Are Remyelination Strategies Realistic?

October 21, 2017

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00:00 This afternoon even though it’s a lot of information about a diverse array of topics you’ve gotten a sense that the amount of very impactful research around these rare diseases is just exploding. When we did the research talks even 10 years ago they were nowhere even close to the level and diversity of different studies that are going on.

00:23 What I wanted to do with the last Talk of the day is to bring this home if you will you heard great talk several great talks today about where we are relative to stem cell therapy and Transverse Myelitis and it’s a question that we get on a regular basis. And so I’d like to take a lot of the information you’ve gotten today and give you updates and put it in context to where we are in timelines. So how do we make therapeutic possibilities reality and a version of this was presented today. But it’s important to go through the stages. So the first is what’s called preclinical development. You have to develop whatever agent whether it’s a stem cell or whether it’s a molecule you have to develop it and you have to test it. And you in that testing both have to prove that there is a reason to believe it will be efficacious.

01:14 And then a hundredfold more you have to prove as best as you can that there is no obvious or expected toxicity from that therapy. And so there is a lot of work that is done before any agent goes into a human being for the first time to try and make sure that there will not be any untoward effects. The preclinical development the preclinical testing for any therapeutic agent can literally take years or even decades in order to get through a lot of the issues once you have something that you think is both safe and effective then at least in the United States. It’s a little different around the world but it’s a lot of analogies. But in the United States you seek regulatory approval through the FDA. They grant what’s called an IND. You submit an IND application an investigational new drug application.

02:06 They review it. There can be meetings and discussions and they basically they don’t give approval but they don’t forbid you is the way it works. So you can submit an IND application and you wait 30 to 40 days. And if they don’t say no you’re allowed to go forward is how it works. So you go through that process which includes all of your preclinical testing and preclinical development data as well as your described clinical trial as you see it. And they can ask you questions on any of this and they can ask you questions on where is your agentmanufactured. What’s the quality batch to batch. Why did you pick this trial design versus another trial design. We do not like the outcome measure your use and we do not like the age of the population you’re using anything and everything can be scrutinized in that application and there is there to make sure that good safe science moves forward.

03:00 Before we just start subjecting willing participants to anything that we could imagine. And then you move into what’s called a phase one or a first in human clinical study and phase one studies are designed. Primarily to measure safety. And as long as we make sure an intervention whatever it be whether it’s a stem cell or a drug is safe then you move on to phase two and phase three studies to get approval to market that therapy to the rest of the world. So as you saw earlier today when we’re talking about stem cells we have known about these cells for decades. So why does it take so long to move from the knowledge of a potentially therapeutic intervention to actually having that in your intervention ready to go into humans.

03:44 Well as we showed earlier we know that you can take a pluripotent stem cell an embryonic stem cell put it in a dish. Wait a few days come back later and you’ll see little myelinated neurons and muscle and heart cells and blood cells and maybe a tooth and that’s great. It’s very powerful and it’s very reproducible. But the trick is most of us do not want a tooth in our spinal cord. Most of us do not want heart muscle in our brain. We want to make sure that we can control the development of these cells to a point that when they are given to a human being introduced into a target tissue that we know what’s going to happen.

04:23 And as was shown earlier one of the biggest concerns is in tumor formation will the cells start to reproduce in a way that may initially look helpful but ultimately prove harmful. So it’s the control of the cells that has taken decades to mature to a point that we can really start to talk about human trials. So in the setting of remyelination if we apply this and you’ve seen a version of this slide earlier today we know that if you start with embryonic stem cells you can get to a neuro progenitor cell and then they can differentiate into what are called glial restricted precursor cells and those can then form oligodendrocytes, oligodendrocyte progenitor cells and astrocytes lots of different cell names. The key is what you want to remyelinate is oligodendrocyte progenitor cells and you’ve seen images of these in different talks today and I was I was thrilled to see the different ways this has been approached both from getting the immune system to promote your own endogenous oligodendrocyte progenitor cells remyelinate any damage that’s been done.

05:23 But also in through cell therapy to create these cells and then introduce them to a human being that needs them for repair reasons. So part of the preclinical work that’s gone on in stem cell therapies relative to the diseases we’re worried about is improving that we can control cellular development all the way through oligodendrocyte progenitor cells. And then you have to prove the negative you have to go to the FDA and you have to say. I have dishes and dishes and dishes of oligodendrocyte progenitor cells and I’ve looked them I’ve looked and I’ve looked and I don’t see any liver cells or I don’t see any heart cells.

