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Next Steps to Cures – 2018 NMO Patient Day

Michael:

So how do you follow that? 10 years of tremendous progress. Allie, Victoria, thank you so much. It’s wonderful to see all of you. Many familiar faces, many new faces. Hopefully what you’ll see today is some information that you’ve come to learn about and know about and feel like you’re part of, and you’ll see some things that are brand new. And one of the points of emphasis that Victoria made and we’re always focused on is the next step. It’s fine to reach the goal, but we’re always about, okay, what about the next step? What about the next step?

Michael:

There are two kinds of cures. One is called a functional cure. That is, if you have a disease and you could be treated with something occasionally, let’s say it’s once a week, once a month, once every six months, what have you, and you basically don’t have the symptoms and there are no major side effects. That’s in effect a cure. It’s a functional cure. But there’s also what’s called an absolute cure. And this is where a disease is turned off once and for all. And the foundation is focused on both of those types of cures. We’re going to talk a little bit about the functional cures, and those occur by way of approved therapies. And we’re going to talk about absolute cures, and those occur by way of resetting the immune system.

Michael:

So without really going too much over what Victoria talked about, which is an amazing amount of progress… I mean, I hope you realize that in the scope of time, relative to drug development and academic research, 10 years is the blink of an eye. And we have done so much in so short a time that, as Victoria said, many people are looking to the foundation and its blueprint to focus in on how to solve diseases that they’re interested in. But I just want to briefly review what you might consider a glimpse into the next steps to cures.

Michael:

And there’s really some simple steps that bring an immense amount of talent and intellect and effort and money together for solutions. The first is to light a research fire, and we’ve done a lot of that. We’re going to count on you to do a lot more of that. Approved therapies. Once there is an approved therapy, a lot of other dominoes fall that will open doors for even faster new drugs that might be even better and safer. I want to talk briefly about relapsed biomarkers and preventing relapses. How many of you would like to have no more relapses? Thought so. Okay. And then finally, a couple of words about tolerizing to cure.

Michael:

So if you think about lighting a research fire, how do we do that? Well, you’ve heard that there have been millions and millions of dollars put into research over the last 10 years from Bill and Victoria. And if you quantify the impact, you can see here that there are ways to really illustrate how big of a splash this has made. Victoria mentioned a slide that was shown while she was talking that in the last 10 years, if you search the keyword “neuromyelitis optica” on the publication search engines, there have been 4,352 papers published just in 10 years. That is a huge amount of information. Just look at last year. 10,845 citations. That means that over 10,000 times a paper focused on neuromyelitis optica was cited by another paper saying, “You know what? You guys should look at this paper because it has something important in it.” That is a huge amount of progress. And it’s shaping the field, it’s changing the field of NMO.

Michael:

If you ask, “Well, okay, it’s nice to, to publish a lot of papers, but was there anything meaningful in those papers?” Well, here’s a quick breakdown of what topics were covered. Auto antibodies. We all know that there is an evolution ongoing in terms of NMO, IGG or anti-aquaporin-4. There is another antibody called anti-mog, and there are now other antibodies that are starting to come on the radar screen, including a molecule called anti-GRP78 and others. And the question is, what of these antibodies is most important in a given person? Because some patients have one kind of antibody, another patient may have a different antibody. We need to understand this.

Michael:

Epidemiology and etiology, that is, the demography and the cause of NMO, is a huge topic in the literature now. Where does it start? Why does it start? What are the factors? Is there a risk that I can tell in advance? Who gets NMO? Where? Those are the kinds of topics in epidemiology and etiology.

Michael:

Diagnosis and imaging. We were talking last night at the CIRCLES meeting. Today, the time from onset of disease to diagnosis is a few months. 10 years ago, it was a few years. That’s a huge change. And if a person can be diagnosed and treated quickly, the course is typically much better.

