benefits seen in the leg muscles.

The researchers reported that nabiximols were generally well tolerated by people in both studies. Urinary tract infections were the most frequently reported adverse events, affecting 7% of people receiving nabiximols in the first study. Other issues reported included vertigo, fatigue, nausea, dry mouth, dizziness, and sleepiness, with each condition affecting less than 10% of people receiving nabiximols There were six serious adverse events in the nabiximols group in the first study, while one person in that study’s placebo arm had a serious adverse event. In the second study, one patient in each group had a serious adverse event. In the first study, 7% of people in the nabiximols group stopped participating in the trial due to adverse events; none of the patients in the second study withdrew from the trial because of side effects.

Research has shown that a majority of people with MS are affected by spasticity. Many of those people report receiving insufficient relief from currently available therapies. This analysis of two studies suggests that another approach, not currently available, may someday help address a significant unmet need for people in America living with MS-related muscle spasms and stiffness.

• World Health Organization. WHO endorses landmark public health decisions on essential medicines for multiple sclerosis. July 26, 2023. Available at https://www.who.int/news/item/26-07-2023-who-endorses-landmark-public-health-decisions-on-essential-medicines-for-multiple-sclerosis . Accessed September 15, 2023.
• U.S. Food and Drug Administration (FDA). FDA approves first biosimilar to treat multiple sclerosis. August 24, 2023. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-biosimilar-treat-multiple-sclerosis . Accessed September 15, 2023.
• Tremain, A.C., Wallace, R.P., Lorentz, K.M.  et al.  Synthetically glycosylated antigens for the antigen-specific suppression of established immune responses.  Nat. Biomed. Eng   7 , 1142–1155 (2023). [found at  Synthetically glycosylated antigens for the antigen-specific suppression of established immune responses | Nature Biomedical Engineering ]
• Wexler, M. ‘Inverse vaccine’ approach lowers disease in MS mouse model: ANK-700 is being tested in early MS clinical trials.  Multiple Sclerosis News Today . September 14, 2023. Accessed online September 22, 2023 at  MS disease activity in mice lowered with ‘inverse vaccine’ technique | Multiple Sclerosis News Today
• Williams, SCP. “Inverse vaccine” shows potential to treat multiple sclerosis and other autoimmune diseases.  University of Chicago’s Pritzker School of Molecular Engineering (PME) News . September 11, 2023. Accessed online September 22, 2023 at   “Inverse vaccine” shows potential to treat multiple sclerosis and other autoimmune diseases | Pritzker School of Molecular Engineering | The University of Chicago (uchicago.edu)
• Nakamura K, Zheng Y, Ontandea D, et al. Effect of ibudilast on thalamic magnetization transfer ratio and volume in progressive multiple sclerosis. Mult Scler J . 2023;29(10). doi.org/10.1177/13524585231187289.
• Fox RJ, Coffey CS, Conwit R, et al. Phase 2 trial of ibudilast in progressive multiple sclerosis. N Engl J Med . 2018;379:846-55.
• Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med . 2017; 376:209-220.
• Chisari CG, Bianco A, Brescia Morra V, et al. Effectiveness of ocrelizumab in primary progressive multiple sclerosis: a multicenter, retrospective, realworld study (OPPORTUNITY). Neurotherapeutics . 2023. doi.org/10.1007/s13311-023-01415-y.
• Lebrun-Frenay C, Siva A, Sormani MP, et al. Teriflunomide and time to clinical multiple sclerosis in radiologically isolated syndrome: the TERIS randomized clinical trial. JAMA Neurol . Published online August 21, 2023. doi:10.1001/jamaneurol.2023.2815.
• Chitnis T, Foley J, Ionete C, et al. Clinical validation of a multi-protein, serum-based assay for disease activity assessments in multiple sclerosis. Clin Immunol . 2023;253.109688.
• Bar-Or A, Thanei G-A, Harp C. Blood neurofilament light levels predict non-relapsing progression following anti-CD20 therapy in relapsing and primary progressive multiple sclerosis: findings from the ocrelizumab randomised, double-blind phase 3 clinical trials. EBioMedicine . 2023 Jul;93:104662. doi: 10.1016/j.ebiom.2023.104662.
• Grimaldi L, Papeix C, Hamon Y, et al. Vaccines and the risk of hospitalization for multiple sclerosis flare-ups. JAMA Neurol . Published online September 5, 2023. doi:10.1001/jamaneurol.2023.2968.
• Khodaie F, Moghadasi AN, Kazemi AH, Zhao B. Effectiveness of acupuncture for fatigue in patients with relapsing-remitting multiple sclerosis: a randomized controlled trial. Acupunct Med . 2023;41(4):199-205.
• Nicholas J, Lublin F, Klineova S, et al. Efficacy of nabiximols oromucosal spray on spasticity in people with multiple sclerosis: Treatment effects on Spasticity Numeric Rating Scale, muscle spasm count, and spastic muscle tone in two randomized clinical trials. Mult Scler Relat Disord . 2023;75.104745. doi.org/10.1016/j.msard.2023.104745.

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 [email protected] .

Written by Tom Garry, Medical Writer Reviewed by Dr. Barry Hendin, MSAA Chief Medical Officer Edited by Susan Wells Courtney, MSAA Senior Writer

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Latest Research on MS

Cutting-edge treatments make it possible to live better with multiple sclerosis (MS) than ever before. Researchers constantly learn more about the disease and come up with new ways to fight it. Discoveries today could pave the way for a cure in the future.

