Thomas Chen, MD, a neurosurgeon at Keck Medicine of USC, discusses innovations in the treatment of brain cancer, including a new technique for delivering drugs to the brain.
Hi. My name is Tom Chen, and I'm professor of neurosurgery and pathology at USC. Today, I'm gonna talk to you about very exciting motive Delivery. It's called intra nasal delivery, and we're using intra nasal delivery for delivery and treatment of brain tumors. And I'm also gonna talk to you about other clinical trials that we want to do along this route. So I want to know. I want you to know that I am founder and CEO of a startup company that called Neon Technologies. And I have shares in New York Technologies. What is, um, intra nasal delivery? While intra nasal delivery is something I think that you're all familiar with and basically is delivery along the cranial nerves and the cranial nerves that we were talking about is the 1st and 5th cranial nerve. Now, what happens with the cranial nerve delivery is that what we're trying to do is bypassed the blood brain barrier. As you know, many drugs, they're resistant to getting across the blood brain barrier because that's one of our forms of protection with nasal brain delivery. What we're doing is that we're inhaling a drug and allow it to go through the nerves of the of the nose to the something called olfactory nerves. Ah, factory nervous, the first cranial nerve, and it goes from the olfactory nerve to the factory bulb factory track than to the brain. And using this route, we basically are delivering drugs to the brain, using the cranial nerves. The other cranial nerves that we have determined in the laboratory setting that's involved is the fifth cranial nerve. The fifth cranial nerve is the trigeminal nerve and its supply sensation to the nerve to the face and also allows, since it allows delivery to the area of the brain stem. In this picture, what you can see is what I'm talking about. You see how Mrs delivered to the nose and that that Mrs then carried to the olfactory nerves toe that come out and then through the crib, inform play through the factory ball of factory tracked to the brain. Now this is a picture of patient undergoing international therapy. You see how he's breathing of this treatment through the nose, and then it goes through the nose to the brain itself so that, as you can see, the very noninvasive treatment, um, and and a very noninvasive way of getting drugs to the brain. So what we did was that we have a drug. It's called Neil 100. Neil 100 is based on another drug called Peril. Alcohol Peril. Alcohol is this south cycle inhibitor and peril. Alcohol is also a rast oncogene inhibitor. We have also developed the neo 100 as something something called er stress inhibitor, uh, and and that it induces, er stress and causes a popped ASUs. And here I have a schematic of basically what we're doing for synthesis of this Neil 100 or purified pure alcohol, we have a trial that's ongoing. Right now it's a call on open label phase one slash two a dose escalation trial to determine the safety and efficacy of neo 100 recurrent gray for gliomas. Gliomas are basically cancers of the brain. They're they're the most common intrinsic. Neil plasm and great four is the highest grade. It's also called glioblastoma, and this trial is basically based on glioblastoma. Is that have already Rickard despite treatment with radiation and chemotherapy. So what we did was that we obtained something called i n d i N d is investigator new investigative, new drug, and well, and we obtain the fast track status and orphan drug status for our drug, our enrollment criteria. Basically, you have to be a great for, um, glioma or G B M. You need to have failed. Um, standard therapy, which is chemotherapy drug called Temodar and radiation. You need to be a vast and naive, which is a another drug that we use. A second line therapy is the anti angiogenesis drug. You need to have a karnowski score greater than 60 and tumor less than three by three centimeters. And what we have done is that we have running this trial in several sites across the United States at USC, the Cleveland Clinic, University of Wisconsin University of Washington, and we're currently enrolling patients. Now I want to show you what we're doing with our Phase one trial. The Phase one trial has already been completed, and what you can see here is that we were asked by the FDA to do a dose increasing trial. Um, using four chords cohort one is the lowest dosage and 96 mg per dose. Patients get a four times a day, and so At the end of the day, they get 384 mg of our Neil 100. As we dose escalated up to cohort four, you can see that they got these patients get up to 288 mg per dose four times a day, or 1152 mg per day total. Now we enrolled a total of 12 patients for this trial, and you can see how it goes from, UH, three patients is three patients for cohort, and you can see that it's a from a gender standpoint, was the equals division of male and females. Most of the patients were basically between 50 to 70 years old. The ethnic group was reflective of what's, uh, of Los Angeles, which included Caucasian, Asian and Hispanic patients. We had mgmt status, um, the term, whether they're methylated, I'm methylated. The MGMT is basically a DNA repair enzyme. If the patients are methylated, they have a defect in the MGMT and therefore they're more sensitive to team is on my treatment on. We also had the meta bog marker i D. H one status, determined as wild type or mutated and then also there Karnowski score, whether they how they were performing and then tumor location. And you can see from the tumor location standpoint, most of the these patients are basically in the frontal temporal occipital lobes. Ah, now a zey Phase one study. We want to know what the adverse events are and adverse events we looked at were included general disorders, no nervous system, disorders related to the brain, skin, respiratory problems or blood and lymphatic system disorders. And we great according Thio, the dose escalation of going from 384 to 101,001 and 52 mg per day and then we determine whether are these, um side effects that are recorded, uh, possibly related or definitely related to treatment now one. The score