PART II: A Regenerative Leap for Epilepsy… Dr. Cory Nicholas, Co-Founder and CEO, Neurona Therapeuitcs
This podcast continues our interview with doctor Corey Nicholas, the founder and CEO of Neurona Therapeutics. If you've not listened to part one, it may be found at biotechnation.com or your favorite podcaster. Recalling that epilepsy is a condition shared by some three million Americans with fifty million or more worldwide, Neurona has developed and begun their very first treatments. This entails inserting additional inhibitory cells into the brain. Their efforts are focused on the most common type of epilepsy, temporal lobe epilepsy.
Dr. Moira Gunn:There are now interim results. Okay. So now we are many months, many months since we first talked. Was it two years, I believe? And you're now in the midst of a phase one two, as we say, an accelerated study.
Dr. Moira Gunn:And while that's not completed, for a portion of it, there is an early readout. So let's talk about what you did in this study what you see as a result.
Dr. Cory Nicholas:So the phase one, trial that's ongoing originally was in 10 subjects, 10 patients. Five received the low dose of the cell therapy that's called NRTX one thousand and one, developed by Neurona Therapeutics. And then a second five patients received the higher dose than NRTX-one thousand and one. Since those patients have been treated, we've enrolled an additional, eight patients into the trial, So four more at the low dose and four more at the high dose. You know, given how well, things were going, we we decided to expand it.
Dr. Cory Nicholas:But that was, that happened later, and so we don't have the data yet on that expansion group. But we do have some, data now on the first ten patients and we shared this recently at the American Academy of Neurology Annual Meeting in, San Diego this past month where we now have at least one and a half to two years of follow-up on the first five patients to receive the lower dose of the therapy. And these were people who had that same form of epilepsy that we were talking about earlier. These are, adult patients who have drug resistance seizures coming from one temporal lobe and had failed a number of medications and decided to try the cell therapy instead of the lobectomy or laser ablation surgeries. And one of the, well, we always ask the doctors why their patients decided to come into the trial because it's very brave.
Dr. Cory Nicholas:First in human trial don't have any evidence of precedent of safety or efficacy. And so that is truly heroic and altruistic for these early patients to enroll in a bold effort like this, not knowing the outcome. But they all say that, one of the advantages of coming in to the study, the cell therapy trial is that you can always have the other surgeries later if the cell therapy were not to work, that everything stays on the table essentially. Whereas conversely, you can't do it the other way around. If you go in and you have a lobectomy to remove that part of the brain or a laser ablation to destroy that part of the brain, There is no part of that brain left to regenerate.
Dr. Cory Nicholas:And so you'll never be able to have, you know, a cell therapy or any other option in the future. And so I think that, the mindset for many of the early patients, not to put words in their mouth, but what we've heard word-of-mouth is that, you know, this is something that they could, you know, as long as it's safe, they could try, and still have all of those options ahead of them. And so they all came in and they had a single dose of the cells and, we've been following them and the trial is still ongoing. So this is all preliminary, but, we've seen substantial seizure reduction in four out of those first five patients. And so, one of them has become completely seizure free, for two years.
Dr. Cory Nicholas:Two more of them have become nearly seizure free, meaning that, just their most severe seizures have been, completely, eliminated, also out for two years. And then a, fourth patient has had about an 80% reduction from baseline. And so a very successful outcome. And then we've had one patient of the first five that has not responded yet. Now this has been very encouraging, because many of these folks, as I mentioned, have the hardest to treat seizures.
Dr. Cory Nicholas:Some of them were having, you know, 20 to 40 seizures a month, right, despite being on medications. And so some of them have spoken out to the press on their own accord and have, commented on how, you know, positively transformative this has been in helping them to get their quality of life back. And obviously, you know, the trial is still running and time will tell, But, but it's been really phenomenal and encouraging for the first five patients who overall have had a, as a group, a ninety two percent, median reduction in their baseline seizure frequency. And that was at the one year mark. And now that they're in the second year, as I mentioned, so two of them are at two years and three of them are at a year and a half, the four that responded in the first year have had a durable response in the second year.
Dr. Cory Nicholas:And that's one of the things we didn't know when we spoke, you know, many months ago is, you know, that's great that we're seeing some early, glimmers of hope, but will it be durable? And, so far, you know, fingers crossed for these folks, it has been. And, and that's also after the, the patients have come off that immune conditioning, treatment. And it's been very, very good to see that there hasn't been any sign of relapse or, you know, loss of response in the first five patients.