MS can affect you from head to toe. It happens when your immune system goes haywire and attacks nerve cells in your brain and spinal cord. This inflames and damages your nerves’ protective coating, called myelin . That means your nerves can’t message each other as they should. It leads to mental and physical problems, and sometimes disability.

Disease-modifying therapies (DMTs) are drugs used to prevent MS from getting worse. The American Academy of Neurology recommends that people start using a DMT soon after diagnosis to protect their myelin. This can:

• Reduce the number of new MS attacks, called relapses
• Delay disability
• Limit new inflammation in your central nervous system (CNS)

What’s New?

The FDA has approved more than a dozen DMTs for MS . New ones are coming out at lightning speed.

The focus of research has shifted in recent years. T cells, a type of cell in your body’s immune system, were long thought to be responsible for MS. But recent studies show that another type of immune cell, called B cells, also play a role in the attack on your myelin. New treatments target these cells.

Ocrelizumab ( Ocrevus ) kills certain B cells in your blood . It’s approved in the United States for all forms of MS. But it's the first drug used specifically to treat the primary progressive type of MS . The National Multiple Sclerosis Society calls ocrelizumab a "game changer." You get it in an IV every 6 months.

Another drug that targets B cells has been approved by the FDA for relapsing MS, the most common type. Ofatumumab is already used to treat some kinds of leukemia . It’s a shot you give yourself once a month.

Researchers compared ofatumumab to teriflunomide ( Aubagio ), a daily pill commonly used for MS. The study found that ofatumumab led to 50% fewer relapses. It also cut the risk of disability getting worse by about 30%. And it reduced the number of new MS lesions (scars).

Other recent treatment highlights include:

• In 2018, fingolimod ( Gilenya ) became the first drug approved to treat relapsing forms of MS in children as young as 10. (It's also used in adults.) Fingolimod is a once-a-day pill. It traps certain white blood cells inside your lymph nodes , glands that help filter out harmful substances in your body. This means the cells can’t get into your central nervous system, which reduces the damage from inflammation .
• Siponimod (Mayzent) was approved in 2019 as the first oral drug to specifically treat active secondary progressive disease (SPMS with relapses). It’s similar to fingolimod. It also treats clinically isolated syndrome (CIS) and relapsing-remitting disease (RRMS).
• Ozanimod (Zeposia) won approval in 2020 to treat adults with relapsing types of MS. Like fingolimod and siponimod, it works by keeping some white blood cells out of circulation. You take it as a daily pill.
• Cladribine (Mavenclad) was approved in 2019. It targets T cells and B cells. It treats relapsing types of MS, including active secondary progressive disease but not CIS. You get it only if you can't take other drugs for MS or when those drugs don’t work. That's because of safety concerns, including a higher risk of cancer and birth defects in unborn children. You take it as a pill in two cycles over 2 years.
• Diroximel fumarate (Vumerity), approved in 2019, also treats relapsing MS. Researchers think it changes the response of your immune system so it causes less inflammation. It may also help protect your nerve cells from damage. It's similar to another drug called dimethyl fumarate ( Tecfidera ).

What’s on the Horizon?

MS researchers continue to find new ways to use current drugs.

Ibudilast is a drug used in parts of Asia to treat asthma and some effects of strokes. In a second trial study of this drug, researchers found it slowed brain shrinkage in people with progressive MS. The FDA put ibudilast on a fast track for possible approval once its trials are finished.

One important question researchers have is: How can we repair myelin? Treatments under the microscope include:

• An antihistamine (a type of drug often used for allergies ) called clemastine fumarate ( Tavist ). It was found to improve nerve signals in people with damage to their optic nerves. This suggests that some myelin was rebuilt.
• Metformin , a common diabetes drug. In one study in rats, it repaired stem cells that build myelin. The drug mimics the effects of intermittent fasting (eating every other day), which also helped repair myelin in the same rat study.

Stem cell transplants are another area of research. The National Institutes of Health is paying for a multi-city study to see if they work better than drug treatments for people with severe relapsing MS. Previous studies show they can work.

Here’s how it’s being tested: Half the people get the best available drugs that could improve their MS. The other half get what’s called an autologous hematopoietic stem cell transplant. The stem cells are taken from your own bone marrow and frozen. Next, doctors give you chemotherapy to kill the immune cells that cause MS. Finally, the bone marrow stem cells are infused back into you.

The hope is that the transplanted stem cells flood your immune system, reset it, and stop the attack on your myelin. It could keep the disease from getting worse, mean you don’t need lifelong MS medications, and possibly bring back some physical abilities.

Stem cell transplants are risky. So it’s important to find out if the benefits outweigh the risks, when compared with medicines that also can have side effects.

Other Research

Biomarkers: These are signs from your body fluids or imaging (like MRI ) that help you and your doctors keep track of the progression of your disease so that you can treat it most effectively. For example, a simple new blood test that measures small amounts of neuron-derived proteins (neurofilaments) may be used to predict how serious your MS will be and how well your treatment will protect brain tissue. Scientists continue to study known biomarkers for more information and to look for new ones.

Genes: These make up the biological instruction manual from your parents on how to build and maintain your body. There are genes known as "susceptibility genes” that seem to raise your risk for MS. Scientists are studying how these genes work in the nervous system in order to learn more about how they could lead to MS. This includes studies about the way genes that underlie gender affect MS.

Environment: Certain things that happen in your environment, like a lack of vitamin D or exposure to the Epstein-Barr virus, may affect the likelihood of you getting MS. Scientists continue to study this and to look for other factors.

