One of the essential pathways that cancer takes in order to spread to other parts of the body has long been identified as the Axl/Gas6 pathway; knowing this, researchers have tried for more than a decade to find a way to halt, block, or otherwise remove this pathway from being available to cancer cells, thereby potentially curing cancer. But until about four years ago, the only research efforts that existed were focused on knocking out or making the Axl component unable to bind with Gas6, which would shut down the pathway as a whole.
CEO of Aravive, Jay Shepard, joins the podcast to discuss why this approach has had only variably successful results, and why the approach they are taking has already shown a great deal of promise. Rather than targeting Axl, the team at Aravive has created a “decoy” of Gas6, which essentially acts to fool Axl into binding with it instead of natural Gas6. The idea was created by Stanford scientist and current founder of Aravive, Amato Giaccia. In pre-clinical trials, this method stopped or reversed metastasis in cancers, and cured resistant ovarian cancer in 20-30% of mice. Shepard discusses the ins and outs of this unprecedented research, the potential it holds, how it would take shape within the current landscape of cancer therapies, and what’s next on the list.
Press play to hear the full conversation, and check out https://ir.aravive.com/ to learn more.
Richard Jacobs: Hello! This is Richard Jacobs with the future tech and future tech health podcast and I have Jay Shepard, the CEO of the company called Aravive. The website is ir.aravive.com. Aravive is a clinical stage biotech company. They focus on developing innovative therapies that target survival pathways for cancer. So without getting into the specific receptors and pathways, which we’ll talk about in a little bit, I just want to welcome Jay. Thanks for coming, Jay.
Jay Shepard: Thanks for having me. Richard.
Richard Jacobs: Yeah, so tell me a little bit about the company and how the company’s premises focus came about. Why cancer and what particular types of cancer do you focus on?
Jay Shepard: Yep, sure, so Aravive was sort of born out of research that was done, four or five years ago at Stanford under the leadership of a scientist by the name of Amato Giaccia and he was the founder of Aravive. And the premise was that, you know, there’s, there’s, one of the fairly well known mechanisms of sort of metastasis is the, what they call the AXL/GAS6 pathway. And what that means is that when the pathway, when it’s a lock and key sort of mechanism, so you know, AXL is a receptor in the body and GAS6 is a ligand. And when those two entities merge with one another, they cause, I mean to over simplify, they cause cancer to metastasize and they also can cause a drug resistance. And so, you know, over the last 15, 10, 15 years, there’s been a lot of work that’s been done to try and shut down that pathway, to, you know, shut down and sort of short circuit the whole GAS6/AXL pathway so that you can minimize drug resistance and metastasis. And there’s been a number of companies that have really focused on sort of shutting down the, the AXL part of the equation and the you know, there’s been mixed results in terms of small molecules trying to sort of shut down the AXL part of, the GAS6/AXL pathway. So what Amato Giaccia and his colleagues at Stanford did was what if we can short circuit the whole process by using a biologic approach, very specific biologic approach to shut down the GAS6 pathway. And if you could figure out a way to bind GAS6, then the whole sort of lock and key mechanism you short circuit the whole thing of the ligand and receptors sort of binding with one another. And so, they did figure out a way to do that. And so, what Stanford invented and developed was a process by which they’ve created a, what we would call an AXL decoy. Sorry, a GAS6 decoy. So, what happens is you administer this product, it’s called AVB-500 administered into the body and what happens is that the GAS6 sees it and it binds with that, versus natural gas checks and then thereby when you bind it up, it short circuits the whole process. And if you bind up GAS6 then the body can no longer sort of bind the natural GAS6 to AXL and it shuts down the whole process. And so.
Richard Jacobs: Quick couple questions here. So on cancer cells themselves, on the surface of the membrane, is that where this GAS6 receptor or ligand exists? Mechanistically, what’s where?
Jay Shepard: Yeah, it is on the surface of the cell membrane. That’s, exactly where it is.
Richard Jacobs: So certain cancers, it’s not available on all cells, but cancer cells for some reason they change the expression of the cell. And then this receptor appears on the surface. Is that what happens?