one is basically the lowest grade that you can have, and it goes up to score. Four was the severity and you can see what happens is that the treatment adverse events are most likely related to the nose and rhino re of being one problem and then skin irritation. But there was no definitive problem with mile toxicity or head or other severe central nervous system toxicity. So from a standpoint of dose escalation, this was a very small increase in increase in terms of adverse events experienced by these patients. Now what we did was that we grated these patients in terms of how they did. Okay. Now, in terms of the completed cycles, each cycle was one month. And so if Asian completed, for instance, instance two cycles, that means that they've had two months of treatment and and and they stopped the treatment because they had an increase in their, uh, disease by m r. I scan. And so we basically took the patients as how many cycles did they complete? And the Reynaud basically is a memory criteria for progressive for progression, and so a Reynaud score of P D means that they have progressive disease. Arena score SD means that they have stabilization of disease. And then we looked at how how long they survived and this was great in terms of months, and you can see that patients, um, sometimes had no response at all, and they had a survival time, actually, only two months, and then there's some patients that have very good survival time. ASL long as 33 months after treatment, and we created these patients on how they're doing currently, whether they're still alive or deceased, on whether it is still ongoing treatment. Now, what was very interesting about the study? Even though this is just purely a toxicity study, we found that basically three patients were alive much longer than we suspected. One patient has actually been alive for almost close to down three years now. And you may ask, How long do these patients with recurrent GBM normally survive for? And the answer is about nine months, and so to have patients that are survived survival as long as 33 months. That's really a very big difference now. I should also add that in terms of survival, we also did analysis based on, uh, mounting progression free survival but overall survival. And here is a curve of progression free survival, and this was mapped out for six months and you can see that in cohort one. These patients did not do very well from the standpoint progression free survival. But we increase the concentration, especially in court three thes patients that very well in terms of progression free survival. This is a picture of some of these Marie scans. Uh, this is the in a is the picture m r I scan of the patient that has been alive with 33 months. You can see how she started October 2017 with this white area that basically shows that her recurrent tumor and as she inhaled the Neil 100 you see how that white area has decreased in size. Another patient, um, started may in 2018 and you can see that white area showing her brain tumor. And as she inhaled it over one year time period, you see how that white area or contrast enhancing era completely goes away. We looked at overall survival for these patients, and these are basically months and starting the Neil 100 therapy. And you can see that basically, in the patients that have all the patients that have been treated, how that there's an overall survival in 24 months off 37%. And this is something that we would not expect to have seen in just, um, recurrent glioblastoma as we map it out into patients that have been, um, had tolerate treatment for more than five cycles. or less than five cycles, you can see how the patients with more than five cycles that dark line has basically had a very long survival time. And then what was very interesting In terms of the markers? We looked at the genomic markers, including MGMT status and I. D H one mutations, and we found that the patients that were I D. H one mutant had a very long survival time compared to the patients that had I D h one wild type. In fact, the I. D. H one mutants are all three of the patients that have survived on still getting treatments. These were all I. D H one mutants. And when we compare our study with other phase one trials, you can see that basically our survival time at six months, nine months, 12 months and overall median survival where among what? It was basically the best that could was achieved compared to other phase one trials. So our conclusion for our trial is that neo 100 is very well tolerated, no significant side effects patients. Sorry. This right treatment regimen very well without on did it induces radiographic reduction size and recurrent GBM in a dose dependent manner. We had three long term survivals grand two years, all with I. D. H one mutations. This allow us them to look at Andi. Think about future enrollment Will focus on recurrent GBM patients with I. D. H one mutations. So we have other plans for intra nasal delivery. Uh, in low greatly. Almost these patients almost all have I. D. H one mutations and with and we're planning to enroll these patients for trials as well. Skull basement in jail most often have I. D. H one mutations as far as 50% of these patients and were planning to do a trial with this. And then we also want to use Neil 100 as a solvent for delivery, other drugs to the brain and then administration. Neil 100 in faith in newly diagnosed clear Blackstone's during the team is on my rest period of the stupid protocol. So basically, in our trial, um, today that I have presented, we have very promising results for our phase one trial. I want to emphasize to you that this is a phase one trial and therefore the patient numbers are small. However, we're going to expand this into a phase two. A. I think the most clinically important result that we obtained for this phase one is that one the study. This trial is very safe. And then to that, we have a biomarker that can potentially be used to identify patients that can respond is to this trial. And these were baby patients with a D. H one mutations. We feel that this mutation basically identifies. I put a particular patient with a recurrent glioblastoma that may respond to long term treatment. Thank you very much.