Gut microbiome : This is the natural balance of bacteria in your gut. The nature of this microbiome seems to change with MS. Scientists are studying whether it may be possible to change the microbiome with specialized probiotics to help lessen or prevent the development of MS in some people.

Immune system: Your body’s immune response has long been known to play a part in MS. Scientists continue to study the specifics of this process, including how B cells, T cells, dendritic cells, and natural killer cells work in the disease. This has already led to some treatments and may lead to more.

Imaging: Pictures of your brain and spinal cord (neuroimaging) can help better diagnose MS , as well as track disease progression and treatment. In addition, scientists collect imaging of the brain, spinal cord, and parts of the eye (retina) to look for changes in the course of MS over time. In this way, they hope to learn more about how the disease works as well as the positive and negative effects of different treatments. Scientists continue to look for more powerful and accurate imaging to track MS, especially in the development of new MRI, or magnetic resonance imaging, machines.

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• Rituximab treatment stabilizes disability in SPMS patients: Analysis

Off-label use of antibody therapy over 2 years also found to reduce relapses

by Andrea Lobo, PhD | September 5, 2024

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Treatment with rituximab, a CD20 inhibitor used off-label for multiple sclerosis (MS) patients, can stabilize disability progression and reduce disease activity in people with secondary progressive MS (SPMS), according to a review of several published studies.

These benefits were reported over a mean follow-up of two years, and were particularly more prominent in patients with shorter disease duration and those with higher disability levels before starting the treatment.

Based on their findings, the researchers suggested that longer-term treatment with rituximab might be helpful for patients in the later stages of MS.

“Considering the observed benefits, continuation of [rituximab] treatment in MS patients upon reaching the progressive phase could be a viable option, particularly for those with active disease,” the team wrote.

The study, “ Rituximab in secondary progressive multiple sclerosis: a meta-analysis ,” was published in Annals of Clinical and Translational Neurology .

ECTRIMS 2023: Declining risk of SPMS conversion seen in registry

Researchers analyze 13 studies to find effects of rituximab treatment.

Most people with multiple sclerosis are initially diagnosed with relapsing-remitting MS , or RRMS — a form of the disease marked by periods of new or worsening neurological symptoms (relapses), followed by periods of total or partial recovery (remissions). As the disease progresses, many of these patients will transition to a progressive form of MS known as SPMS, in which symptoms get progressively worse with time, independently of relapses.

While seen as different disease entities, “evidence indicates that RRMS and SPMS may not have clear boundaries,” the researchers wrote. Thus, per the team, some treatments may be similarly effective in both disease forms.

Rituximab (marketed as Rituxan and others) is an antibody-based therapy sometimes used off-label in people with RRMS. It targets the CD20 receptor at the surface of B-cells, leading to their death and easing inflammation. However, “data on its impact on SPMS disability progression are limited,” the researchers wrote.

To know more about rituximab’s effectiveness in SPMS, the team of researchers, from Thailand, examined data from 13 previously published studies that had assessed the outcomes of SPMS patients given at least one infusion of the medication, which is approved as a cancer treatment.

A total of 604 patients, mostly female (65.7%), were included in the analysis. They had a mean age of 44.6 and had been living with MS for an average of 14.2 years at the time they started rituximab. In most cases, treatment was given as an initial dose of 1,000 mg two weeks apart, followed by 500 to 1,000 mg doses administered every 6-9 months.

The results showed that, after about two years of treatment, there were no significant changes in the patients’ mean disability levels, as assessed with the Expanded Disability Status Scale (EDSS).

“This suggests a potential benefit of [rituximab] in stabilizing disability progression in SPMS,” the researchers wrote.

Rituximab for MS may safely control disease in children, teens

Patients with worse disability at treatment start see greatest benefits.

The stabilization in disability levels was particularly evident in patients with relatively high levels at the treatment’s start — those with EDSS scores higher than 5 — and in patients with a disease duration shorter than 10 years. Age at treatment initiation did not influence the outcomes.

Data on annualized relapse rate — the average number of relapses over one year — was available for 245 patients across seven studies. These results indicated that rituximab significantly reduced the number of relapses per year by 0.74.

Two studies assessed the proportion of patients with confirmed disability progression over two years, which essentially is an increase in EDSS levels that’s confirmed in a subsequent doctor’s visit. One study demonstrated that MS disability worsened in a third of the patients, while improving in slightly more than a quarter (26.6%). In another study, the proportion of patients with confirmed disability worsening was 12.5% in the rituximab group, compared with 25% in the control group.

Rituximab demonstrates a clear ability to reduce relapse frequency and shows promise in stabilizing disability progression … while maintaining a favorable safety profile.

Finally, among the two studies with MRI data before and after treatment, the proportion of patients with inflammatory lesions decreased by more than 50%.

Adverse events associated with rituximab were experienced by 20.7% of patients. The most common included infections and infusion-related reactions.

“Rituximab demonstrates a clear ability to reduce relapse frequency and shows promise in stabilizing disability progression over the medium term (2 years) while maintaining a favorable safety profile,” the researchers wrote.

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Multiple Sclerosis Models Clarify Role of Glia, Hint at New Targets

Credit: Juan Gaertner/Science Photo Library/Getty Images

A team of scientists from the New York Stem Cell Foundation (NYSCF) Research Institute and Case Western Reserve University has created the largest reported collection of stem cell models from multiple sclerosis (MS) patients. The researchers used the stem cells to identify unique ways in which glia—integral support cells in the brain—contribute to the disease. They suggest their study is the first to report that glial cells from MS patients have intrinsic hallmarks of disease, independent of immune system influences. The results point to the power of stem cell research to provide new insights into disease biology.

