PART 1: A Regenerative Leap for Epilepsy…Dr. Cory Nicholas, Co-Founder and CEO, Neurona Therapeutics
We're talking about an experience of success in science and biotech that we don't often see. Usually, we're hoping for a little better quality of life or precious time, even a little more time in extending a life or stopping the progression of a medical condition for some relatively short period of time. But today, we're talking about something that has all the earmarks of a great leap forward, both for science and for biotech. I'll be speaking with doctor Cory Nicholas, the cofounder and CEO of Neurona Therapeutics. And without stepping on Neurona's good news, let me just say that they've essentially been working on delivering to the brain something essential it lacks, and they've been working on it for over two decades.
Dr. Moira Gunn:In their very first treatment, they focused on the most common type of epilepsy, temporal lobe epilepsy. While epilepsy in general is a condition shared by some three million Americans and fifty million more worldwide, Neurona's potential is not limited to temporal lobe epilepsy or even epilepsy alone. There are many disorders of the nervous system, and epilepsy is just one. Neurona's technique may also have potential for other neuropsychiatric disorders, including Alzheimer's and dementia, Parkinson's, and even brain trauma and PTSD. But all that is looking ahead.
Dr. Moira Gunn:What we have today is clear progress for the underlying science and a durable two year success for Neurona's first one and done therapy. We'll talk about exactly where Neurona is in its bio entrepreneurship journey, which started on that long ago lab bench to this place today where it may actually be able to help millions of people live lives they simply didn't think possible. And now, Doctor. Cory Nicholas. Doctor.
Dr. Moira Gunn:Nicholas, welcome back to Biotech Nation.
Dr. Cory Nicholas:Thank you, Moira.
Dr. Moira Gunn:Now we have some really good news to report in Neurona's quest to develop effective treatments for epilepsy. But before we get to that, let's give everyone a view of what the experience of epilepsy is like for people who have this condition and the treatments currently available to them.
Dr. Cory Nicholas:Well, epilepsy is a huge unmet need and I think most people don't realize the severe quality of life issue that it poses. Epilepsy affects three million people in The United States And despite there being over three dozen medications for seizures, most adults with epilepsy continue to have seizures. And it's thought that an estimated one third to one half of people living with epilepsy have their seizures, poorly controlled by the current medications on the market. And so unfortunately, for about a third to a half of the population with epilepsy, the current medications just aren't good enough to control their seizures and to allow, folks living with this, disorder to, do the things they want in life. And so for this reason, you know, there's a definite need for alternative therapies.
Dr. Moira Gunn:Now, we certainly can say that the seizures themselves will stop you from doing a lot of things. You don't want to be out and about or driving a car or anything like flying a plane and suddenly have a seizure. But the medications, any of us who take medications, are subject to side effects.
Dr. Cory Nicholas:Right, and many of these medications work by reducing activity in the brain. And so a common adverse effect of the anti seizure medications is somnolence or sedation fatigue. And a lot of these can be can be troubling. And a lot of the medications can also affect, as you as you said, cognitive function and can, impair memory. And so, absolutely.
Dr. Cory Nicholas:And and many times one drug is not enough. And so a lot of the patients that we see are coming in on a polypharmacy cocktail of multiple medications, and each of them have their own contraindications and are not so well easily combined with one another. And so a lot of the combinatory effects aren't known. And so this is a definite concern and risk.
Dr. Moira Gunn:So what do you do if the current medications don't work?
Dr. Cory Nicholas:So people who are drug refractory, meaning that, you know, they're not responding to at least two or three of the anti seizure medications on the market, and oftentimes they've tried many more than that. And at this point, if folks have access to, health care, which of course is, not a given in our, challenging health care environment, then people would be referred to a neurologist and then on to a comprehensive epilepsy center. And these are accredited epilepsy centers, that are called, the National Academy of Epilepsy Centers, and they have levels to them. And so level three and level four are the top centers. And there's about two fifty of these centers across The United States where if people aren't responding to medications, that's ideally where they should go to seek additional care.
