Breaking Barriers in Brain Cancer... Dr. Thomas Chen, Founder and CEO, NeOnc Technologies
Glioblastoma, brain cancer, one of the biggest challenges to effectively treating it is simply getting drugs to the brain. Today, Doctor. Thomas Chen, the director of neuro oncology at USC and founder, CEO, and chief scientific officer of NeOnc Technologies tells us about the scientific journey of a new way of delivering drugs to the brain. Doctor Chen, welcome to the program.
Dr. Thomas Chen:Thank you so much.
Dr. Moira Gunn:Now you're going to take us on quite a journey today, but I wanna start with a look at our current situation independent of that journey. And today, we're gonna be talking about brain cancer. And as you say, brain cancer is a disease of the brain, and we all understand at various levels that it's hard to get drugs to the brain. We always hear about the blood brain barrier. And, so whether your drug is a pill or an IV drug that goes into your bloodstream, it has the challenge of getting to the brain.
Dr. Moira Gunn:How has that stymied the search for drugs to treat brain cancer?
Dr. Thomas Chen:So, when we talk about treatment, basically we're talking about how do we deliver the drug appropriately to the target, in this case it's the brain cancer. And then once it gets to the target, does it have good activity? And so those are the two things that we need to address when we talk about any sort of developing any treatment, new treatment modalities for brain cancer. Now, the first part, getting drugs to the brain, that's the part that you've been addressing. And what I can tell you is this, we have many drugs that actually work pretty well on cancer cells.
Dr. Thomas Chen:And they have one problem, is that they cannot get to the brain. Now, in terms of getting to the brain, if you are what we call water soluble, water soluble means that it dissolves well in water, so you can give it like intravenously or orally, it goes in the bloodstream. Those types of molecules do not cross the blood brain barrier very well. In fact, the types of molecules that cross the blood brain barrier well are the ones that are said to be lipophilic, which means that they're fatty and they can cross the blood brain barrier better. And so many therapeutics, many people, are working towards developing drugs that can cross the blood brain barrier better by making them more lipophilic.
Dr. Thomas Chen:Now there are actually people also looking at, receptors that level the blood brain barrier to see if their drug can bind to a receptor and let that receptor carry it across the blood brain barrier. So there's lots of very fascinating, work that very smart people are doing to try to get across the blood brain barrier to the target. We're still having a lot of trouble with it.
Dr. Moira Gunn:So the barrier's the barrier.
Dr. Thomas Chen:Barrier's the barrier, yes.
Dr. Moira Gunn:Now let's get to your journey, and where do we start? And I wanted to start by talking about a naturally occurring molecule, which you've told me about, that we call POH, perilyl alcohol. What has POH got to do with anything?
Dr. Thomas Chen:Actually, para alcohol was, first worked upon by an American biochemist. He was a professor of biochemistry at University of Wisconsin. His name was Michael Gold. And unfortunately Michael Gould has, passed away. But what he did was that he was working on this molecule called para alcohol.
Dr. Thomas Chen:It's actually a natural derivative. It's isolated from, citrus fruit, and you can also get it from cherries. Michael Gold found that para alcohol, when he added to his cancer cells that were dividing in culture, was a very good cell cycle inhibitor, meaning that it inhibited the cell from dividing further. And using that knowledge, what he and his colleagues did was that they developed a formulation for the peri alcohol, and they tested it in cancer patients. Now what they did was that they tested it in patients with colon cancer, they tested it in patients with breast cancer, but they tested in, these patients up to phase two.
Dr. Thomas Chen:And what they found was that, yes, the peri alcohol did have an effect on the cancer cells, but the problem was that it had a lot of systemic side effects when you give it orally. But it was just poorly tolerated. And in terms of how it affected the cancer, it was also not as well as they would have liked to be. And as a result, what happened was that the para alcohol was then stopped from the standpoint of treatment. And what happened then was that one of my colleagues, his name is Clovis Fonsacop.
Dr. Thomas Chen:Clovis is a neurosurgeon from Rio De Janeiro in Brazil. And, he's kind of an out of the box thinker. And he went to, University of Wisconsin and he, Michael Gold was telling him about para alcohol and Clovis thought, Hey, you know, that sounds like an interesting drug for maybe treating brain cancer. And Michael gave him a jug of para alcohol.
Dr. Moira Gunn:Just a jug, like a thermos of
Dr. Thomas Chen:Yeah, like a big container. Clovis, at that time there was no TSA or anything, and Clovis just lugged it home to Rio De Janeiro. And so he thought that, I'm a neurosurgeon, I would like to try on my brain cancer patients. But at that time, a new procedure for delivery to the brain was actually getting developed in animal models, and that's called a nasal brain delivery. And the whole concept of the nasal brain delivery was that instead of trying to go through the blood brain barrier systemically, what you're trying to do is now deliver, you're bypassing the blood brain barrier, and you're delivering the drug via the cranial nerves.