The study’s findings also open up new possibilities for treating MS. By identifying specific glial cell behaviors that contribute to the disease researchers can explore potential therapies that target these cells directly. This could lead to more effective treatments that go beyond simply suppressing the immune system, and so offer new hope for patients.

“Our findings represent a significant leap forward in our understanding of MS and underscore the vast potential in glia as a target for therapeutic intervention that could transform the treatment landscape for many patients,” commented research co-lead Paul Tesar, PhD, the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics and director of the Institute for Glial Sciences at Case Western Reserve University School of Medicine, and NYSCF—Robertson Stem Cell Investigator Alumnus.

Tesar, together with co-lead Valentina Fossati, PhD, NYSCF senior research investigator, and colleagues reported on their studies in Cell Stem Cell , in a paper titled “ Patient iPSC models reveal glia-intrinsic phenotypes in multiple sclerosis .” In their report, the team concluded: “iPSC-derived MS models provide a unique platform for dissecting glial contributions to disease phenotypes independent of the peripheral immune system and identify potential glia-specific targets for therapeutic intervention.”

MS is an autoimmune disease that occurs when the body’s immune system mistakenly attacks the protective myelin sheaths that surround the nerves in the brain and spinal cord, resulting in significant neurological disability. “Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS), resulting in neurological disability that worsens over time,” the authors wrote. “While progress has been made in defining the immune system’s role in MS pathophysiology, the contribution of intrinsic CNS cell dysfunction remains unclear.”

“Most research and therapeutic strategies have so far focused on blocking the overactive immune system, but how cells in the brain itself, especially glia, contribute to the initiation and progression of MS remained a mystery,” added Fossati. “ The mechanisms behind chronic MS progression are only partially understood, highlighting an urgent unmet need,” the team continued. “Human models based on induced pluripotent stem cell (iPSC) technology are increasingly used to investigate complex CNS disorders and provide the opportunity to investigate glial dysfunction in MS.”

For their study the researchers harnessed NYSCF’s automation platforms to create induced pluripotent stem cells from skin biopsies of individuals with MS, resulting in the largest collection of MS patient stem cell lines to date, spanning diverse clinical subtypes. The scientists then converted the iPSCs into glial cells—which include oligodendrocytes and astrocytes—to investigate their role in the disease. “… we generated a collection of induced pluripotent stem cell (iPSC) lines from people with MS spanning diverse clinical subtypes and differentiated them into glia-enriched cultures,” they noted. Fossati added, “By generating glia-enriched cultures from stem cells, we have been able to study their role in MS independently of the complex environment in the body, which is constantly altered by the presence of immune cells and inflammatory signals.”

The team also observed that a set of genes associated with immune and inflammatory functions were particularly active in stem cell-derived glia cultures from MS patients, matching what they see in brain samples from deceased individuals with MS. “Using single-cell transcriptomic profiling and orthogonal analyses, we observed several distinguishing characteristics of MS cultures pointing to glia-intrinsic disease mechanisms,” the authors stated. “We found that primary progressive MS-derived cultures contained fewer oligodendrocytes. Moreover, MS-derived oligodendrocyte lineage cells and astrocytes showed increased expression of immune and inflammatory genes, matching those of glia from MS postmortem brains.”

The NYSCF scientists in addition leveraged their latest advances in artificial intelligence to detect differences in astrocytes that are not easily seen by the human eye. “… our morphological analysis supports the hypothesis that inflammatory clusters in MS astrocytes make them distinguishable from their healthy counterpart,” they commented. Fossati further noted, “The fact that glia created from stem cells show similar features to glia in MS patient brains shows us that stem cell models provide a pretty accurate reflection of what happens in the brains of living patients, and that we can use them to gain important insights into this disease.”

Because of the autoimmune activity in MS, many current therapies target the immune system. These drugs help reduce the frequency of immune attacks, but they, unfortunately, fall short of preventing the neurodegeneration that drives disease progression. In their paper, the team concluded, “… our study demonstrates that iPSC-derived glial-enriched cultures from people with MS are a powerful model to identify CNS-intrinsic phenotypes in MS. Future studies using human iPSC-derived models are necessary to fully understand glial contributions to MS pathogenesis. These findings could unveil novel glia-specific therapeutic targets to halt or reverse MS progression.” Added Jennifer J. Raab, PhD NYSCF’s president and CEO: “This study is a remarkable example of team science … It is through unique collaborations like these that we can move even faster toward new treatments for the major diseases of our time that patients urgently need.”

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New research: Getting NIS2 ready

Mike Hughes

Business Group Director, Security at Microsoft Western Europe

New research: Getting NIS2 ready   

The European wide directive Network and Information Security 2 (NIS2) comes into effect on 17 October, with the aim of strengthening Europe’s ability to collectively defend against cyber-attacks and protect the region’s critical infrastructure.  

This new directive will impact upwards of 180,000 organizations, from healthcare and transport, to manufacturing and supply chain. Most organizations are aware of NIS2 and what it aims to achieve (as well as the costs), but research from IDC has shown that only 14% of organizations are fully ready for NIS2. The majority, at 77%, are partially there.  

 With so few organizations across the NIS2 finish line and the official deadline for compliance fast approaching, I wanted to share some of the findings from this research, and how you can move your organization’s transformation efforts forward.  

