S5E29 Developing new DMTs with Professor Stephen L. Hauser

20:48 “There is no question that infection is a very important part of understanding the mystery, not only of MS but of all other autoimmune diseases. Autoimmune diseases have almost certainly increased dramatically in modern societies, even though the historical record is difficult to follow. Our societies have also changed dramatically over time, and because of that, we come into contact with viruses and bacteria at different times in our lives, in different ways than we did in the past. We think that infection, especially when it’s encountered later in life, can trigger a misdirected immune response in MS against myelin and other brain substances.”

37:02 “I think we’re moving to a whole new concept of how to treat MS and other autoimmune diseases that is a little bit like cancer therapies, where we will induce a complete remission and then maintain and monitor that remission. What do we mean by a cure? In some forms of B-cell cancer, for example (cancer is not multiple sclerosis) but in B-cell cancer, if all evidence of the disease is gone for three years, then the lifetime risk of it ever recurring is less than 1%. That could be the kind of goal that we could have for people with MS.”

38:53 “A healthy lifestyle is key; it can have a huge effect. A regular balanced diet [and] adequate sleep is as important as anything else. Our immune system changes dramatically when our sleep is too short or interrupted. I’m a big believer in exercise and in doing things that you love to do, find the path that makes you optimistic and self-confident despite having MS. These can have huge advantages for people [with MS]. Being in tune with your body, and your needs, and being as healthy as you can, is enormously helpful.”

Overcoming MS  00:01

Welcome to Living well with MS this podcast comes to you from Overcoming MS, the world’s leading multiple sclerosis healthy lifestyle charity, which helps people live a full and healthy life through the Overcoming MS program. We interview a range of experts and people with multiple sclerosis. Please remember, all opinions expressed are their own. If you were able to, we would be grateful if you could donate to help support the podcast and other work of Overcoming MS to help give hope to those impacted by multiple sclerosis. If you enjoy the show, please leave a review. These are quick to do and really help us. And now here’s your host, Geoff Allix

Geoff Allix  00:43

Welcome to the latest edition of the living well with MS podcast. Joining me on this edition is a very esteemed guest. We have Dr. Steven Hauser, who’s a neurologist, an immunologist who currently leads the UCSF Weill Institute for neurosciences which I believe it’s University of California in San Francisco. It’s the largest Neurosciences Institute in the US. He’s Harvard educated, he’s studied and treated MS extensively for over 50 year career. It’s worked with respect responsible for the development of B cell therapies for MS including Ocrlizumab or Ocrevus. He served the Obama administration as a member of the Presidential Commission for the Study of Bioethical Issues, and is the author of the new book, The Face Laughs While the Brain Cries, check out the show notes for links to that. Dr. Hauser is dedicated to understanding MS and translating that understanding to into better answers for people. So welcome Dr. Hauser.

Professor Stephen Hauser 01:40

Hello, Jeff, I’m delighted to be here with you and your listeners.

Geoff Allix 01:45

Thank you for joining us. So to start off with, that’s quite an esteemed career. And I mean, dropping, dropping names, like Obama is quite a quite a good name drop, I would say. So could you introduce yourself and tell us a bit about yourself your work and also the new book?

Professor Stephen Hauser 02:06

Thank you, Geoff. Delighted to. And thank you for the very kind introduction. As you said, I’ve been a researcher in the MS field and in autoimmunity for nearly half a century. I’ve had great good luck as a scientist, a physician, and have spent my career trying to understand the root cause of MS and of other autoimmune diseases. And of course, as a physician to develop more effective therapies. My memoir is called The Face Laughs While the Brain Cries as you mentioned, I wrote it because I wanted to share a story about medical discovery and tremendous progress against MS. I think that it’s a story about faith in science, and how science can improve our lives. It also tells real stories of people with MS. Those afflicted before treatments were available and after. And another theme is that medical research is just so very fragile. But above all, I hope that the book will increase a little bit the public’s interest and confidence in science and also will be engaging and fun to read. When I began my career, there were no treatments for MS. And there was also a pessimism that progress would ever be possible. So it’s really quite remarkable that today we can turn off the disease and many people, especially those in whom MS is just beginning. And the prospect of lives free from disability is a reality today. This is a magnificent advance and one that was possible because of the efforts of many hundreds of dedicated people working together across boundaries and borders, but especially patients who trusted us and courageously agreed to participate in the clinical trials that are really the only way to test if the ideas from the laboratory are really on track.