Dr. Thomas Chen:And what people found in the animal models is that there are two cranial nerves that are particularly important for nasal brain delivery. And the first cranial nerve, I think everybody knows, is what's called the olfactory nerve. That's the nerve related to smell. And what they found was that in these patients with the olfactory nerve, that the olfactory nerve was a very good conduit for delivery of molecules to the brain. This is what they found in animal models.
Dr. Thomas Chen:And also the fifth cranial nerve is the one that's involved with sensation to the face and ability to chew. And so this sensation of face, the fifth cranial nerve, is also associated with the nasal brain delivery. So here's the thing. So Clovis thought that, hey, you know, so could you bypass that oral side effect by inhaling it with the nasal brain delivery? So the drug, instead of having to go through your whole body system to get to the brain, could you just inhale that drug and take it up to the brain and have an effect in the brain cancer?
Dr. Thomas Chen:And so Clovis started treating patients. And so what happened was that he treated about 300 patients and these patients had basically almost no side effects. And on top of that, some of these patients actually had long term survival and their tumors actually got smaller. And this was like, you know, for us, it's like when we see a brain tumor getting smaller on imaging, that's like a home run. And so Clovis presented his data to the Brazilian Neurosurgical Society.
Dr. Thomas Chen:And he won first place that year for that. And because of that, he won the first place prize was that he could go to any lab that he chose and work there as part of, and he would be granted a stipend basically. And so he chose to come to USC and work with me.
Dr. Moira Gunn:He chose your lab, that was the prize.
Dr. Thomas Chen:He chose my lab, that's right. And when he came, he was so excited about his work. He showed me his MRI scans and, you know, he really had like patients that had very large brain tumors, get smaller on further imaging. And I told Clovis, I said, Well, if this is as good as you say it is, how come nobody else in the world is doing this? And I said that, Well, you know, what we should do is that we should do a validation study in The United States and we should, run it through several academic centers here and see if we can get the same results you do.
Dr. Thomas Chen:Now, at that time, I was thinking, okay, so in order for me to get this drug out to a stage where I can do a clinical trial, where I can get an IND approved, that all requires money. Okay? And so I told Clovis that what we need to do is that we should form a company and we should, get IP for the compound And then we should apply to the FDA for an IND, which is Investigational New Drug, and see if we can, raise some money from the company having some property and then run a clinical trial. So that was our plan. So then what I did was that I went to, USC and we, put together a patent.
Dr. Thomas Chen:And the patent was basically for the use of para alcohol for treatment of brain cancer. But I told Clovis that para alcohol is a commercially available compound. And therefore, there would not be any sort of intellectual property aside from the fact that you're now using it for intranasal delivery. So what we did was that we went to a local chemistry lab and we asked the question, can we make that per alcohol purer than what it is now? And so what we did with our local chemistry company, and they're called Norac Pharma, is that we asked the question, could we purify this?
Dr. Thomas Chen:And could we purify this under GMP or good manufacturing practice conditions? And you need to have a drug to be GMP ed in order to be used in human patients. And so, what we were able to do is that we were able to add a purification stuff to this chemical per alcohol, and we made it into 99.6% pure. And it was done under GMP conditions. And after we had done that, we went to the FDA and we wrote a patent for this purification process.
Dr. Thomas Chen:And we got the patent granted. And then not only the patent granted, but we also applied for orphan drug status for this drug, and we also applied for fast track status. But I think most importantly is that we had a designation of a new chemical entity with our purification step. We then took this set of information, and then we wrote an IND for a clinical trial. And at that time, we wrote it for Phase IPhase IIa, and we submitted it to the FDA, and they approved it.
Dr. Thomas Chen:And I think that part of the reason we got approved so rapidly was because the FDA recognized that we're really dealing with the disease that's life and death. And so with that, then what we then did was that we got approved and then we selected some sites to be in this trial. And the sites that were involved was the University of Southern California, the Cleveland Clinic, the University of Washington up in Seattle, and University of Wisconsin. And with those sites, we then ran a clinical trial. Now, what I can tell you from our Phase I testing was that one, the patients tolerate very well.
Dr. Thomas Chen:They basically had no side effects, just like Clovis was telling me with his patients in Brazil. Two, they didn't have any of the common toxicities that you would think from chemotherapy. They didn't their bone marrow was absolutely normal. They didn't lose any hair. They really didn't have any nausea, vomiting, and no headaches from inhaling this product.
Dr. Thomas Chen:And so the patients actually tolerated very well and did very well. Now, what we then did was that as we went up the dosing, we found that basically this held through even from the lowest dosage to the highest dosage. Now, along the way, we also are monitoring these patients in terms of how they're doing clinically. And so even though this is a toxicity trial, we're still getting our MRI scans every two months and seeing how the tumor is doing. And what we found was that in some patients, their tumors got smaller after inhalation, after treatment with this therapy.
Dr. Thomas Chen:And in fact, in one patient, the tumor actually disappeared on MRI scan. And it's what we call a radiographically complete remission, when the tumor goes away in MRI scan. And we had four patients that actually lived for longer than three years. Now, so you can say, well, you know, you only had 12 patients. But the thing is that the patient population that we were treating, we were not expecting these types of results because the patient population we were treating were patients that had failed conventional therapy.