NIS2 Capable  

IDC has found that over 90% of organizations impacted by NIS2 are aware of it and have taken first steps in taking action to align with the directive.  

About one in five (17%) are categorized as IDC as being NIS2 ‘capable.’   

 Organizations at this level of readiness have a long way to go however, with the need for many to implement all necessary compliance procedures and policies.  

Let’s take incident handling as an example, which is a key requirement of NIS2. With large organizations often being the target of multiple, complex cyberattacks, the rapid co-ordination of multiple stakeholders and timely reporting of incidents is what allows for quicker response and recovery, as well as minimizing the impact on essential services and the wider economy. Having robust technical protection will clearly help but organizations also need to think through the complete response to a security incident.  

Technologies like Microsoft Defender  and  Microsoft Sentinel will help security teams handle incidents with a real time, comprehensive view of security issues. But the work on becoming NIS2 ready relies on an organization’s ability to create a fully robust set of compliance procedures and policies that engage the board and wider organization. This is what ensures that everyone is on board with how to respond to a security incident and how to keep the business going with a minimal impact on operations.  

NIS2 Equipped

The next level of readiness IDC identified was NIS2 ‘equipped.’ About one-third (33%) of organizations fall into this category, and are characterized as being able to address most NIS2 requirements.   

The way to move beyond this level of readiness is to conduct a gap analysis of your security measures, and also what’s needed to meet NIS2 requirements or security standards such as ISO 27001.

Let’s consider supply chain security as an example, which is another key NIS2 requirement. When organizations enhance the security and resilience of their own organizations, cyber-criminals will look for other routes to compromise security via weaknesses in an organization’s supply chain.  

Addressing supply chain vulnerabilities is key to ensuring your own assets remain secure. Microsoft tools like Compliance Monitoring, Security Posture Management and Conditional Access Policies  can help you control and manage the external access of organizational assets and customer tenants, but your security will still be dependent on your ability to identify gaps and challenges in your security posture.   

All organizations impacted by NIS2 should be in the process of identifying the challenges they have and develop action plans now.  

Are you NIS2 ready?  

According to the IDC, organizations at the ready level for NIS2 (14%) exhibit the highest degree of preparedness for incident handling, have business continuity measures in place and deploy robust technology to ensure supply chain security and advanced encryption or cryptography.  

At Microsoft, we stand ready to help organizations of all kinds use  NIS2 as an opportunity to advance their cybersecurity posture. Our unique perspective in the security market and comprehensive suite of secure cloud-based solutions can help you identify, prevent, and mitigate against the cyberthreats we are facing today and in the future.    

Source: IDC Infobrief, Sponsored by Microsoft, NIS2 Readiness: A Guide for Organizations in Europe, #EUR252440224, July 2024  

> Read the IDC report in full  

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More From Forbes

Prediction: microsoft azure to reach $200 billion in revenue by 2028.

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BELLEVUE, WA - NOVEMBER 28: Microsoft CEO Satya Nadella smiles during the question and answer ... [+] portion of the Microsoft Annual Shareholders Meeting at the Meydenbauer Center on November 28, 2018 in Bellevue, Washington. Microsoft recently surpassed Apple, Inc. to become the world's most valuable publicly traded company. (Photo by Stephen Brashear/Getty Images)

The period after the dot-com bubble including the financial crisis of 2008 were difficult years for Microsoft. The stock returned a mere 37% compared to Amazon’s 657.9% in the same time frame and Apple’s 5150%.

Microsoft’s stock greatly underperformed prior to Satya Nadella as CEO

Microsoft’s trajectory changed when Satya Nadella, formally of the Azure division, became CEO in 2014 after working his way up through the company over the course of 19 years to president of the cloud business. The stock is up 1,000% in the ten years since Nadella took the helm using his multi-decade cloud experience to steer a remarkable turnaround from a corporate reputation mired in fighting open-source communities and anti-trust issues. Since Nadella became CEO, the returns in Microsoft’s stock have exceeded Amazon and is tied with Apple, as of writing.

Microsoft’s stock has outperformed since Satya Nadella became CEO in 2014

The competitor Nadella faced in building Azure is arguably the toughest competitor in technology – Amazon Web Services (AWS); not only for the vendor lock-in qualities of cloud IaaS as migrating a tech stack is quite costly in both time and money, but also because AWS had the first mover advantage of a four-year head start. In the tech industry, a lead this long is considered insurmountable.

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Over the past ten years, Microsoft strategically exceled by targeting the Fortune 500 with 85% running on Azure today. Retaining the Fortune 500 in the migration to the cloud was accomplished through hybrid computing where Microsoft was first-to-market on serving a mix of on-premise, private and public clouds for their large enterprise customers. As the leader in on-premise systems, Microsoft was perfectly positioned to win with hybrid architectures. The company took this a step further and undercut other services on prices across its suite of software and platforms to win aggregate, long-term contracts.

This past month, for the first time, Microsoft has announced it will be re-organizing its reporting segments, which will afford investors a better apples-to-apples comparison between Azure and AWS. According to Wells Fargo, the new Azure reporting segment stands at an estimated $62 billion as of June 2024, compared to $105 billion for AWS.

The lead we see from Microsoft today on AI revenue streams is critical enough and predictive enough that it points toward Azure surpassing $200 billion by 2028, catalyzed by the OpenAI investment, Copilot’s rapid integration into nearly every Microsoft software product, having the ace of spades — which is an operating system used in 72% of the world’s laptops and desktops, and perhaps the simplest reason of all —- Microsoft excels at the enterprise.