Michael:

Biomarkers and omics. You’ve heard omics. You know more about them than you think. Genomics, proteomics, et cetera. It’s the whole universe of studying a system. Biomarkers are molecules and cells that tell us what is happening in a disease. And I want to talk a little bit about those. Models of the disease, some clinical trial papers, tolerization is now on the radar screen of publications and other topics.

Michael:

One of the important things that comes from lighting a fire is passing the baton. So if you ask, “Okay, well, $50 million have been spent on all of this research. What next?” Well, take a look at this, which you can look at from the NIH Reporter. You can go online, punch in NIH Reporter, and it gives you all the lists of NIH-funded grants. And without going into the details here, just in 2016-2017, the NIH funded NMO studies to the tune of over $8 million. That’s what we mean by lighting the torch. Bill and Victoria made an investment, and now others are taking it forward. They’re carrying the torch. The red circles up there just indicate those individuals that have been supported by the foundation and have now gone on to get NIH grants, which carry the torch.

Michael:

And for those of you who are active or have participated in CIRCLES, just a quick snapshot of what you have helped do. So there are currently 14 sites in North America. Victoria mentioned over a thousand patients. There’s over 1200 individuals enrolled. About 70% of them are cases. About 25% are controls. Why do we need individuals to enroll who don’t have disease? Well, we need to know not only what happens when disease occurs, but we need to study what doesn’t happen in individuals who are closely related. So it’s very important. We really appreciate all of your working on this together with us. Victoria mentioned over 50,000 biospecimens, a million data elements. We’d like to say that we’re not building an NMO museum. This is not an archive to be sealed and put in the back of a warehouse. This is a living, breathing biobank, and people are using it now more and more from studies of genetics and epidemiology, as I mentioned, to biomarkers, therapy and beyond, and we’ll talk a little bit more about that.

Michael:

The actual first papers that focus on how CIRCLES was developed, what it does and some initial findings will be published in the next couple of months. So look forward to that. And the bottom line here is none of it could have been done without you and those around the country and the continent who have participated in CIRCLES. So thank you so much, not just the patients, but the caregivers and the families who have really helped do this with us.

Michael:

We talk about clinical trials and approved therapies. For a hundred years, there was no clinical trial in NMO. And in the last 10 years, three Phase III pivotal registration clinical trials. There are actually now more Phase III trials that I’ll mention a little bit later. There are six Phase III trials now on the clinicaltrials.gov website, if you look at it. Three of them, as Victoria mentioned, are nearing the finish line. And we’ll hear from a couple of the companies today. There are six others that are now in Phase II status, and 15 or more that are preparing for liftoff. Now I don’t know about you, but that is a big number of studies, clinical trials, focused on NMO, when 10 years ago there were almost none.

Michael:

And of course, if there is an approved drug, it means that the regulatory agencies have found it to be safe and effective. But there’s also upside to approving a drug that you might not always think about. Right now, if you enter a trial in North America, in some arms of some studies, there are individuals who are on placebo. When there is an approved drug, placebo goes away, because now there’s something to compare it to. That in turn opens a whole pipeline to speed other drugs for testing. So it’s success begetting success.

Michael:

A couple of words about relapse biomarkers. The foundation has put a lot of effort into finding markers that predict relapse. Wouldn’t it be nice if every few days you could take a little dipstick or something and swab the inside of your cheek and stick it in a little box, and if the light is green, you just go out and play tennis or go to the mall or go to school or go to your job? And if the light is yellow, it says, “Hey, call your doctor and maybe check it out.” Wouldn’t that be great, before you have a relapse?

Audience:

Yes.