Dr. Moira Gunn:What about side effects?
Dr. Cory Nicholas:Yeah, so far, we haven't seen any adverse events related to the cell therapy. And, yeah, there have been some, mild to moderate effects due to that immune conditioning in the first months. Those have generally been well managed. And, for these first five individuals that have now come off of those immune suppressant agents, all the adverse events that were attributed, have have, fully resolved. So there has been nothing, that's persisted, that's been averse.
Dr. Cory Nicholas:And and that's, what we had seen preclinically as well. And you never know until you test it in humans, obviously, but we had a very, we had good reason to believe that, you know, the cells were gonna be safe. And, this is, you know, through rigorous testing preclinically in a variety of models. And it's also by design. And so these neurons, they're not just indiscriminately pumping out GABA.
Dr. Cory Nicholas:It's not like a drug that's pumping out the GABA. The cells, as I mentioned, become part of that network. And so because they're part of a network, they become regulated by the network. And so we think of them as providing the GABA on demand. And so they respond to a seizure by providing a proportional amount of GABA and they achieve this level of homeostasis that's really unique as a cell therapy.
Dr. Cory Nicholas:It's very much unlike any other, modality where you're giving a drug and it's just, you know, blasting GABA in the brain and putting the brain to sleep. And in all of our preclinical testing, we never saw any type of sedation or memory impairment or fatigue, or any other kind of adverse effects. So we had a high degree of confidence, but of course, you know, seeing that it's been well tolerated in the first patients is, very gratifying.
Dr. Moira Gunn:That's really an interesting perspective as well, because it's like, well, now you're gonna be generating this. We need this. It's like, no. You only need it at certain times. And if any of us say, well, I've never had a seizure, you don't know that you didn't have incipient ones that your GABA just calmed right down.
Dr. Moira Gunn:Never saw it.
Dr. Cory Nicholas:That's exactly right. And so, in fact, one of the patients of the first five who's had a really nice response actually came in for an EEG. And the EEG measures these lower level of spikes in this part of the brain, and they're almost like the monomer building blocks of a seizure. And so even though this patient was having only, I say only tongue in cheek because this patient was having, I believe, 40 seizures a month, which are, you know, behavioral seizures. They were having a thousand epileptic type of spikes per hour.
Dr. Cory Nicholas:So to your point, Moira, this epileptic activity is oftentimes subclinical, and people don't know that that's happening underneath and driving the gradual buildup of this activity that eventually, you know, runs away like a runaway train and causes a seizure.
Dr. Moira Gunn:Now there is not just a tremendous unmet need here. I know the FDA has given you expedited review designation and you've begun to design a phase three clinical trial. What do you expect to see in this phase three trial, knowing that your phase one, two is ongoing?
Dr. Cory Nicholas:Right. So we, based on this early data, submitted an application to the FDA for what's called an RMAT designation, which stands for Regenerative Medicine Advanced Therapy. And that's, similar to a breakthrough designation, but for regenerative therapies. And, to be eligible for this, you have to have some clinical data that suggests that this could be, you know, potentially, efficacious and, you know, filling an important need as a regenerative medicine for serious, illness. And, you know, given that we were seeing encouraging signs of seizure suppression and safety, and I did mention also that, we've not seen any permanent cognitive deficits.
Dr. Cory Nicholas:We've not seen memory loss or, you know, any type of, impact on on, you know, quality of life or, you know, other other type of neuropsychological, impacts. In fact, you know, we we've seen a couple of the patients with significantly improved scores on these very, sensitive neuropsychological tests. And so with this body of evidence, the, FDA granted us the RMAT designation in the middle of last year. And then this provides additional meetings with the agency to discuss how to best advance the program in a safe manner. And and so with this, these conversations have led to an alignment with the agency on the design of a single phase three study.
Dr. Moira Gunn:I'm speaking with doctor Cory Nicholos, the cofounder and CEO Verona Therapeutics,
Dr. Cory Nicholas:a former member of the faculty and postdoc in the Department
Dr. Moira Gunn:of Neurology at UC San Francisco. His research work, in part, evaluated the therapeutic potential of interneuron cell therapy in neurological disease. I'm Moira Gunn. You're listening to Tech Nation. When might you be recruiting for that?
Dr. Cory Nicholas:And so the, plan is to start enrolling in the second half of the year, this year.
Dr. Moira Gunn:So this year, 2025.