Geoff Allix 04:32

Yeah, a lot of people with MS say the mice always get the best drugs. So I believe you suffered from a number of allergies, eczema, asthma as a child, so other autoimmune conditions. So could you explain what exactly is autoimmunity? Because we hear this that could all be kind of heard from another doctor. They could all be connected and there’s so many different conditions. We If you’re not catching something you’re not, you know, it’s not like COVID or something you body is doing something to itself. So what exactly is autoimmunity? And how does it relate to multiple sclerosis and inflammation that we hear about?

Professor Stephen Hauser 05:17

Well, Geoff, inflammation is caused by an activated or turned on immune system. The immune system is designed to protect us against invading organisms, bacteria, viruses, fungal infections. In autoimmunity, the immune system turns against the body, it turns against itself. And in MS, the immune system attacks the nervous system, myelin and nerve cells. As many listeners know, normally, each nerve cell connects with 1000s of others through electrical signals and wires. But when the myelin covering is attacked, and it’s attacked by the immune system, the nerves can short circuit like frayed power cords. And then over time, connections are lost. Nerve cells die and symptoms of brain disease appear. There are auto immune diseases against every organ in the body. And these are all caused by a misdirected immune response.

Geoff Allix 06:37

So what do you think? Are they connected? I mean, is it likely if you have one you’d get another? Is your, your body hardwired if you like to have autoimmunity?

Professor Stephen Hauser 06:50

I don’t know if we’re hardwired but there’s no question that some of us are more predisposed than others to allergic and autoimmune disease. Some of this is inherited. And some of this is due to environment. What we do know is that certain people have family members that are at risk for multiple different autoimmune diseases, not only multiple sclerosis, but illnesses like psoriasis, which is very common in people with MS an autoimmune disease of skin, thyroid, autoimmune disease, also very common in people with MS and then less often others like diseases of the joint, the autoimmune disease, rheumatoid arthritis, or type one diabetes and autoimmune attack on the pancreas. So there are special families where auto immune diseases occur commonly. And those families have been incredibly important in understanding the inherited factors, the genes that contribute to MS and other autoimmune diseases.

Geoff Allix 08:07

So because my I’ve said this many times on this podcast that my father had MS. Unfortunately, he died relatively young. He didn’t really have treatment at the time this was in the, you know, he was diagnosed in the late 70s would have been when he died in the late 90s. But also, I mean, I think now well, definitely there’s a genetic connection, because I know a lot of people with MS who have family members, way beyond what would be statistically normal. But also my mother has rheumatoid arthritis. So is that So potentially, that could also be a genetic connection, even though it’s not the same condition that that I could actually be inheriting a form? Although I don’t have rheumatoid arthritis? It may be that a predisposition for autoimmune conditions might be

Professor Stephen Hauser 09:01

there to me, there is no question that inherited factors play some role, but in our larger population, they play a minor a relatively minor role. Through wonderful global collaborations spearheaded in the UK, and the United States working in partnership together along with colleagues in Australia, many nations in Europe. The genetic architecture of multiple sclerosis has really been identified. And the genes that were most easily found are those that contribute to risk for MS and to in some respects to other autoimmune diseases. There are more than 230 risk genes that contribute to MS of the 23,000 genes that we have in our body, but these even all together are probably less important for most people, then effects of environment.