05:59 And so the question is from a regulatory standpoint how many dishes should we make somebody look at ‘til we’re comfortable that the process worked. And so the bar was set very high relative to preclinical development for stem cells. The other part of preclinical development that has been addressed today is you have to prove that the cells are going to do what you want them to do or what you intend to do. So even though in a dish you can see these cells reach out their arms to the naked axons of demyelinated neurons and make new myelin and you can take mice and do the same thing and there’s been beautiful work at Ohio State working with mice and showing remyelination from these oligodendrocyte progenitor cells.

06:40 You have to set up as many possible tests of this notion that you can to prove to ourselves to prove to you and to prove to regulatory agencies that the cells that you claim are remyelinating will actually remyelinate both in a dish and in an animal before they go to humans. When you do the preclinical testing of cells for remyelination you have the two parts you have to have not just a dish but an animal model of remyelination you have to transplant the cells of interest. Show that they remyelinate. And then there’s the second part of the preclinical testing in the same animals and many many many others. You have to assess for any untoward effects. So for those of you who’ve had transverse myelitis it would be a real bummer to put stem cells in your spinal cord and elicit a new inflammatory event to the spinal cord that that would not go so well that’s not what we’re shooting for.

07:38 So we have to make sure we have protocols to prevent that secondary inflammation. Likewise as was noted earlier we have to make sure as best we can that the risk of tumor formation is as low as we can get it. These are the hurdles these are the things we have to do if we’re really going to turn stem cell therapy into reality for our conditions. So what are the necessary requirements for regulatory approval for an IND. So you have to show preclinical efficacy data and all of the cell culture models the animal models what we’ve talked about you have to show safety data in a wide array of different systems using a variety of animals.

08:15 Toxicology data you have to make sure that the cells you’re putting in do not lead to a secondary toxicity to the liver to the kidneys or to white blood cells et cetera. Then you have to look at manufacturing data. You can’t just grow these in your garage and batch to batch and say you’re ready to go. They have to bedone in very specific facilities with very specific quality assurance. And you have to present all of this and a clinical trial designed to the FDA in order for them to review it before we are ever allowed to move into a human being. So the this is the reality. These are the hurdles these are the things we have to do if we’re going to take the hope for stem cells and move into clinical trials for transverse myelitis and related conditions.

09:00 So the challenges around study design. Who should be in a phase one trial. The FDA had lots of questions over the years on should we take somebody who is in the throes of an acute event or should we wait till somebody is six months or a year. Could you wait too long. Could we miss an opportunity to repair. So who do we include in that phase one trial. How do you deliver the cells. We have a lot of data to say that if I inject these cells into the bloodstream they might not go exactly where you want them to go. Can I put them in the spinal fluid or do I need to do what they did in places Holoclar and directly inject them into the tissue that you’re interested in which would mean going to the operating room doing a surgery and injecting cells into the spinal cord.

09:42 How do you monitor for safety what are the tests you need to do in order to ensure you’re not having untoward effects. How do you monitor for efficacy. How do we judge if the cells are helping somebody or not and how long should we follow patients. So if there is a risk of a tumor formation shouldn’t I follow someone for the rest of their life to see if they ever generate a tumor. These are a lot of the challenges. And then when you get to a Phase 3 study you take the data from a phase 1 and you use that to design the next. This is the lifespan of going from an idea and going from a hope to actually making something a reality. So let’s talk about where we are as we sit here today on this pipeline of development to give you the state of the state for things relative to stem cell therapy.

10:30 So and when are we going to get there. So let’s start with preclinical development what’s been done and you’ve actually seen some of this data in some form. Today. We know how to control stem cells and generate glial-restricted precursor cells. So the secret sauce for generating these cell lines is no longer a secret it’s used in labs all across the country in different ways. And there is very good data to say you can reproducibly create a set of cells that do not include other cells. So you can reduce the risk of somebody growing a tooth in their spinal cord when you inject glial-restricted precursor cells from embryonic cells. They will stay as glial-restricted precursor cells.

