Transcript of How A Drug Gets
DEVELOPED AND TESTED
Host: Joel T Nowak
Guest: Dr. Marianne Sadar
Mr. Nowak: Today, we have the great fortune to have a personal friend of mine in real life and absolutely brilliant prostate cancer researcher to talk with us about an investigational drug that she has invented or I should say developed.
My guest, Doctor Marianne Sadar, is the distinguished Scientist at the British Columbia Cancer Agency having received her PhD from University of Bradford in United Kingdom in Biochemistry. She also has done post-doctoral work at AstraZeneca in Molecular Biology and at the British Columbia Cancer Agency, the Department of Endocrinology with her post-doctoral work specifically in prostate cancer. She has served on over fifty grand panels including five years at the NIH study session for drug discovery and has been and is still the Chief Scientific Officer of the Bio-technology company which she has founded called ESSA.
Doctor Sadar discovered a novel drug target for prostate cancer. She screened drugs against this target and brought a clinical candidate into clinical trials that are currently ongoing in both United States and in Canada. This is the first drug in clinical trials, targeting the N-Terminus of the Androgen receptor. Her work is a first in type to the entire field of steroid hormone receptors with no whether small molecule inhibitor reported to bind to the N-Terminus.
Dr. Sadar, I was wondering if you could tell us a little about your research specifically translate, what it is that I said so that we can understand it?
Dr. Marianne Sadar: My research is focused on advanced prostate cancer. It's focused on the protein in the human body that causes most prostate cancer to grow and rapidly proliferate.
The treatment for advanced prostate cancer is unfortunately castration which is to reduce the male sex hormone. That male sex hormone works on this protein called the “Androgen Receptor” that I've been studying for twenty years.
What I've been doing is trying to figure out how this androgen receptor continues to fuel advance prostate cancer even though these men are castrated. What I've been doing for the past twenty-one years, trying to find therapeutics, trying to find drugs that will benefit these men for a longer life, improve their quality of life.
Mr. Nowak: Are there other drugs that target this particular protein, the Androgen receptor?
Dr. Sadar: Yes. When men with advanced prostate cancer are treated for advanced disease, they received LHRH analog which reduce their testosterone levels and that really targets androgen receptors because it reduces testosterone levels, male sex hormones that binds to the androgen receptor.
There is also Abiraterone which is used, which reduces the amount of androgen in men that are receiving it and that has been official effect and it works again on reducing testosterone or the steroids that bind androgen receptor.
There are also anti-androgens, there are a number of anti-androgens, probably the best known one is Enzalutamide but there's also the whole family which is Bicalutamide, Flutamide, Nilutamide, there's a lot of these anti-androgens.
They work on the opposite end of (edit note - the androgen receptor from) where my drug works. They work in the same spot that testosterone and other steroids will bind to androgen receptor so, it's like a competition. They will fill the spot that testosterone normally would fit on the androgen receptor to prevent the testosterone from working on the androgen receptor.
It is a well-known target, but what's unique about my research is, that's not the important part of the androgen receptor because in advanced disease that part of the androgen receptor where testosterone interacts with the androgen receptor, it might not be made anymore and it might be a truncated androgen receptor. So, that would mean all of these therapies, all the anti-androgen's, Abiraterone, castration wouldn't have any effect on these truncated androgen receptors.
We are targeting the part of the androgen receptor that hasn’t lost (editor note – or been truncated) in the disease and that's called the N-Terminal Domain.” So, it's present on all forms of androgen receptor that caused the disease to keep proliferating and growing.
Mr. Nowak: The time that this drug would probably be used would be at the time that a man becomes castrate and when these other drugs stop working?
Dr. Sadar: That's where we're starting. We're starting our clinical trial, that's ongoing right now, it's a dose escalation study at the phase one. It is in men that have become resistant to Abiraterone or to Enzalutamide or some men receive both of these therapies so, that's where we're looking now.
We're looking at quite late in the disease so, after men have received a lot of treatments and those treatments no longer work, that's where our drug has been slotted in to see if we can help those men. In the event that our drug works, “hoorah,” then we'll try to move the drug earlier, we'll try to move it into earlier disease because theoretically it's having the effect that we see in the laboratory, it should help men with earlier disease as well.
Mr. Nowak: How do you see this effect in the lab?
Dr. Sadar: We have a lot of different models. You can never truly mimic human disease like treating a patient so, we have different cell lines. These cell lines were made from men that had metastatic disease and that metastatic disease was removed, their cells were then grown into culture dish and then we try our drugs on these cells that are grown in culture dishes.