Dr. Cory Nicholas:And now at these centers, patients will be evaluated, for the nature of their seizures and the location, in the brain at where they start and how they spread. And this is done using the latest state of the art imaging and EEG technologies. And unfortunately for about a third of people that undergo these, monitoring, workup tests, they find that the seizures can't be pinpointed to a particular place in the brain. And at this point, many people have no other options. Now for two thirds of people, generally speaking, they can find a point in the brain where the seizures start.
Dr. Cory Nicholas:And these are what's called focal onset epilepsy. Most times they start in the temporal lobe of the brain, but there are many others that start in other lobes of the brain. And if they can pinpoint an epicenter for seizure onset, then some of those folks can be eligible for a surgical procedure to either remove that part of the brain or to destroy it with a laser. And in well selected people, this can potentially be a good option, but it does, due to the destructiveness of those surgeries, it does carry a risk of impaired brain function. And most notable in the temporal lobe is memory loss.
Dr. Cory Nicholas:And this can be irreversible on cognitive function. And so for some, it's not a good option, especially, you know, folks that are younger that have, you know, their lives ahead of them, ambitious life goals. That that just some, you know, it's not a good option, for for those individuals. You know, and and for others, they're just simply not eligible because of this risk. And, the surgeons don't want to touch areas of the brain that are, quote, unquote, eloquent, areas of the brain.
Dr. Cory Nicholas:And so the, and and for all, it's a very scary prospect, obviously, to go in to have a part of the brain removed or destroyed, and to potentially come out of the operating room as, you know, a different person in in a way. Now for some, it can be a good option. And so they should be evaluated and, you know, these options should be thoroughly discussed. In some cases, you know, going in sooner rather than later is highly advised by epilepsy physicians, because the sooner you can get evaluated, if you are a good candidate, to have the seizures dealt with before the repeated seizures can damage the brain as well. And so you wanna get that evaluated by, you know, a neurologist and a neurosurgeon and an epilepsy center as soon as possible.
Dr. Cory Nicholas:But the point is here is that the current surgical options are still, largely suboptimal, because they pose a risk of irreversible, impairment for some people that go through with them. And so this is why what we're doing at, Neurona has so much potential in that, you know, we're developing a cell therapy that could possibly, restore function to this part of the brain, and and repair that part of the brain in a nondestructive manner, potentially regenerative manner, and in this way preserving cognitive function and hopefully taking care of the seizures.
Dr. Moira Gunn:Now from your last visit to biotechnician, Doctor. Nicholas, you reminded us that we had billions of nerve cells throughout our bodies and that we had even more neurotransmitters communicating between all these nerve cells operating all the time even as we speak. And some are excitable neurotransmitters as in get excited, and some are inhibitory as in calm down. Remind us about what neurotransmitters do, especially in the brain, and what do they have to do with epilepsy?
Dr. Cory Nicholas:So brain cells come in a couple of main flavors. The first are glial support cells and the other are the, neurons, or neuronal cells, which the, the neuronal cells are the cells that conduct electricity through the nervous system. And the neurons connect to one another through synaptic connections. And in those synaptic connections, there are these little chemical messages called neurotransmitters, which communicate from one neuron to the next and propagate that electrical impulse through the circuitry. And so most of the neurotransmitters and the neurons in the brain that are secreting these neurotransmitters have an excitatory role in that one neuron communicates to the next and excites the next, which excites the next.
Dr. Cory Nicholas:And this is which what propagates electricity and and, you know, signals through the the nervous system. And this excitatory neurotransmitter, the the predominant one in the, in the forebrain is called glutamate. Now what a lot of folks don't know is that, and that's the majority of of the neurons in in the brain. But what's not understood is that there's a minor population of neurons representing about 30% of the neurons in the brain that are inhibitory. And these neurons secrete the key inhibitory neurotransmitter that's called GABA, which stands for gamma aminobutyric acid.