Geoff Allix 10:12

Okay. So just to change tack a little bit in, in your book you’ve written, and hopefully, hopefully I’m quoting this correctly, “physicians care for the soul as well as the body.” And also you wrote, “the purpose of medicine is to treat the person not the illness.” I would say that many people with MS when they visit their consultants and neurologists, they would find that it’s quite time limited, and sometimes lacks personalization, I wouldn’t say it’s always the case. It does depend where you are. So certainly in the UK, we’re very fortunate that we can have amazing health care at no cost, which is brilliant. So I’ve had very expensive treatments, which I haven’t had to pay for. But on the other hand, my neurologist is certainly very time limited, and can only see me at most annually. And for quite brief periods of time. He doesn’t lack personalization he’s absolutely wonderful. But the nature of his job is he has to be quite brief, he’ll see lots of people, other places, there’ll be a different situation, it depends on the healthcare situation. But I think a lot of people find that their consultant might be rushed might lack personalization. So do you have any tips to deal to connect your neurologist? You know, what sort of questions would you have? How would you get the most out of your few minutes that you have, potentially just once a year?

Professor Stephen Hauser 11:43

Such a difficult and important question. I think first, be prepared. Write down perhaps two or three important questions, and begin with those questions, then not questions that are important to perhaps the physician but those that are important to you. Focus on the problems that are bothering you. You may well need referrals to experts in different areas to help with rehabilitation or visual or bladder problems. But make sure that the things that you care about are at the top of the agenda. Find a physician who cares about you, not only your MS. Someone who will be your advocate, it may not be the expert consultant, it may be a general practitioner. For many patients who are receiving highly effective medicines for MS. Today, MS attacks may be completely prevented. And in some ways care is simpler than it is in the past. I think a focus on treating symptoms becomes so important and on guiding decisions that have important consequences to one’s life. So I think the value of the interaction, the face to face interaction with caregivers, is so important. And finding physicians and therapists who care about you and can help you, I think is key. Sometimes, if you are interested in joining a clinical study, that could be a way to have additional time with experts, while you’re helping the effort for not only yourself but for hopefully many, many others.

Geoff Allix 14:01

I have heard that I mean, it does somewhat depend on where you live, but certainly in the UK if you’re near a large population center. And can take part in a trial of people I’ve spoken to have been on trials they just said it was like having the most like bespoke pristine healthcare system that you could ever afford. You know, they were they were getting endless tests, checkups, people, but they were really they were genuinely interested because partly they probably were anyway but also because it mattered for their research. So suddenly they became it became the they were in their condition was important for the researcher it was and they just said the treatment was amazing. Even if you’ve given the placebo, which they don’t know, but they said even if you were just given a placebo, you’ll get amazing treatment for the period of time.

Professor Stephen Hauser 14:56

In my career, Geoff the joys of medicine have been amplified by the time that we have to really interact with people. Because we are both researchers and clinicians. And by bringing both worlds together, I think relationships are built. So it’s been one of the joys of medicine. For me, there are also ethical challenges whenever a caregiver is also a scientist and transparency. Looking in the mirror, asking for outside advice frequently, is so important because even in a clinical research environment, that the interests of the patient has to come first.

Geoff Allix 16:01

And could I ask you a bit about other autoimmune brain conditions? So how does MS. How is it similar to how’s it different from other conditions are, such as Parkinson’s or autism? Are there similarities between them? Or are they completely distinct?

Professor Stephen Hauser 16:24

Well, I’ve thought a lot about this because as as you may know, from my book, I was surrounded as a youngster by brain diseases. Autism is present from early childhood. It’s a horrible condition for patients and loved ones often. But one gets used to it often enough in a family circle. Parkinson’s begins late in life, also a very difficult time. But MS is different. It strikes just as our lives are beginning to blossom, teenage years early adulthood. It also presents uncertainty that many people feel is just as big a problem as the MS itself. Will my MS be disabling or just a nuisance? Should I change my career plans? What about my marriage plans? Should I tell my folks? what about my boyfriend? How should I think about my future? For all these reasons, I think MS can be a particularly cruel and unfair disease.