We have a lot of molecularly engineered cells that have “read out” systems on them so, we know if our drug is working. For example, we engineered our human prostate cancer cells, these are cells that were originally from a man who had a prostate cancer metastasis to his lymph node in his sub-clavicle region. We engineered those cells so that when the androgen receptor which is the target was pushing proliferation and causing cells to grow and divide, that the cells would emit light.
How we screen for drugs was, let's see what drugs can turn off the light and so, there's specific equipment for that. We screened about 36 thousand drugs, that's actually relatively low, but we got lucky. Always a little bit of luck help.
So the drug that we found was FE506. It turned off the light and then there is a whole battery of tests (edit note – we then put the candidate drug through). We test how specific the drug is. Does it kill other cells, which wouldn't be good because we only want to kill prostate cancer cells. We don't want to kill bladder cells or epithelial cells in the intestines.
So, we start to check how specific the drug is for prostate cancer, and then of course we do our animal studies which most closely mimic human disease, and that's where you take these human prostate cancer cells and you grow tumors in animals. Unfortunately, you have to do this, because that's the closest to humans and these tumors will grow in these castrated animals just like what happens in human disease. We gave the animals our drug, our FE506, and we would see this wonderful effect, reduced tumor growth. It sort of the full life from in the bench to animal testing, and then of course in order to get into clinic we had to do the FDA protocols for safety and toxicity.
Mr. Nowak: And what's involved in that?
Dr. Sadar: Oh boy, [laughs] an enormous amount, it's very expensive. I couldn't do that in my lab so, now the biggest hurdle was money. I can do the molecular biology and the academics so, I received grants, a lot of grants, lots from the US Army, from NIH to do the biochemistry and molecular biology.
Now, in order to get the dollars to create a drug that goes in the clinic and to pay for all of the tests that the FDA required, all these safety and toxicity tests we had to spin out a company just to get private money from Angel investors, from venture capitalists, from investment banks, etc. That was the point of where we had to now look to other places for money to look at commercialization of this technology so, that was the first step to do all these tests.
Once we had the company in place, many very qualified people in areas that I have no expertise were hired. They started to do the chemistry, they started to look at the toxicology of the compound, how long does the drug last in animals? Does it stay in the blood long enough to potentially affect the tumor or does it just go through the body immediately and never really get absorbed, all of these factors have to be considered before creating a drug.
It's extremely expensive so, the company was formed. People were hired to interact with the regulatory people at the FDA, a Chief Medical Officer was hired, Frank Pravil who was a superstar in the field, he did many of the Enzalutamide clinical trials.
It now became a little bit of a monster that, in order to get in the clinic, you have to now have so many different areas of expertise well beyond my lab, my [laughs] little tinny lab. So, it bloomed.
Mr. Nowak: You've created or certainly with the impetus to start this thing, it's kind of your baby. What's it like to lose some control of your baby, do you feel that way?
Dr. Sadar: Absolutely, I feel that way. It's having to build trust. This is my baby, I've worked for twenty years on this to then pass it over in to hands that aren't my hands. I have to have trust that those are good hands that it's going into that they're going to do everything they can to make sure it has the best shot possible of succeeding in the clinical trials.
I've done everything that I could here in my lab, I've had over twenty years, I've had at least ten to thirteen people working on it every single day for those twenty years, it's a lot of time and effort. There is the trust, there is the learning to let go a little bit. I can't run the clinical trials, I can't do the chemistry so, I have to believe that it's in good hands, and it is.
The people that ESSA has hired are absolutely outstanding, they're superstars, I've only mentioned one, but there's a whole number of superstars that were hired into this company. I can breathe easy, I can realize that it's in good hands.
Mr. Nowak: Actually, I want to go back a little bit to something you've said, when you described the trial which is a phase 1 trial, if you would for those people who may not know what phase 1 trial is, if you could give a brief description of that and you also mentioned the word, “dose escalation,” if you could describe what that means I would appreciate it.
Dr. Sadar: Yes. So, this is the first in human clinical trial meaning, this drug that we've made has never ever been put into humans before, you have to make this enormous leap. Everything we've done has been an animal, animals have much faster metabolism, they handle drugs differently than humans. So, how do you decide what dose should be the first dose in humans that will be safe?
That's really what a phase 1 is, figuring out what dose is safe in humans. What is the highest dose you can put into humans that are still safe, meaning you're not getting a lot of really horrible toxic effects that would compromise the patients’ health or compromise the patient from continuing on the drug, that's what a phase 1trialis.