Jay Shepard: Yes. There’s a number of different cancer types, I think we believe that most cancers express or over-express GAS6 and AXL. But there are certain cancer types that where GAS6 and AXL is orgastics. I should say is highly expressed. So, you know cancers like ovarian cancer, pancreatic cancer, AML, triple negative breast cancers, head-neck cancer and renal cancer, they all overexpress GAS6 highly. And so, , you know, it, it is expressed in virtually all cancers. There are certain cancers that, you know, really overexpress it.
Richard Jacobs: How does this cause metastasize? Do the cancer cells express both GAS6 and AXL and then through cancer to cancer cell communication, they are letting each other know, go ahead and find a new spot metastasize? Or, you know, what’s the mechanism of metastasis to this ligand receptor?
Jay Shepard: Well, I think some of these highly scientific questions probably would be best served by speaking with some of our scientists. But basically, like I said, most every cancer expresses GAS6 and AXL. And they are present on the surface of the cancer cells and when they’re expressed, they sort of cause a chain reaction. Once the GAS6 binds up with AXL, it causes a downstream effect of metastases by the epithelial. Cells become cancer cells and then they start growing and metastasizing and by administering our product and focusing on, you know, our biologic approach versus a small molecule approach. It basically shuts the process down effectively by going after the ligand versus receptor. And so, you know, from a very high level perspective, that’s how our drug works.
Richard Jacobs: So what does the small molecule drug do versus the biological solution that you created them until when small molecules bind to these receptors or they just bind to each other, the AXL binds to the GAS6 or you are finding something else to step in there and bind to it instead is that what you are saying?
Jay Shepard: Yeah, so what I’m saying is that what the small molecules or the small molecule approach is to right now is they bind with AXL, whereby or whereas we bind with GAS6. So the problem with binding with AXL is that it’s with a small molecule, it doesn’t, potentially it doesn’t just bind with AXL, it potentially can bind with AXL and other sort of AXL look-alikes, if you will. And so it has the small molecule approach while it’s shown to be effective in a number of settings. There’s a scientifically, sort of belief that, potentially, going after GAS6 is more selective because what Aravive has seen in their preclinical models and now they’ve seen in the phase one study which was in healthy volunteers is effectively like a complete suppression of GAS6 and if you shut down the GAS6 ligand then there’s no way that AXL can be activated. As opposed to going after AXL with a small molecule, there is the potential that the binding with AXL is not as selective as the effect that you would get if you bound with just GAS6. So, you’re going after the ligand we are going after the ligand GAS6 versus going after the receptor AXL, which is small molecule.
Richard Jacobs: So, what was the preclinical model? Was it a mouse model or what does it look like?
Jay Shepard: It was mouse models and again, Aravive has data in ovarian and AML in pancreatic, in renal cancer and yeah, they were in rodent models.
Richard Jacobs: So what happened in the preclinical setup? Did the mice already have metastatic cancer and did it just stop communication between, you know, the original tumor or the Metastases or did they have just the original tumor and then it prevents, stopped it from spreading to other tumors or what happened?
Jay Shepard: Yeah, the rodents that you know, were injected with our compound had already had metastases. And what it did was it stopped or reversed the metastases and ovarian cancer for example and this was what we call resistant ovarian cancer or resistant ovarian cancer cells in rodents. In 20 to 30% of the cases of the rodents, it actually cured cancer, which is almost unheard of but it is a preclinical model and we’ve yet to see, you know, we just started administering our drug in our phase one B patient population of resistant ovarian cancer that trial’s under undergoing right now. But again, in the preclinical model and the rodents, they had resistant ovarian cancer and it was already metastatic and it reversed it or shut it down or cured it.
Richard Jacobs: I wonder what these signaling pathways you have used for. So would have the scientists imagined that it’s used for, why would it stop, not only the metastases but whole cancer in general?
Jay Shepard: Well, I think what the scientists at Stanford and other scientists across the world, I think the hope is that if you can shut down the AXL/GAS6 pathway, if you can shut down that process, which is a known culprit of creating metastasis with cancer, if you can shut it down, you can either reverse or shutdown the whole metastatic process, you know, if that’s answering your question. But that has been the hope and the quest, if you will, for, you know, the last 15, 20 years and there’s a lot of different approaches scientifically to shut down that known pathway. But this is the Aravive approach is the first approach that has gone after the GAS6 part of the AXL/GAS6 pathway and so there are clinicians and scientists out in the communities of the world that believe that, you know, this may be, can’t promise it, but this may be a best in class approach to shutting that pathway down. Yeah it would, for patients with metastatic disease, this would be a real significant breakthrough for them. And that’s what we’re hoping and praying that our product will it be able to help with, you know, we hope it all products will, you know, any approach to shut down this pathway. We hope they all work but we’ve got a unique approach and its patented and we’re the only ones that go after this sort of mechanism in the way that we do, which is to shut down the GAS6 piece of the equation.