Geoff Allix 17:54

I mean, although I would say I know a number of people with Parkinson’s. And I think there’s been huge leaps forward in terms of treatment for people with MS. Whereas other conditions like Parkinson’s, they do seem to be, I’m sure that they’re saying, Oh, well, like we keep hearing there’ll be a breakthrough in five years. But they seem to be they haven’t had that breakthrough that we kind of had maybe 10 years ago, where it started to suddenly get lots of things in the pipeline. There’s a huge range of choices. Now, if you go to your neurologist, I think how part of the job actually went if you someone who’s newly diagnosed is actually doing a lot of research. Because there might be a whole load of treatments they’re offered, which Yeah, I do think that with Parkinson’s, especially to seem to be a hopefully they’ll get more treatment soon.

Professor Stephen Hauser 18:53

I think that the wonderful advances against MS are hopefully the beginning of an era that we will see in the near future, where there will be better treatments, repairs, prevention’s cures for the billion people each year who develop a brain disease. Advances like those in MS make government and industry more optimistic that brain diseases can be treated effectively through modern science and proper clinical trials. there was uncertainty if brain diseases were just too complicated. They’re more complicated than cardiovascular diseases or cancer. But at 2023 that has changed and there are enormous efforts underway to find answers. And with advances in science, Parkinson’s disease has become simpler to understand. And hopefully in the near future simpler to treat.

Geoff Allix 20:11

One of the things that’s particularly been in the news lately is the role of infection in MS. So they’re saying there’s they’re almost certain that there’s a connection with Epstein Barr Virus. So what is the role of infections? Because we’ve got an autoimmune condition, right? It’s not, you know, we don’t have something that’s that’s directly reacted, you know, it’s not, it’s not necessarily caused by a disease or you have but is there a role of of infection in brain diseases like MS?

Professor Stephen Hauser 20:48

There is no question that infection is a very important part of understanding the mystery not only of MS. But of all other autoimmune diseases, autoimmune diseases have almost certainly increased dramatically in modern societies, even though the historical record is difficult to follow. Our societies have also changed dramatically over time, and because of that we are, we come into contact with viruses and bacteria at different times in our lives, and in different ways than we did in the past. When it’s working right, our immune system is formed, it’s sculpted, we say in immunology terms, the immune system is educated by the bacterial and viral particles that are all around us and in our bodies. And one purpose of this immune education is to remove cells that also react against normal tissues in the body. And just like school, education is most effective early in life. So we think that infection, especially when it’s encountered later in life, can trigger a misdirected immune response in MS against myelin and other brain substances. So it could be that our focus on hygiene could set the stage for an increased risk for auto immune diseases in general, and MS specifically, and there is very strong evidence that one of those factors in MS, as you say could be a later exposure to Epstein Barr Virus, then our immune system, ideally intended that to be.

Geoff Allix 23:10

So we’re actually by overly, being overly hygienic, especially with children or babies, then actually, that in itself is not necessarily a good thing. And maybe when you say, No, don’t play in the dirt. That’s exactly what your kids should be doing. It’s a little bit I mean, obviously, it’s a difficult one, you need to be hygienic, but also maybe actually playing in the dirt is not a bad thing for kids, or they need to pick up a few bugs.

Professor Stephen Hauser 23:42

I have written about this in the face laughs because it in my own experience. It played such an important role as I reared my own children and my focus on hygiene with my oldest child, as many parents do, may be may have been an incorrect focus that is not necessarily a good thing. It’s worth remembering that we’re a pretty young species, human beings we’re 7000 generations or 180,000 years old. And until 10,000 years ago, we were living in hunter gatherer groups of no more than 10 or 20 people, sharing the germs of very few people who were often related to us. And then about 10,000 years ago came animal husbandry and farming, and now some people could feed others in larger numbers, and then came cities and giant cities and technology and we are now living in a very different kind of environment than our immune system had developed expecting. So modern society may in some respects be responsible for the increase in several autoimmune diseases that we’ve seen including MS.

Overcoming MS 25:17

Overcoming MS are visiting Guildford UK on Sunday, the 14th of October as part of the pop up circles tour, you’ll have the chance to connect with others following the Overcoming MS program and hear from a range of brilliant speakers. Find out more and book your free place at overcoming ms.org/community/events.

Geoff Allix 25:40

So you’ve mentioned that you’ve written a book. So would it be possible for you to read a short passage from your book.