New Azure Reporting Reveals 11-Points of AI Contribution

Microsoft offers investors unique insights as to the monetization opportunities for AI. Last year, in the FY2023 Q4 report ending in July, Azure officially inflected due to AI. Per the report: “Azure and other cloud services revenue grew 26% and 27% in constant currency, including roughly 1 point from AI services.” In four brief quarters, Microsoft is now reporting an 8% inflection from AI: “Azure growth included 8 points from AI services where demand remained higher than our available capacity.”

Later, it was stated in an updated FY25 investor presentation that Azure saw an 11 point contribution last quarter compared to the 8 points previously reported. The metric change is due to Microsoft removing Enterprise Mobility + Security (EMS) and Power BI (BPP) from Intelligent Cloud. It’s significant that Azure is seeing low double digits while AWS and Google Cloud are not reporting their exact contribution from AI, rather are remaining vague by saying “several billions” in AI revenue.

The reporting changes also update Azure’s growth rate to 33% for the fiscal year and an impressive 35% growth in constant currency. Prior to the metric changes, management guided for a slight deceleration in Azure growth in Q1’25, with growth of 28% to 29% in CC (vs 30% this quarter), yet they expect an acceleration in H2’25 as their capital investments increase AI capacity.

Microsoft Azure recently updated metrics to show higher AI contribution of 11 points

According to Wells Fargo, the new metrics suggest an annualized run rate for Azure of approximately $62 billion. Investors will get the official number in next quarter’s earnings report.

Management has stated the primary issue is being capacity constrained, which all things equal, is bullish for the medium-term as it implies demand exceeds supply for Azure AI and Azure’s consumption business. Per management in the most recent earnings call: “And in H2, we expect Azure growth to accelerate as our capital investments create an increase in available AI capacity to serve more of the growing demand.”

Azure AI is a platform for developing custom AI applications and solutions. Companies use Azure AI to integrate generative AI and multimodal language models into their applications for features such as search, image recognition, natural language processing, speech to text and other AI features using developer tools, such as APIs and SDKs. The platform also offers lifecycle management for data preparation and model development and training for machine learning, supporting popular frameworks PyTorch and Tensorflow. Azure OpenAI provides access to OpenAI’s GPT-4, GPT-3.5, Microsoft’s DALL-E models, and Meta’s Llama models for companies to build custom generative AI applications and AI assistants. Companies run models on their data to improve workflows through Azure AI Studio.

Azure AI customers totaled more than 60,000, implying customer growth rate of nearly 60% YoY and up over 13% vs Q2’24 with average customer spend continuing to grow. The number of Azure AI customers using data and analytics tools also grew nearly 50% YoY.

Where Azure stands apart is that its security segment is one of the largest in the world. In 2023, it was stated Microsoft’s security segment was at $20 billion with 860,000 customers. The number of customers has been updated to 1.2 million, and if we do some simple math, that would imply the security segment is at $28 billion today – far exceeding all best-of-breed cybersecurity companies combined.

Also tied to Microsoft’s strong presence in security, the Federal Government often gets overlooked in terms of its AI impact to Azure. In a blog post, the company CTO Bill Chappell wrote: "[…] generative AI capabilities through Microsoft Azure OpenAI Service, can help government agencies improve efficiency, enhance productivity, and unlock new insights from their data. Many agencies require a higher level of security given the sensitivity of government data. Microsoft Azure Government provides the stringent security and compliance standards they need to meet government requirements for sensitive data."

Key metrics for Microsoft have been on fire lately. Bookings increased 17% YoY and 19% on a constant currency basis. This was significantly above expectations and driven by growth in the number of $10M+ and $100M+ contracts for Azure and Microsoft 365. This compares to 29% growth (31% on CC basis) in Bookings last quarter and compares to a -2% decrease (-1% on CC basis) in Bookings in the year ago quarter. Commercial RPO grew by 20% YoY to $269 billion. This compares to 20% growth last quarter and 19% YoY growth in the year ago quarter.

Microsoft's Commercial RPO grew by 20% YoY to $269 billion. This compares to 20% growth last quarter ... [+] and 19% YoY growth in the year ago quarter.

Source: I/O Fund Stock Research

If Azure were to continue its growth rate today on the assumption that any acceleration from AI offsets a deceleration on traditional cloud revenue (due to repatriation from moving cloud workloads to on-prem, for example), then Azure would reach revenue of $178.3 billion by 2028. That’s the bare minimum base case.

If we assume that AI contributes an additional 10 points for the next two years, and then tapers off to 8 points of AI contribution, and finally 4 points of AI contribution due to a higher revenue base, while also offsetting up to a 6-point decline in traditional cloud workloads, then Azure will reach $206.7 billion by FY2028 (ending in June of 2027).

Microsoft Azure has a possible path to surpassing $200 billion by 2028

There are some analysts forecasting $41.6 billion for AI revenue for AWS by 2027. It’s reasonable to assume Microsoft’s AI revenue will be higher as it’s the only company reporting details on AI revenue across the Big 3 and at a double-digit percentage of 11% nonetheless (or about $7 billion in AI revenue) compared to vague comments of “several billions” of AI revenue from Azure’s competitors, and likely to be the $3 to $4 billion range. Therefore, assuming Microsoft has $55 billion in revenue by 2027 compared to AWS’ $42 billion is a reasonable assumption.