Dr. Cory Nicholas:And its role is to inhibit the other cells from firing. And so it's a very delicate balance between the inhibitory cells and the excitatory cells that allows our brain and our neural networks to function in a normal state. And there's this optimal set point of activity that's very important to maintain, in order to have a healthy functioning nervous system. And what can happen in epilepsy and in other diseases is that these two, signals can become imbalanced And you can have too much of the glutamate, too much of the activity, and not enough of the GABA, which leads to this hyperexcitable imbalanced state that is essentially the definition of an epileptic seizure.
Dr. Moira Gunn:I'm speaking with Doctor. Corey Nicholas, the co founder and CEO of Neurona Therapeutics, a former member of the faculty and postdoc in the department of neurology at UC San Francisco, his research work in part evaluated the therapeutic potential of interneuron cell therapy in neurological disease. Now I remember you telling us before that you are born with all the inhibitory brain cells for life. They're created pre birth.
Dr. Cory Nicholas:Yes. And that's true for most of the neurons in our brains is that they are generated during the peak period of neurogenesis before birth in utero in the second and third trimester. And as far as we know, for most of the neurons in our brains, there is no stem cell after birth in our adult brains that can replenish aging or dying neurons, either through aging or through different types of traumas from the environment or from genetic predisposition. And this is why disorders of the nervous system are so, so difficult to treat.
Dr. Moira Gunn:Now let me ask you this before we get on to Neurona's big idea, and that is that we can certainly observe epileptic seizures, but can we do we actually have a test to ensure that's what we're looking at? Do we have a technology or a set of technologies to tell us?
Dr. Cory Nicholas:Yes. So seizures come in different flavors as well, and it depends on where the seizure starts and how it spreads through the network. Epilepsy is truly a neural network disease. And depending on where in the brain that electrical hyperactivity is occurring, it can have different physical manifestations on behavior. And seizures can start, and by the way, are usually not predictable.
Dr. Cory Nicholas:In other words, they're spontaneous, They can strike at any moment, and this is why they can be so scary. And oftentimes, they start as a an aura or a hyperintense feeling of euphoria or confusion. And this can then evolve as the electrical activity starts to spread around the brain into more disabling phenotypic manifestations such as twitching of the hands or lip smacking, impairment of vision. These can then evolve further into complete loss of consciousness events where someone can freeze for quite a long period, and this can result in crashing a car or, you know, walking into the street. And then of course, as the seizure engages both sides of the brain more fully, this can result into the most severe type of seizure, which is, the grand mal atonic colonic seizure, which often involves, you know, full convulsing and, falling to the ground.
Dr. Cory Nicholas:And, you know, these, seizures oftentimes, you know, people think that, if you're only having, you know, one seizure every month or one seizure a year, it's not a big deal. Well, it is a huge deal because you have just one or two of these in a year or ever in life, and that can damage the brain from a single event. It often sets the brain up for future events that can strike. And so it's very common for people with epilepsy to have had their first seizure during childhood, oftentimes after a fever called a febrile seizure, and then not have a seizure for decades. And then suddenly later in life start to have spontaneous, chronic recurrent seizures, to then be formally diagnosed with epilepsy later in life.
Dr. Cory Nicholas:And so just having a single severe seizure can be very, just devastating. And not to mention that, you know, a seizure can can result in a in a fall and can result in having to go to the ER. Burns are very common. And then, of course, there's always a risk of SUDEP, which stands for sudden unexpected death from epilepsy. And that is obviously just not acceptable.
Dr. Cory Nicholas:The thing about epilepsy that is so hard is that you never know when a seizure's gonna strike, as I said, but you also never know when it's gonna spread. And so these can strike and stay mild and never evolve, but they can also continue to spread around the brain and evolve into a very serious event.
Dr. Moira Gunn:So in one sense, they they create damage and extensive damage go on themselves.
Dr. Cory Nicholas:That's exactly right. And it's thought that the more seizures you have, the easier it is to hit that threshold where the brain can continue to cease. And so it can be very progressive in this way.