Dr. Cory Nicholas:That's right.
Dr. Moira Gunn:Fall of twenty twenty five. Watch this space, I hear. I hear. Yes. Which is extremely fast, especially on ongoing phase onetwo.
Dr. Moira Gunn:It's like they see real promise here, obviously.
Dr. Cory Nicholas:Right. Well, phase onetwo primary endpoint is at one year. And so the first five patients at the lower dose have surpassed the one year endpoint in the phase one, two. As I mentioned, they're now off almost near the end of the second year. And then we had a second dose that was a higher dose in another five patients that we reported interim data on at the AAN meeting, which is also showing promise and we're seeing a similar reduction, although that cohort hasn't yet made it all the way to the one year mark.
Dr. Cory Nicholas:And so we're seeing, you know, encouraging effects at both dose levels. Preclinically, didn't see a difference in the dose levels with respect to safety or efficacy. And so we think that they're behaving in much the same way. But in other words, by the middle of the year, we will have completed the one year endpoint on both of the dosing cohorts and we'll be ready to pick a dose to go into the phase three. And the phase three is designed as a randomized double blind controlled trial of the cell therapy versus a sham control group.
Dr. Cory Nicholas:And the sham control group in this case, is, sham procedure. And so, patients that come into the study will be randomized and meaning that they won't know which arm they're gonna be put into. And two thirds of them will receive the cell therapy and one third will not. And they will essentially be anesthetized and nothing will enter the brain. So there's nothing injected, there's nothing touching the brain.
Dr. Cory Nicholas:It's essentially a sham procedure, and they'll wake up not knowing if they had the cells or not. And then, we will follow these patients for a period of time until they reach the primary endpoint, at which point they'll become unblinded and they'll find out which group they were in. And if they were found to be in the sham group, they will then have the opportunity to receive the cell therapy at that point.
Dr. Moira Gunn:Now when I first interviewed you, we were just wishing and hoping we'd see some results here. And not only, has this all been moving along, Dorona has another phase one, phase two on a on a different aspect, if you will, of this, as well as a number of pipelines and some new science. Some of that new science, I'm not even sure what it's about. But why don't you give us a shot? Tell us about your your other pipelines and and clinical trials, and tell us about your new science.
Dr. Cory Nicholas:Right, well, we're very excited about NRTX-one thousand and one for the treatment of focal epilepsy beyond just the one temporal lobe that we're currently treating. And so we have a second phase one, two trial that is active, actively enrolling in, people that have the same disease, MTLE or mesial temporal epilepsy, on both sides of the brain. So both essentially has two seizure foci. And then in this population, in a single procedure, we'll be, injecting the cell therapy into both of the temporal lobes simultaneously. And in this way, you know, attempting to quench the seizures coming from both temporal lobes of the brain.
Dr. Cory Nicholas:And this is a population that has, if you can believe it, even higher unmet need because people that have two seizure foci in both temporal lobes are not eligible to have lobectomy procedures by and large because if you destroy or remove both temporal lobes, you become severely amnestic, right, because the temporal lobe is the part of the brain that controls memory formation. And so this population of patients truly has no other option. And, we're very hopeful that the same results can be extended to this group. And, this trial is actively enrolling. It'll be in 10 adults.
Dr. Cory Nicholas:And so you can go on our website, neuronotherapeutics.com, to find out more information about the trials and the eligibility criteria. We have another study that's also active. That's a continuation of the first, the unilateral trial that I just went through. And this is in a slightly different population of patients that has epilepsy coming from the part of the brain that is not damaged on the MRI. It's a bit of a nuance, but these individuals have their seizure foci identified exclusively by EEG, which in many people, they cannot see where the seizures are coming from on the MRI.
Dr. Cory Nicholas:And so it's very important to be able to triangulate the seizure focus by EEG and to show that we could administer the cells into this population identified in this way, to hopefully have the same outcome and broaden the applicability. And so trials are ongoing. We have studies running at approximately 30 centers across The United States. These are the accredited comprehensive centers that I mentioned earlier. And so, you know, encourage folks to to go and if they or, loved ones are affected with drug refractory seizures, to go to a level, three or four center period to have a workup to evaluate options.