11:10 We know in preclinical testing that those oligodendrocytes that grow out of them will remyelinate. This has been shown in labs at Ohio State University and across the country where we can see these cells grow out and make myelin around an axon and bring back the integrity of that axon. What about preclinicaltesting. So we have preclinical development preclinical testing. So we’ve looked to see in animal models of demyelination could we grow myelin just going to show one example here this is from a mouse study of what’s called the Shiverer mouse. So the Shiverer Mouse has a genetic mutation where it doesn’t make myelin and it’s a uniformly basically fatal mutation for the mouse without myelin over a period of time the mouse dies. And if you look at the brain you can see axons but you see no myelin.

12:02 If you inject these glial-restricted precursor cells into the mice not wherever you see blue. That’s myelin. So a normal mouse brain is off to the left the Shiverer Mouse is in the right middle and on the right is a Shiverer Mouse that had stem cells injected into the brain. And so you can see those stem cells making the myelin wrapping around the axons in the brain and not all but at least 50 percent of the mice now survive and develop. So you can rescue the mouse from the mutation that it had that prevented myelin formation. So this is preclinical testing to say OK these cells can actually help. What about regulatory approval. So in order to do this there’s a lot of testing that has to happen and a group that we partnered up with one of the organizations that has worked on one line of these glial-restricted precursor cells are called Q cells.

13:00 We work together to put together the regulatory filing with the FDA taking all of their preclinical testing all their preclinical development and clinical trial designs that we put together with the Transverse Myelitis Association and with our centers and we submitted this to the FDA. So using Southwestern and Q Therapeutics with input from SRNA collaborated and put in the application and as of July of this summer it was granted by the FDA. So the FDA gave us approval to move into human remyelinating trials for transverse myelitis to take these remyelinating cells to put them into humans for Phase 1 trial. So how do we get from regulatory approval to actually a phase one.

13:46 Well somebody’s got to pay for it. So we worked hard and we worked collaboratively to try to make this work. So the CONQUER program at UT Southwestern secured a one and a half million dollar gift over the last year to fund all of the clinical portions of the phase 1 trial. SRNA has been working through The Eclipse Fund and through other mechanisms to raise costs to cover accessory costs outside of UTC Houston and we expect to begin enrollment in about six months. The way the trial is designed as a phase 1 trial will be to take nine adult transverse myelitis patients who are more than a year out from their injury and are not ambulatory. Go to the operating room with one of our neurosurgeons directly inject the cells into the spinal cord and then follow over time to look for both safety safety safety safety and fingers crossed obviously we hope for efficacy.

14:45 So as we sit here today with everything we’ve discussed relative the stem cells and we’ve had the conversation in the presentations for 15 years relative to stem cells it’s it’s good to be able to present to the community that we’re actually going to take the first leap and we’re going to be looking for individuals as we get to the spring to go through the phase 1 trial.

15:06 So this work takes a community it takes a very large community. There is no one individual who gets this done. As we started this symposium with the beautiful words from Sandy about Pauline in the history of how we got here it’s worth noting that this is something that Pauling talked about on a regular basis and asked about she knew this was happening. We had regular conversations and she was very excited about what was to come. It’s obviously heartbreaking to us that she’s not here in person to see this come to fruition but we are going to be doing this on her behalf and on behalf of the entire community. So we are excited. We know there is a lot of work to be done when it comes to stem cell therapies relative to transverse myelitis. But at some point you just have to take the leap and start trying these in a methodical and safe way.

16:05 And that’s what we’re going to start doing in the spring. So as I had in the last presentation at least in terms of the UT Southwestern crew This takes an incredible village to do this type of work. Taylor Hinojo this summer in the audience. So Jan, Jan is in charge. She is the boss for the Phase 1 trial so she will spend the next two years doing everything from making sure the FDA and regulatory agencies have everything they need to make sure all our patients are cared for it enrolled an ethical and comprehensive manners. And so if you have questions either Jan or myself are happy to answer them before I turn things over to Carlos to take any questions and close and moderate. I just want to say thank you to the Transverse Myelitis Association for putting this together for you guys for being brave for two whole days and showing up and making it to the end.

16:58 To Chitra Krishnan and the entire crew on the board they do an amazing job in Sandy we know how difficult this has been. And we were all so so thrilled that you came to join us. We it means a lot. We appreciate it and we love you.