Professor Stephen Hauser 25:48

I’d be delighted to and might begin by describing the context of this section. The development of treatment targeting an unusual type of white blood cell, a B cell would be a paradigm shift for the field of MS, research and care. B cells are a type of lymphocyte, a white blood cell that can make chemical bullets called antibodies, and can also direct other cells of the immune system to turn on or turn off. So the idea that B cells might be involved in MS was quite unconventional, but it was based on years of research and very solid evidence. But it was still going against the grain of the field and had many naysayers. So in this section, I’ll describe what happened on an August afternoon, in 2006, when we opened or unblinded the results of the first preliminary clinical study to see if killing B cells in the bloodstream could have any effect on multiple sclerosis. This was a moment that changed everything. Today, we would unblind the results of our first study, treating MS with a B cell antibody, we’d see if the treatment worked. It was a miracle that we made it this far, the cards were stacked against us. Most everyone, including the Federal Government, were convinced that T lymphocytes, not B lymphocytes, were the villains in MS. B cells were the good guys. They said, kill them off with your treatment, and you’ll make MS worse. That’s what happens in mice. If our treatment does the same to people, we could hurt them. So needless to say, when we unblinded the trial on that late August afternoon, the stakes were high. And when we opened the folder containing the results, what we saw was extraordinary. There was a nearly complete and almost immediate elimination of inflammation in our treated patients. And improvement was already evident on the first MRI scan taken just four weeks after treatment as a precautionary safety measure. Added to be sure that by removing B cells, we did not make MS worse. By the next MRI, eight weeks later, MRI activity was reduced by more than 90% a positive effect that was sustained throughout the duration of the study. There were also big reductions in new MS attacks, which was amazing because the study was so small, but most stunning was the rapid onset of action. Because the benefit appeared almost immediately. It could not have been due to a reduction in disease causing antibodies, as this would have taken much longer to occur. The only reasonable explanation was that the B cells themselves were at the heart of MS. Nature had revealed one of its closely guarded secrets, how the brain was attacked. The program leader at Genentech, the company that sponsored the trial, with whom I’d worked arm in arm, who rode shotgun to make sure we could stay on course despite the obstacles, whose career was on the line with this one could not contain her tears, a mixture of relief, exhaustion and joy, we discovered an incredibly potent, effective and apparently safe new treatment.

Geoff Allix 30:13

And was this what ultimately became Ocrevus or Ocrelizumab?

Professor Stephen Hauser 30:19

Yeah, so this was with an earlier drug called rituximab. And we then went forward to develop a more modern drug with more favorable attractive characteristics, called Ocralizumab or Ocrevus, and subsequently, another called Ofatumumab that has been recently, several years now in general use

Geoff Allix 30:52

How is that process? How do you go about developing the drugs? You’ve identified the target? And then how do you actually look into developing a drug to target the B cells that are causing the problem?

Professor Stephen Hauser 31:08

Well, it was very fortunate that the discoveries were made at the time when the biotechnology industry was at its birth. And it was extraordinarily lucky that the first monoclonal antibody therapy that was ever approved by the FDA, by the Federal Food and Drug Administration in the United States, was a treatment that killed malignant B cells in patients with B cell cancers, a disease called lymphoma. So there was a ready made drug for us to try. And there were so many aspects of the story that were unexpected. That was why I called it a miracle. One of the parts of the miracle was that the drug happened to have been developed by my college roommate. And it was our friendship that helped us at critical times, get through many points along the journey where this could have stopped. We had wanted to test rituximab while we were developing the better drugs, but for numerous reasons that would not prove feasible. And I still am disappointed that we were never able to fully develop rituximab as an approved treatment for MS because it is clearly quite effective.

Geoff Allix 32:53

And where does it go next? So what So is there is there more on what’s next in B cell research and MS?