The FDA actually tells the company which dose they can start with and that's based on their animal studies, their toxicity studies that they had to give the FDA. So, the FDA can decide what dose is the first dose that you give patients. So, in our clinical trials, they're all prostate cancer patients, none of them are healthy, there's not a placebo arm, there's nothing like that, all of them are patients, all of them receive the drug.
You start with three patients per cohort, so the first three patients have been dosed at the lowest dose and for us that was eight milligrams in a patient. Once they go through thirty days and there's no adverse, serious adverse event then, another group of patients can then start on a dose that's higher, keep testing, three patients, moving up the amount of drugs that they're receiving until you start to see some toxicity.
Its cancer, so you want to get as much drug as you possibly can into patients because you want every chance possible of affecting the tumor so, you really want to have what's called a maximum tolerated dose.
That's what a phase 1 is, so it's finding the dose. It's not really about seeing whether the drug works or not, the dose that we're starting it with right now, that we've finished the first three patients was a very low dose, it's not predicted to be efficacious, because it's so low. You may get some clinical data, because we are monitoring blood levels, we're monitoring PSA, we're doing all these things.
Once we get to an efficacious dose which keep your fingers crossed that we do, and that we can put a lot of this drug into patients. We should get some sort of readout about whether we're having any effect on PSA levels. Patients will tell you if they're feeling well or not, you get a lot of feedback from patients.
Once you find that dose then you start the phase two studies, and the phase two is really to give an indication of whether the drug has any effect on the tumor.
Mr. Nowak: And, how do you evaluate in the phase 2, whether or not it's had an effect on the tumor?
Dr. Sadar: In our trial, there's always PSA that's one of the major readouts, it's usually a fifty percent drop in PSA. We're looking at tumor volume, I think we are doing some analysis of how much tumor burden these patients have and I'm not sure what else actually, probably the quality of life as well and maybe Morphine use. I'm blurry here on all the aspects of the clinical trials, because I'm not a clinician, our Chief Medical Officer Frank Pravil designed all the clinical trials.
Mr. Nowak: Are you still working on this drug in the lab or is that something that is not happening anymore?
Dr. Sadar: We are working on this drug in the lab. What my academic research is looking at is, we know that prostate cancer forms resistance to drugs, that's been the problem. You treat men with these therapies and eventually develop resistance so you switch to another drug and eventually develop resistance. Of course, we're thinking what if our drug develops resistance? What resistance would that be? What mechanism would that involve?
So, to try to address that, what my lab did is incubated these human prostate cancer cells with our drug, for a very long period of time, it was about a year and a half. Eventually we saw resistance, so eventually the prostate cancer cells started to grow in the presence of our drug, that's resistance. The good thing is that it took a year and a half and so if you put this into perspective, in tissue culture, Enzalutamide causes resistance with long term culture in three months so, ours caused resistance in a year and a half so, six times longer.
If that pans out clinically that would be wonderful. We still need to understand how the cancer cells are forming resistance to our drugs. So, we're now analyzing these cells and we have picked up one potential pathway that is manageable. I'm not going to describe more here because the work is just not complete enough, I would like to make sure I'm standing on really firm ground. But, in everything that we've looked at we have a resistance mechanism that we seem to be able to hold, and that's the whole theory behind it.
If you can understand the resistance you can potentially do combination therapy in order to prolong the efficacy of the drugs or maybe even potentially cure the patient if you do a cocktail.
Mr. Nowak: That's an amazing word to use when we talk about Metastatic Prostate Cancer, it's a word that I don't like to use. It's really optimistic and potentially so exciting, sounding.
Dr. Sadar: That's always been the goal of my lab, we'd really like to just get rid of the prostate cancer, just get rid of it (get it out) out of these men.
Mr. Nowak: Which brings me the question, how did you get into prostate cancer? Why prostate cancer? Why not breast cancer, kidney cancer, arthritis?
Dr. Sadar: I was very interested in cancer, my sister died of cancer when I was a child. So, I was a very aware of cancer, I knew that I would just wanted to work with cancer. To me, there weren't different types of cancer as a kid, just cancer. That's all you hear, you don't hear its Leukemia, you don't hear it's whatever. As a child I wanted to be a cancer researcher.
When I went off to do my PhD, I did it on the dioxin transcription factor, the dioxin receptor in fish. I had a wonderful PhD experience. When I came back to Canada, I never thought I was smart enough to do human medical research. I wanted to stay in Vancouver, because that's where I was living so, my friends and family pushed me in to applying for a position with Dr. Nicholas Perkowski. Dr. Nicholas Perkowski was an MD, PhD, he was the discoverer of dihydrotestosterone which is really what fuels prostate cancer and Intermittent Androgen Suppression. He was a real superstar in the prostate cancer field. I was lucky enough that he hired me.