Dr. Moira Gunn:Okay, so what was Neurona's big idea?
Dr. Cory Nicholas:Well, our idea at Neurona was to develop a regenerative cell therapy that could provide balance to the brain in a nondestructive way. And so rather than the current surgical paradigm of having the seizure prone part or parts of the brain removed or ablated with a laser, we wanted to put the missing cells and the missing inhibitory tone back into those parts of the brain. And so to regenerate the cells that are missing and to then deliver that cell material precisely where it is where it belongs and to in this way regenerate and restore and repair the nervous system.
Dr. Moira Gunn:So you're talking about those GABA cells, the the the GABA inhibitory neurotransmitters. You're saying if we can put those in, the ones that say calm down in a sufficient balance, so it balances the excitability transmitters, then you're actually you can stay in balance and avoid the seizures.
Dr. Cory Nicholas:That's precisely right. And so we are delivering neurons that are those inhibitory, GABA secreting neurons, and these are called interneurons. And we're putting these neurons, precisely at this epicenter of where seizures start and allowing these cells to bring that GABA inhibitory signal that's been missing in this part of the brain and to reconstitute that using this cell therapy approach so that we can re achieve that balance and that set point and quiet the seizure storm.
Dr. Moira Gunn:Now two questions here. First of all, how do we get these GABA cells and do I need my own? And the second question, I realized I asked two questions there, but the second question is how do you get them into my brain?
Dr. Cory Nicholas:Right. So there are a couple of different approaches for accomplishing this goal. One is to use stem cells that are patient specific, but the other is to use stem cells that are what's called off the shelf or one cell line for all recipients. We've chosen the latter path so that it's an off the shelf therapy, meaning that the cells are ready on demand. They don't have to be manufactured separately for each person.
Dr. Cory Nicholas:And because of that, they are, the therapy is actually frozen and it's ready when patients enter our studies. And it's suitable for all essentially. There is no matching immunologically or conditioning. We do give a short course of what's called immunosuppression in the early phase of the therapy to facilitate long term survival of the cells because we do intend for this to be a one and done procedure. So we think, and to the best of our ability in all of the preclinical testing that we've done, that one administration of this procedure will be sufficient, hopefully for a lifetime, and that these cells are intended to, migrate into that neural network in the brain and become part of that network, and they make those synaptic connections.
Dr. Cory Nicholas:And once they do that, we think that they will be a permanent resident and that they will be, you know, part of the brain in the recipient, for for a lifetime. And so the cells are delivered in an image guided procedure. And so I mentioned earlier that when patients come to a comprehensive NAEC, National Academy of Epilepsy Center, for a workup, EEG and MRI imaging are performed. This is where the surgeon and the neurologist can triangulate the seizure onset zone good candidates for this type of therapy. And so they can see by MRI and are some other imaging modalities such as PET and or by EEG as to where the seizures are starting.
Dr. Cory Nicholas:And it gives them a target for where to put the cells. And then the cells are then the the frozen product, which contains these inhibitory cells, is, thawed and then it's, loaded into a MRI compatible, cannula or needle essentially. And then that is carefully guided using intraoperative MRI or CT into the part of the brain where the seizures are coming from. And then these cells are carefully and slowly infused into that part of the brain. And the infusion process takes one to two hours depending on the dose we're using.
Dr. Cory Nicholas:And so it's a relatively it's a very small volume, but it's infused at a very slow and careful rate. And then the delivery cannula is removed and the patients have all come out of the procedure just fine. Then they stay overnight in the hospital for observation. But to my knowledge, everybody has gone home the next day and, has been doing very well.
Dr. Moira Gunn:You've just listened to part one of a two part interview with doctor Cory Nicholas, the cofounder and CEO of Neurona Therapeutics. In part two, we will hear about the unprecedented interim results of this important phase onetwo study. More information about Neurona Therapeutics is available on the web at neuronatx.com. That's Neurona, n e u r o n a, neurona t x dot com.