Professor Stephen Hauser 33:07

I think one principle of all modern trials, and especially those for MS is that we learn as much about disease by the effects of our treatments as by any experiment in the laboratory. But it’s only by bringing these two worlds together where the most dramatic progress can be made. And this is certainly the case in the MS story. The dramatic effectiveness of B cells resulted in a reevaluation of the basic biology of MS, along with how other therapies against MS might be working. And with this new focus on B cells as a critical player in the MS disease cascade, it now became clear that B cells that were hiding in protected areas just outside of the brain in an area called the meninges. And around blood vessels in the brain, that these B cells were there and were resistant to probably all of our treatments because they couldn’t reach the B cells in these areas, and that they were making chemicals and communicating with other immune cells in a way that was driving slow degeneration of cells of the nervous system, myelin and nerve cells and causing neuro degeneration and causing progression. So there is now a very sharp focus on developing therapies that will eliminate these residual B cells that are hiding in and near the brain and that are driving progressive MS. So I am extremely optimistic that current trials focused on remediating progression, alleviating progression are going to be successful. And perhaps the treatments are in two areas. The first are to treat more aggressively at the beginning of MS before these B cells and other cells move into the nervous system, where they are resistant to treatment. So if we treat at the dawn of disease more effectively, can we cure the disease? And second, for people who already have had MS for a number of years, there are treatments now in therapeutic trials that we hope can eliminate those B cells that are residing in the nervous system and that current treatments cannot reach. I think we’re moving towards a point in MS care, where we will treat very aggressively at the beginning of the disease in patients who wish to have this sort of treatment. Treatments with highly effective therapies like B cell therapies like Alemtuzumab, map like Natalizumab or Tysabi, and that after induction of a remission, we will then either maintain with a less aggressive treatment, or stop treatment and monitor and develop biomarkers that will tell us if and when retreatment is necessary. So I think we’re moving to a whole new concept of how to treat MS and other autoimmune diseases that is a little bit like cancer therapies where we will induce a complete remission and then maintain and monitor that remission. And when we can declare victory is the great question. When is there a cure? And what do we mean by a cure? In some forms of B cell cancer, for example, and cancer is not multiple sclerosis, but in B cell cancer, if all evidence of the disease is gone for three years, then the lifetime risk of it ever occurring is less than 1%. That could be the kind of goal that we could have for people with MS.

Geoff Allix 37:58

That would be fantastic. It’s very optimistic. We are saying as well. I think that’s gives a lot of people hope. Just to change track, so Overcoming MS it’s a program which is largely lifestyle modification. It does include disease modifying therapy, where appropriate, so we’re not an anti disease modifying therapy approach at all. But it also encourages lifestyle changes. So looking at diet, exercise, mindfulness, alongside disease modifying therapies. So what would be I mean, firstly, do you think lifestyle has a factor with the course of MS? And secondly, would you have any tips for for lifestyle modifications for people who have MS.

Professor Stephen Hauser 38:53

Lifestyle as is so important for all of us? And I think especially for people with overactive immune systems, and people with MS. A healthy lifestyle is key. It can have a huge effect. A regular balanced diet. Adequate sleep is as important as anything else. Our immune system changes dramatically when our sleep is too short or interrupted. I’m a big believer in exercise and in doing things that you love to do, find the path that makes you optimistic and self confident despite having MS. These can have huge advantages to people. I don’t believe in focusing so much on all of these things that you withdraw from life and aspiring to make big accomplishments in the world. But being in tune with your body, and your needs, and being as healthy as you can, is enormously helpful.

Geoff Allix 40:27

That is fantastic advice. I think, firstly, I would encourage everyone to check out the show notes and there’ll be links in there to The Face Laughs While the Brain Cries because I did I have seen an edition of that. And it is, as you say, it’s an entertaining book as well as an educational book. So it’s, it’s, it’s not a boring read. But you will learn a lot of information while having having an enjoyable read as well. So I think well worth checking out the book and just to thank you very much for joining us on this edition of Living Well with MS. Dr. Steven Hauser.

Professor Stephen Hauser 41:11

Thank you so much, Geoff. My pleasure.

Overcoming MS 41:15

Thank you for listening to this episode of living well with MS. Please check out this episode’s show notes at overcomingms.org/podcast you’ll find useful links and bonus information there. Have questions or ideas to share. Email us at [email protected] We’d love to hear from you.

Overcoming MS 41:42

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