What I did my PhD on was the dioxin receptor and the transcription factor. There were things that I did with that transcription factor which was very similar to what I went on to do with the androgen receptor, Androgen receptors also is a transcription factor.
What is a transcription factor? It's something that binds to DNA to turn on lots of genes, to turn on the production of, making lots of different things in the nucleus of cells. So, it wasn't a big jump, for me.
I still remember when Dr. Perkowski offered me the job, in my first day on the job it was the best feeling ever. It was a gorgeous day in Vancouver, I walked down the road by the BC Cancer Agency, happier than ever that I was a medical researcher and I had a chance to make a difference.
Mr. Nowak: I think, that you already made a significant difference the potential of what you're doing could be such a breakthrough for men with Metastatic Prostate Cancer. I always I said hesitate to use that word “cure”, if you can stretch the resistance and prevent the resistance, that's darn near close.
To get a little personal with you if I might, you're a woman. We know that men and women are not the same within science and are not treated the same. So, I'm wondering would you be willing to share a little bit about your experience of being a woman in science?
Dr. Sadar: Sure.
Mr. Nowak: You didn't expect that. I'm sorry.
Dr. Sadar: No, no. It's a good question. As I've gotten older I would say it changed. But when I was younger, I would go to conferences and people would automatically assume that my students who are post-docs must be Dr. Sadar, not me and you did get dismissed more easily than I believe a man would get dismissed. Credibility sometimes was the issue.
Being a young woman in the field. I still remember the very first conference I went to, there was only one woman speaker at the conference, it was a conference all about neurology, it was actually the Society of Basic Neurologic Research, and there was only speaker that was Natasha Capriano, I think that was 1995 or 1996. I hate to say it, she in spite of giving the most amazing talk, some of the men that I sat with, all they talked about was how she looked and that just made me feel sick. They were very complimentary, Natasha's a beautiful woman, but you know what? [laughs] It was just kind of disappointing that they weren't listening to what she was saying.
I have found that, but it's gotten better, I would say it's gotten enormously better in the twenty years, whether it's just because I've become an older woman now, but I don't think so? I think, the world has changed in twenty years, I think the medical field now views women with as I use the word “respect” and not so easily dismissed, but it's still as tough being a woman and I will say, especially tough in biotech. Women do bring different perspective, I would say that ESSA's board has a woman on it, it's me, but the rest are all, well let's just say it lacks diversity. I bring the diversity card to the board, and I don't think this is really uncommon, I think it's harder for women to become board members. Hopefully that's changing too.
Mr. Nowak: Right. So, I'm going to bring us back to the clinical trial if I may, you're currently in phase 1 which is a dose escalation trial, if I understand correctly at some point you'll come to a dosage that you decide or the FDA or you in consultation with the FDA decides that's your target dose, you've gotten the proper saturation and toxicities are manageable, I would assume is the way to look at it, and then the next step which you reflected on is to a phase two, is that a reasonable summary?
Dr. Sadar: Yes, that's very accurate.
Mr. Nowak: You're still in phase 1, a man who may be interested in learning more about this phase one and perhaps how to get involved or even perhaps as you move into a phase 2 because I am very optimistic that you will. How would they go about doing that?
Dr. Sadar: On the website, clinicaltrials.gov, there is a description of the clinical trial if you put it in a search of EPI-506 you'll find the trial, there are only five sites for the phase one. There is a low number of patients because it's three per dose. The five sites are one in Canada which is the BC Cancer Agency in Vancouver, Canada, there's University of Washington in Seattle, Karmanos Cancer Center in Detroit, there's Ann Arbor in Michigan and there is Scottsdale in Arizona. So, there are these five sites, it's a very low number of patients right now in the phase one, but I definitely encourage men to look in to it.
Mr. Nowak: Could they reach out directly to one of the centers or they need to go through the clinicaltrials.gov website?
Dr. Sadar: On the clinicaltrials.gov website it will say who are the medical oncologist at each of these sites. That's probably one of the most efficient ways of inquiring. Basically, it would be going to their own oncologist or neurologist that they're seeing and discussing with their oncologist or neurologist, the clinical trials is EPI-506 and then getting more information about entering the trial.
Mr. Nowak: They should go through their oncologist or the neurologist but they could also reach out directly, I assume?
Dr. Sadar: They could and this why I mentioned maybe speaking to their own oncologist, there area lot of eligibility criteria. So, it's whether they fit into these eligibility and criteria. Like, for example we were a little bit late with some patients in our first dose and that was because patients can't be on other treatments, if they're on other treatments they have to be washed out. It's the half-life of the drug which can be up to a month, things like Enzalutamide have a very long half-life. So, it might be efficient to talk to their doctors about whether they fit the eligibility criteria.