Dr. Cory Nicholas:And, of course, if you're interested in the trial, could talk to your physician about whether or not you would be a good candidate for the cell therapy investigation if that's of interest. Beyond temporal lobe epilepsy, we do have very much, interested in testing whether or not this same therapy can be effective in seizures coming from other lobes of the brain beyond the temporal lobe. And there are many adults and children that have, different ailments in the cerebral cortex. Many, have what's called focal cortical dysplasias where a part of the brain doesn't develop normally and can cause seizures that are difficult to manage. And so many of these are in areas of the brain that can't be removed, what are called eloquent areas of the brain.
Dr. Cory Nicholas:And so we would like to test, in the future whether the cell therapy approach can be safe and effective in those folks. And then beyond epilepsy, we and by the way, there are other epilepsies of interest. I should mention that there are many epilepsies in other parts of the brain that start in one or more places, we're not sure why they start and there's no clear fingerprint to to see where they're coming from. We're interested in those. There are also others that are due to, to secondary to traumas, like a traumatic brain injury or a stroke or a tumor.
Dr. Cory Nicholas:And so these are sort of where we're headed with the, with this approach. And then beyond epilepsy, we are interested in, Alzheimer's disease, Parkinson's disease, neuropathic pain, and potentially neuropsychiatric disorders like schizophrenia and PTSD. And that's a big, basket of things. But the thing that's common about them all is that they share this hyperactive pathophysiology, this hyperactive circuitry of too much electrical activity coming through that circuit. And so at its core is the same fundamental of putting these inhibitory cells to quiet that part of the brain, repair that part of the brain in a homeostatic, you know, manner.
Dr. Moira Gunn:So you're after it. You're you're looking for too much excitement. You're very calm, Doctor. Nicholas. I like this.
Dr. Moira Gunn:Now I have to say that you've been at this a long time. It must feel great to finally see some some just real results here.
Dr. Cory Nicholas:We've been working on this for a very long time. This goes back to the late nineteen nineties, in the labs of my cofounders at the University of California, San Francisco, where many of these discoveries were first made. And it has been a long journey, and it's very gratifying to see it move truly from bench to bedside. And, you know, to see the early results are fantastic. And also, you know, it always has to come with the level of scientific rigor and, the caveats that it's still early, and so we need to keep testing it.
Dr. Cory Nicholas:And and we think that the phase three study that will be designed in anywhere between, 30 and, 90 patients, and we're still fine tuning the sample size based on the maturing dataset from the phase one, trial, which we aim to lock down by the middle of the year and then in advance of starting that phase three trial in, the second half of this year. But we think that, you know, this next trial will be, being that it's a double blind controlled study, will be of the highest rigor to conclusively determine whether or not the approach is working. And, you know, we hope to then at that point, take it beyond The United States and to look, you know, at Europe, for example, and, Asia and and start to advance this for for everyone that may be looking for an alternative.
Dr. Moira Gunn:Well, doctor Nicholas, thank you so much for coming in, and I hope you come back and see us again.
Dr. Cory Nicholas:Well, thank you so much, Moya, for having me back on. It's a pleasure. And I just want to thank the amazing team at Neurona for their dedication in developing this and continuing to advance this therapy and program for epilepsy and other disorders of the nervous system. I want to thank our clinical collaborators. As I mentioned, this is a several hundred person effort now with, 30 medical centers around The United States and growing.
Dr. Cory Nicholas:I want to sincerely thank the patients and their families who are part of this program and by participating in this, advancing our understanding, and hopefully, making this available for more patients in the future. And I I lastly, I want to thank the California Institute for Regenerative Medicine, which has helped to fund a lot of this work. And so we're very lucky, here in the state of California.
Dr. Moira Gunn:Doctor. Corey Nicholas is the co founder and CEO of Neurona Therapeutics. More information is available on the web at neuronatx.com. That's neurona, n e u r 0 n a, neurona t x Com. Each of the clinical trials for which Neurona is actively recruiting and which Doctor.
Dr. Moira Gunn:Nicholas has just described are presented in detail on the Neurona Therapeutics website. It identifies participating centers, direct contact information, eligibility parameters including precise inclusion and exclusion criteria on becoming a study participant, timelines, the measurements being examined, the participation level required, and how travel expenses, if any, will be handled. This information can be found under the tab Clinical Trials at Neuronas website, neuronatx.com. For information about Level three and Level four epilepsy centers near you, the National Association of Epilepsy Centers links 300 member centers in 44 states. The website is naece epilepsy Org.
Dr. Moira Gunn:Wide ranging information about epilepsy, as well as understanding and living with epilepsy, is available from the Epilepsy Foundation. Their website is epilepsy.com.