Copilot’s Rapid Integration

While OpenAI’s Chat-GPT and Google’s Bard /Gemini have gotten all of the attention, Microsoft has been quietly building an AI software empire with Copilot. Copilot features are designed to boost productivity and are integrated across consumer and enterprise software, including Windows, Edge, Office, Bing, Teams, Loop, Dynamics and Viva.

Copilot utilizes large language models that require Azure consumption. To prepare for this moment, Microsoft invested $1 billion in Open AI in 2019. Over the last five years, Microsoft has increased its investment to $13 billion. Open AI’s Chat-GPT are some of the large language models that power Microsoft’s Copilot. OpenAI leads the market on LLMs and every time Chat-GPT is integrated into a product and used across OpenAI’s user network, money funnels to Azure as Microsoft is the exclusive cloud provider in exchange for allowing OpenAI to access Azure’s infrastructure at a reduced cost. Around the time that Chat-GPT was noticed by Wall Street, Microsoft’s management team said the following about its impact on Azure:

“Second, even Azure OpenAI API customers are all new, and the workload conversations, whether it’s B2C conversations in financial services or drug discovery on another side, these are all new workloads that we really were not in the game in the past, whereas we now are.”

Developers pay between $10 to $19 per month for GitHub Copilot. According to the most recent earnings report, Copilot accounted for over 40% of GitHub’s revenue growth this year and is already a larger business than all of GitHub when Microsoft acquired it at $2 billion annual recurring revenue (ARR). GitHub Copilot has been adopted by over 77,000 companies, up 180% YoY.

Copilot Studio, a low-code tool for creating and maintaining copilots, saw a 70% QoQ increase in organizations using it to 50,000.

Copilot for Sales and Service is priced at $50 per user each, Copilot for finance is $30 per user, and for Dynamics data platform use cases, it’s priced as high as $1,397 per tenant. The highest cost is Copilot for Security , priced at $4 per hour, with an estimated monthly cost of $2920.

Although some of the upside from Copilot will be reported in other revenue segments outside of Azure, there are some tie-ins regardless of where Copilot is running. For example, enterprises need data to reside where Copilot can access it, which implies higher Azure revenue. On a more granular level, those who subscribe to Office 365 are often locked-in to Azure Active Directory (AD).

Today, Microsoft has more than 400 million 365 Commercial customer seats and 78.4 million 365 Consumer subscribers, giving a nearly ~480 million customer base to target for AI services. Assuming AI PCs help to spark a strong growth trajectory for Copilot, just a 10% adoption rate across both Commercial and Consumer by the end of the fiscal year would surpass $17 billion annual run rate. It’s likely the 10-year adoption rate will be well above 50% with an addressable market of up to 90% as more AI assistant productivity hacks are developed. This means Office 365 would land somewhere between $86 billion and $156 billion, equal to the current size of Azure or up to double the size of Azure on this revenue stream alone.

While Wall Street is worried about how much AI is costing, the I/O Fund is busy calculating how big the AI opportunity can get in the next few years and how investors can participate. Join our next webinar on Thursday September 12th where the Portfolio Manager will discuss potential entries for Microsoft and other AI-related stocks.

Copilot for Microsoft 365 is priced at $30 a month. The productivity tool combines large language models (LLMs) with the data in Microsoft Graph and Microsoft 365 apps. The use cases of Copilot in Word include giving users the first draft while saving the time on sourcing, writing, and editing the content. Similarly, Copilot in PowerPoint will help to create presentations based on previous content. Copilot in Excel can analyze trends from the data, create charts, and assist in making informative decisions.

In the second full quarter of availability, the number of people using Copilot for Microsoft 365 nearly doubled QoQ. Copilot customers increased 60% QoQ and the number of customers with over 10,000 seats more than doubled QoQ.

Power Platform, a collection of low-code development tools, saw MAUs rise 40% YoY to 48 million. 480,000 organizations have also used the AI-powered capabilities in Power Platform, up 45% QoQ. As stated, Power Platform will no longer be reported in Microsoft’s Azure segment

Copilot on the Verge of Becoming Ubiquitous

Windows operating system is in 72.3% of desktop and laptops. When you consider that Windows has most recently launched on an Arm-based PC with Qualcomm, and will also launch next year with AMD and Nvidia, that market share is likely to grow rather than contract. Similar to the penetration rate of Office 365, Windows dominates PCs regardless if the OEM is Dell, HP, Lenovo, Acer, Asus, LG, Samsung or Microsoft Surface.

Copilot+ for Windows is a sidebar that helps Windows users change settings, find files or summarize text across a desktop. Recall is a feature that helps a Windows user find documents, emails and web pages when a user simply states how they recall the file or digital asset. On some Surface laptops, there is a Copilot key, a digital pen enhanced with AI, sound and voice features enhanced with AI, and enhanced AI cameras.

Both Arm-based and x86 AI PCs are ramping this year with a CPU + GPU + NPU combo that will, in turn, proliferate Copilot+ for Windows, the AI assistant that requires a minimum of 40 TOPS (trillions operations per second). The neural processing units (NPUs) are powerful enough to deliver the official kickoff of AI edge computing as Copilot+ runs AI tasks locally on the AI PC and integrates them into various applications. This is an important moment for AI as prior to NPUs exceeding 40 TOPS, workloads were primarily sent to the cloud. By running AI assistants locally on the computer, suggestions will be faster and more accurate.