Mr. Nowak: Does someone have to live close to the trial site or can someone come from a distance and still participate?
Dr. Sadar: I believe that situation has already occurred where a patient was traveling to the center so, I think it's possible. The only one that I would say it gets more complicated is crossing borders that's beyond my expertise.
Mr. Nowak: Just because one does not live near one of the centers if one is willing to travel they should still follow-up with their physician and talk about eligibility and then if they're still interested to pursue it.
Dr. Sadar: I think so.
Mr. Nowak: The drugs as they take it, is it something that's in pill form, is it infusion? How does a man get it?
Dr. Sadar: It's in a kind of liquid gel capsule. So, I believe it’s kind of like a cod liver oil capsule takenorally, you take it once a day.
Mr. Nowak: So, a man could take their pills and go home and then check in whenever they're supposed to check in again?
Dr. Sadar: Yes, I'm not completely sure of the protocol as it is the safety toxicity whether they have to have their blood levels measured and all these types of things so, I'm not sure how much time they need to be really close to medical facility to monitor these things?
Mr. Nowak: I would like to ask you the question as to how long you think the phase 1 will last, but if I understand correctly you want it to last longer because it means you're able to escalate the dose more and you really don't know where that is. So, timing wise is unknown at this point, is this correct?
Dr. Sadar: Pretty much. There has been discussion that we're probably looking at September, somewhere in that time, the end of the summer.
The company is going to release some of the clinical data from the phase 1 around that time once the phase one is done, and exactly like you mentioned there's--you can't be precise because you just don't know how these things are going to pan out, but that's the rough timeline that we're looking at. We sure hope it's not shorter than that.
Mr. Nowak: [chuckles] So, if you have the data, you release it, there's obviously to a journal article or something of that sort, but you also have to communicate with the FDA, correct?
Dr. Sadar: Yes. I believe that the company has to keep communicating with the FDA all the time, any adverse event has to be reported, all these types of things. I believe it's a very-- becomes a very close relationship with the FDA.
Mr. Nowak: And then, if you want to move on from the phase 1 to a phase 2 and I understand that you're not a trialist, you're the creator so to speak that you then need to go back to the FDA and get their approval to move from a phase 1 to a phase 2.
Dr. Sadar: Yes, I believe that's correct. They have to make sure that the dose and everything is safe.
Mr. Nowak: And then, obviously after that we move into a phase 3 where we would look for other things besides dosage, we look at survival benefit and perhaps quality of life,
I'd like to see that more often as part of end points of clinical trials, that's something I know the advocacy world is trying to get the FDA to acknowledge. We could be talking about many years yet before we could actually see this in the clinic.
Dr. Sadar: Yeah. I think one of the fastest from clinical trials to approval was for Enzalutamide in this field. I think the period of time was about five years which was phenomenal. So, we would like to beat that if we could.
Mr. Nowak: Good goal. A lot of us will be pulling for that. [laughs]
Dr. Sadar: [laughs] I hope so, a lot comes down to recruiting patients, how efficient we are with recruiting patients. A lot of it comes down to also how good the drug is, when patients starts hearing that the drug is working recruitment tends to be faster.
Mr. Nowak: Your results in recruitment is what we need to stay focused on and hopefully see this in the clinic in about three to four years. How does that sound?
Dr. Sadar: Oh, that sounds wonderful. That would be a dream come true.
Mr. Nowak: You have done some absolutely amazing, amazing work and it was-- this has potential to change lives of so many people, not only the men but of course their families and their friends.
As a prostate cancer survivor myself I really want to thank you so much for your hard work and the frustrations that you must've gone through and of course for sharing this information with us. I Just want to say for all of us, thank you so much. I don't know that you have anything you want to add that I've missed or you think people would want to hear?
Dr. Sadar: I will just say one thing, I get to talk to patients quite frequently. The world has made massive improvements to cancer treatment over the years. My sister died of cancer when I was a child and that cancer is now very, very curable, I think the cure rates are about ninety five percent or more.
Things do improve there are cures for cancer, they do develop and so, I think the world stays very positive, conspiracy theories that there's a cure in the drug companies stifling it. That makes me feel very sad because I think the scientist and everyone is trying very hard to improve the quality of life and find cures for cancer and other diseases.
Mr. Nowak: Thank you so much, we really do appreciate it and is it okay if we check in with you down the line to see how things are progressing?
Dr. Sadar: Yes. Yes, please.
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