Richard Jacobs: So I just wonder again, what’s the role of this pathway? Is it for the cancer cells to communicate with each other so that they can have some kind of coordination? And you know, survive in the body and then by blocking this, maybe they were all acting so low and that’s why you have an uncoordinated cancer and the whole thing, then it’s susceptible to the immune response. Or is it that this is communication only between the original tumor and the metastasis? So I guess if it was then you’d see the original tumors survive and none of the metastases survive. So, I guess it must be the GAS6 without knowing is that this is involved in the cell to cell communication between tumor cells specifically. So they’d become uncoordinated and maybe weaker.
Jay Shepard: Yeah, I think, again, I’m not a scientist and I don’t want to pretend to sort of, you know, answer your questions, which are good ones. I don’t want to sort of give you any misinformation, but as I understand it, this process, the scientific process that’s been developed at Stanford, it stops the cancer cells from converting into metastatic cells. And the simple way to think about that is that cancer cells in the body will convert into cancer cells and then cancer cells proliferate, grow and expand in the body and our drug, we believe, we hope that it shuts that process down from happening. So we don’t have clinical results yet in patients but what we think it will do is that it will, in many cases, it will stop the progression of the disease. And in some cases, we’ll reverse it. I mean, that’s really the hope. And what that means is that you’ll stop the cancer cells. They’ll go from, you know, kind of metastatic cancer cells back to normal healthy epithelial cells. So, in terms of, you know, this agent will be, you know, kind of used in combination with other chemotherapeutic agents. So it’s, you know, what we call an adjunctive therapy at this point in time, we’re not really testing it by itself to sort of cure cancer. It’s used to make the cancer agents that are being administered right now in the cancer types I’ve mentioned. It’s meant to be adjunctive and it’s meant to be sort of a helper therapy to make the chemotherapeutic agent more effective in doing their job of shutting down or slowing down the disease progression. In some cases you could get a complete reversal and you know, we’re hoping that, you know, it may, in some cases, you know, people will have what you call complete responses, in other cases you’ll get just responses and you know, that the drug will be very, very effective and we’ll keep people alive much longer. And ultimately there’s the potential of this drug to be used as a sort of maintenance therapy, meaning that people, it’s almost like aids, which has become almost a chronic disease. You know, this type of therapy that we have because it’s such a safe product, it has virtually no toxicity at all in the body. Like people don’t really get, side effects with this drug. This might very well be an ideal agent as a sort of a maintenance therapy drug that people can take almost indefinitely, but we have yet to be able to, you know, kind of prove that hypothesis, but it’s that kind of a drug, it will work adjunctively with other drugs and then potentially longer term as we studied this drug and develop it, it can also be used as a sort of a potentially a maintenance therapy.
Richard Jacobs: Makes sense. So you tested in the mouse model and then the first step, the stage of the clinical trial, what was that like and what’s the current stage that you’re in? How’s that different?
Jay Shepard: Yeah, so this last December we started treating our first patients in what we call the phase one B portion of the clinical development program for AVB-500 and we’re testing the drug in resistant ovarian. So, we’re hoping to complete that part of the study you know, sometime in the second half of this year. And then we will go to, you know, this phase two of this study. So right now we have a number of patients that are enrolled that you know, have had the drug administered and it’s being administered with a drug called either doxil or taxol sort of, you know, the resistant ovarian cancer setting. And so what we’re hoping is that patients will survive longer and then we’ll also see that patients what you call progression free survival, which means obviously the amount of time from when the drug is administered to the time that the disease reoccurs that we’re hoping that our drug will make that period of time much longer, that they slow down the progression of the disease. And that’s the, and then obviously we’re hoping that, you know, we are overall or the patients overall response rates are higher and you know, ultimately that they’re surviving a longer period of time. And that’s what we’re looking for in the phase one B resistant ovarian cancer study. And then the phase two, we’ll basically be looking at the same population, except it will be a, you know, controlled study and it will be randomized either being combined with doxil or taxol against taxol and placebo and doxil and placebos. So that, you know, we can see whether or not our drug made a difference in those settings. That would be the phase two part of the study, which, which would start again in, in the second half of this year.