Dr. Thomas Chen:So these were patients that were what we call glioblastoma patients. So they're the worst type of patients. Their prognosis on the whole is about twelve to fifteen months after diagnosis. And so these patients, undergo conventional therapy, which is surgery, radiation, and chemotherapy with a drug called temozolomide. After they fail that treatment, then they come to our trial.
Dr. Thomas Chen:And so if you ask me like, well, okay, so if you fail conventional therapy, how long do you usually live? And the answer is that most patients have a survival time of about five to six months. So we had, four patients that lived longer than three years. So the question is that what was so unique about their biology that they had such a great response to our drug. And so what we did was that we went back to their tumors, we did genomic analysis, and we actually found that they had something in common.
Dr. Thomas Chen:And that was an IDH1 mutation within their tumor cells. And having that knowledge, I went back to the FDA and I said, we had, even though we were supposed to run just a phase one study for toxicity, we have four patients that did so much better than expected. And so for our phase 2A trial, could we just enroll patients with IDH1 mutations who are what we call recurrent disease and have a malignant glioma. And the FDA gave us permission to do that. And that resulted in our current trial, which is a phase 2A, and we are now almost nearing the end of our trial.
Dr. Thomas Chen:We have seven more patients to enroll from that 25 patient cohort. And then we will be done with the phase 2A. And from there, we will have a readout in terms of how this drug does in this population of patients, 25 patients, in terms of efficacy, which is what the phase II is supposed to address.
Dr. Moira Gunn:What percentage of glioblastoma patients have this IDH1 mutation? Do we even know?
Dr. Thomas Chen:Ah, that's a very good question. So, in the low grade gliomas, in the grade twos for example, up to fifty percent of the patient's tumor could be IDH1 mutations. Now, when you move up to a grade three, that number goes down. So instead of fifty percent being positive, it goes down to about twenty five percent. And then when you go down to a grade four, which is the glioblastoma, it could be present in three to five percent.
Dr. Thomas Chen:And so it is correlated with the grade of the tumor and the higher grades have a lower incidence.
Dr. Moira Gunn:Okay. So at this point in
Dr. Thomas Chen:the
Dr. Moira Gunn:story, you have this phase 2a, you're out of phase one with just the IDH1 mutation. So they're in that stage one, stage two, glioma. And, but what about the rest of the people?
Dr. Thomas Chen:Ah, okay. So, here's the thing is that, well, first of all, I want to say that with the phase 2A, what we want to establish is that there is efficacy with our treatment. Now, what we want to do, because we're going to have to do a phase 2B, And the Phase IIb is most likely going to be about 70 to 80 patients. And so the Phase IIb would be a larger cohort of patients. All patients will be getting treated, unlike a phase three where sometimes there's a placebo, group.
Dr. Thomas Chen:But with this phase 2B, what we're going to do is that we are going to recruit all comers. Okay? So whether you have an IDH1 mutation or you don't have an IDH1 mutation, we're going to be treating them. And then what we will be able to do is answer exactly your question. If you don't have an IDH1 mutation, how does that compare when you have this larger cohort of patients IDH1 mutations and no IDH1 mutations, what is the overall efficacy and survival time for all patients?
Dr. Thomas Chen:And then how does it compare between the two groups? And so that's coming up. That's something that we are planning to do for Phase IIb to answer that question.
Dr. Moira Gunn:So what about everybody else?
Dr. Thomas Chen:Well, what would happen if we took a drug that we know has activity against brain cancer and we chemically bind it to the pair alcohol, could we make a new compound with different properties that may be more effective? And so what we did was that we took our standard of care drug, it's called temozolomide or TMZ, and we chemically para alcohol to it. And then we took this new compound and we put it through our blood brain barrier program.
Dr. Moira Gunn:And by program, you mean a software program, a computer program.
Dr. Thomas Chen:Software program, exactly, exactly. And what we found was that temozolomide does cross the blood brain barrier, but just not that well. And so we conjugated to our alcohol, we found that it crossed the blood brain barrier much better.
Dr. Moira Gunn:Now I want to go back to the first one you did when you just were trying those that phase one, you had four cohorts of three patients, and you were increasing the dosage. And four patients lived, and one at the time was continuing to live. Is that patient still alive today?
Dr. Thomas Chen:Actually that patient is still alive today. And we still, maintain contact with that patient. And that patient, actually, you know, I told you that we get MRI scans every two months. And now she's, I think, getting MRI scans every six months now. And continuing to do well.
Dr. Moira Gunn:Well, doctor Chen, this has been terrific. I hope you come back and see us again.
Dr. Thomas Chen:Yeah. I hope so too. Thank you.
Dr. Moira Gunn:Doctor Thomas Chen is the director of neuro oncology at USC and the Founder, CEO, and CSO of NeOnc Technologies. Three different clinical trials in brain cancer are now recruiting. More information is available on the web at neonc.com. That's ne0nc, neonc Com.