Michael:

Okay. The way to find such a biomarker is we have to screen very carefully, and it takes an intensive study to do that. As you can see on this slide, there are three parallel efforts that the foundation has been involved with. First is CIRCLES that you heard about. It is a biobank, but we’re using it to look for biomarkers. Second is through the international clinical consortium that Victoria mentioned. 90 members and 30 countries strong, not just looking at the CIRCLES data and biospecimens, but comparing those with their own registries. It’s an array around the world that the sum is greater than the parts. Victoria mentioned that we’re going to be launching a study with Verily. Google “life sciences”. And this will be focused on big data approaches to finding predictive biomarkers of relapse. And to do that, we’re going to be asking patients to show up every month. Not every six months. Every month. Because in order to catch a relapse, we have to sample more frequently. So those of you who might be interested, we’re very interested in your potential support and consideration. So keep that in mind.

Michael:

Again, the reason for doing this type of work isn’t so that we know the biomarker, but it’s so that we can prevent the relapse. Very simply put, here’s the way NMO usually works now. Person feels pretty good. Life is okay. Going along, and then a relapse out of the blue. Don’t know what causes it. Don’t really know how to anticipate it. And then hopefully there’s recovery. Wouldn’t it be nice if we could just predict in advance the biomarkers of relapse, intervene with a treatment that prevents the relapse, so that there is no relapse and you go from healthy to healthy? That’s what we’re up to.

Michael:

I want to just take a moment now to introduce a platform that’s called the NMO-PRO. Each of you in your folders has a survey. Actually you have two surveys, and we’re going to talk about one of them now, and this is the NMO relapse questionnaire. You could already start helping us predict relapses if patients would fill out this questionnaire. Don’t put your name on it. There’s no protected information. Just answer the questions as best you can. Fold the thing in half. There’s a basket in the side, or just hand them to someone with a green scarf or a green tie. The more we know about how a patient perceives relapse, the better we can study it. And we really appreciate your help with that.

Michael:

You’ll hear in a few minutes later on today, we have another survey that’s focused on therapies and vaccines. We’ve got a few other NMO-PRO surveys that we’ll be rolling out in the near future. Those will also be available online, and they’ll include diet and nutrition and pregnancy and other very interesting topics. So as Victoria said, we’re going to need your help more and more to go from functional cures to absolute cures.

Michael:

And speaking of absolute cure, the word tolerization is one that you should really put in your vocabulary. When the immune system is functioning normally, the tissues that are part of our bodies are tolerated. The immune system says, “Yep, okay, that’s normal, that’s normal. Oh, there’s a bacteria. That’s not normal.” So that’s, in essence, tolerance: to know the difference between self and non-self.

Michael:

Put another way, if you think about it in terms of NMO, we need to help the immune system understand that aquaporin-4 is okay. Now in order to do that, we have to reset, reboot, your immune system. And it’s in effect the inverse of immune stimulus, right? What we want to do is stimulate, instead of an inflammatory immune response, we want to stimulate a non-inflammatory immune response. We want to turn the immune system off to aquaporin-4. Does that make sense? That’s called tolerization, or the induction of tolerance.

Michael:

And Victoria mentioned that about a month ago, we had a meeting about 20 miles from here, and I just want to point out the importance that NMO is having in the world globally, but also at the NIH. So the individuals in this picture on the left, Dr. Jerry Nepom and on the right, Dr. Daniel Rotrosen. Dr. Nepom is the head of the NIH program called the Immune Tolerance Network. Their entire focus is to help develop drugs and strategies that retolerize, that turn one’s immune system off to an auto-immune target. And on the right, Dr. Dan Rotrosen is the head, at the NIH he’s the chief of the Allergy Inflammation and Transplantation program. They would not have been at this meeting if they didn’t feel like NMO was the model for solving auto-immune disease. And that’s because of what the foundation has done, and what the foundation has done is because of what you have done. So you brought these people to the room.

Michael:

I just want to leave it there, and as we prepare for the session where we always invite you to ask some of the experts, to just focus on all that has been done. Yes, the past, but where we’re going. A glimpse into the future? And with so much momentum and so much belief and your continued effort, we’ll get there. Okay. So thank you so much for being here. Thanks for all you’ve done, and let’s keep moving forward.

 

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