Qualcomm’s Snapdragon X Elite and Plus processors were released this last summer and offer the first GPU, CPU and NPUs that exceed 45 TOPS for AI tasks for Microsoft’s Copilot+ with a long battery life of over 12 hours. This week, Intel released its second-generation Core Ultra chips capable of reaching 48 TOPS that offers a long battery life of over 10 hours with the added benefit of running legacy x86 software without compatibility issues.

Canalys is projecting AI PC shipments to rise at a 44% CAGR from 2024 to 2028, from an estimated 48 million PCs this year, before doubling to more than 100 million in 2025 and rising to over 205 million by 2028. Cumulative shipments of AI PCs are projected to surpass 600 million over the next four years. I’ve covered additional information on the growth of the AI PC market here.

Within this rapid growth, commercial adoption is forecast to be higher, at approximately 60% by 2028 versus 40% for consumer. This is due to the productivity gains that AI PCs can enable via powerful on-device AI as well as benefits to software developers and related roles. For example, Dell’s XPS and Latitude 7455 , equipped with the Snapdragon X Elite can support 13 billion-plus parameter models which means customers can run popular models like Llama 3 directly on their PCs. The fact that commercial adoption will be higher than consumer adoption is a boon for Microsoft Copilot and its suite of enterprise AI-enabled applications and platforms.

Microsoft’s Capex Spending Highest Among Cloud IaaS Providers

Microsoft is unabashedly spending tens of billions on AI infrastructure. In the last earnings report, the company announced strong QoQ increase to its capex for AI infrastructure. Capex was $14 billion last quarter, when it grew 22% sequentially. Microsoft’s capex increased 36% sequentially and 78% YoY to $19 billion in Q4.

Full year 2024 capex was up 75% YoY to $55.7 billion, yet this quarter’s run rate suggests we could see up to $80 billion in capex in FY2025. Compare this to cloud IaaS leader AWS which reported H1 capex of $30.5 billion for a run rate in capex of just over $60 billion. Notably, management is guiding for a further YoY increase in capex in FY’25. I have covered the importance of Big Tech’s capex for AI stocks in an analysis here and also in a previous webinar .

Big Tech management teams have been getting an earful from Wall Street on when investors can expect to see a return. Private investors are busy calculating what level of revenue these companies must generate, estimating the return will need to be as high as $600 billion to justify the revenue Nvidia has reported in its data center segment.

Therein lies the disconnect, which is that Microsoft’s CFO, Amy Hood, states they are capacity constrained - implying the opposite problem, that the capex they’ve allocated is not nearly enough to serve Azure AI demand. Per the last earnings call: “We are – and we've talked about now for quite a few quarters, we are constrained on AI capacity. And because of that, actually, we've, to your point, have signed up with third parties to help us as we are behind with some leases on AI capacity. We've done that with partners who are happy to help us extend the Azure platform, to be able to serve this Azure AI demand. And you do see us investing quite a bit as we've talked about in builds so that we can get back in a more balanced place.”

Microsoft’s management team also pointed out about 40% of capex is spent on land, which is a long-term asset, and the rest is tied to a demand signal for inference. The CFO stated: “even in the capital spend, there is land and there is data center build, but 60-plus percent is the kit, that only will be bought for inferencing and everything else if there is demand signal.”

Therefore, investors have an important decision to make. On one hand, investors could listen to the bearish undertones that high capex spending will not be returned to investors over time, or on the other hand, view high capex spending as a bullish signal of the overflow in demand that will sustain for many years to come, with AI consumption well exceeding the capex being spent to build the infrastructure.

Conclusion:

In 2022, I wrote an 8,300 word analysis entitled Special Report: The New Kings of Tech for our research members that tied together key points on how to position our readers for AI’s big moment - well in advance of Nvidia’s stock surge. Part of this analysis was to emphasize that our readers should shift their mindset from consumer-facing stocks to enterprise-facing stocks. This is not easy to do given the FAANGs are primarily consumer stocks, and it was consumer that drove historic gains for the market over the past decade.

Here is what I wrote at the time:

“The adage is that history rhymes but it does not repeat. I believe a large addressable market is certainly required to produce the new wave of FAANGs – however, rather than consumer driving the gains, I believe it will be enterprises. Below, I discuss the enterprise-level market that will be four times larger than mobile and two stocks that will directly participate. Imagine participating in 4X the FAANGs by 2030. That’s what I believe will happen due to one key trend and I discuss exactly why this will be achieved below.” -I/O Fund’s Special Report: The New Kings of Tech , June 5 th 2022

Nowhere will the AI enterprise advantage be more evident than with Microsoft’s steady ascent over the next ten years, which I believe will end with Microsoft firmly on top in nearly every category the company competes in. A few years ago, I predicted Nvidia would Surpass Apple by 2026. At the time, Nvidia had a $550B market cap and the mere thought was inconceivable . To that point, I purposely did not say Nvidia would surpass Microsoft — as once the AI opportunity fully plays out —- this company will be a tough one to catch.

Microsoft has been a heavy spender on AI infrastructure, with positive read throughs for AI semiconductors we own and a handful that we are tracking to buy soon. Learn more about the I/O Fund’s holdings and consistent deep dive research on AI stocks, crypto and more here

The I/O Fund does not own Microsoft at time of writing but is carefully planning our next entry. Real-time trade alerts are sent to research members and entries are discussed weekly in our webinars.

If you would like notifications when my new articles are published, please hit the button below to "Follow" me.

Please note: The I/O Fund conducts research and draws conclusions for the Fund’s positions. We then share that information with our readers. This is not a guarantee of a stock’s performance. Please consult your personal financial advisor before buying any stock in the companies mentioned in this analysis.

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