Richard Jacobs: Why wouldn’t you do a control of, you know, your drug and no chemo.
Jay Shepard: Because anybody with resistant ovarian cancer that you obviously would treat them and so you can’t, that wouldn’t be fair to the patients, not to treat them with drug, which would be, is typically taxol or doxil. So it wouldn’t be right for us to sort of test it against nothing because that wouldn’t be fair for the patient. So the standard of care is either doxil or taxol so they will either be in that arm of the study or there’ll be any arm of the study where they get those drugs. Plus our drug. So, you know, any of the patients in our study, you know, they’re not giving up anything they’re just participating in a clinical research study that is aimed at trying to figure out whether or not the approach of adding our drug is helpful to their disease progression or not.
Richard Jacobs: You know, Chemo is, I guess you can call it proven effective in some people not in a lot. And the whole reason you have chemo resistant cancers is because of the chemo applied and the nature of cancer changing. How will you ever supposed to separate the effects of this drug and Chemo if you’re not allowed to test it? Alone.
Jay Shepard: Well, I think physicians historically have expected to get a certain set of results when you give to say doxil or taxol, I think they expect to get a certain result in resistance setting. And so let’s say physicians expect to get a three months of progression free survival on average when you give either doxil or you give taxol any resistance setting. You know, what we’re hoping is that when you test, you know, kind of our drug, when you combine it with doxil or taxol, we’re hoping that we can improve on that progression free survival, say on average three months, , by adding our drug in. And I think it’s a pretty direct comparison of okay, if physicians, historically over the last x amount of years, I’ve gotten three months of progression-free survival on those drugs and if you add our product and they get, let’s just say five or six months of progression-free survival, I think physicians will be able to draw a direct correlation and say, you know, as long as the study is powered right and there’s the proper number of patients powered right, you know, physicians would look at that and say, that’s definitely an improvement. And I think patients would be, we’re hoping it would be a win for everybody. So that’s the direct comparison that you would do. You would never sort of withhold the standard of care, whatever that standard of care is from patients in the clinical study because that would be unfair to patients. And the reason that you can add our drug safely and effectively is that you know, sometimes when you add other sort of anticancer or you know, kind of therapeutic options to existing chemotherapy, you get additive toxicity, meaning side effects, and then it becomes sort of a balancing act of, you know, is it worth, you know, adding all the toxicity for, you know, whatever benefit you’re hoping you might get with our drug. There’s not really a trade-off in the sense of you’re not adding toxicity. You’re what we’re hoping is that we’re giving them another agent and they’re getting sort of better efficacy, without adding the side effects.
Richard Jacobs: But that’s a sad thing. If you drag works without any side effects, what do you have to add the Chemo, which has all kinds of terrible side effects, you know, let’s say your drug works then if someone wants to do something else to add to it, you know, let’s say your drug and chemo become the standard of care. Now they have to piggy back on top of those two and do a third in order to get their drug through. It’s kind of like, I don’t know, it just seems ridiculous to me. You know, a few, if they’re willing to do a trial, and I know this is not your fault, if they’ll approve a trial that it has the chemo and placebo. Why isn’t that unfair to the patient? Just because this is not yet proven and it just seems to put anything besides chemo at a disadvantage because they’re forcing it to be given along with it. Would that may not, not even close to the right solution? Maybe, you know, another drug with chemo does have terrible side effects, but alone it would be fine. It would work better but they won’t allow that.
Jay Shepard: Yeah well, we haven’t studied our drug yet, so we don’t know whether it will get a better effect by itself versus some of the other drugs that are what you call it, platinum resistance setting. You know, for example, we’re talking about platinum-resistant ovarian cancer. So we don’t know if our drug by itself, we haven’t studied that way yet. So I think in cancer therapeutics when you develop drugs, what you want to sort of do is sort of be able to add on to what physicians are already doing thing results. Because there aren’t a lot of drugs out there that when you start getting, you know, kind of resistance, you know, in other words, drugs stop working as effectively as they did earlier on. When you have early-stage cancer, when you get to that kind of setting, there’s really not a lot of drugs that are super effective, but there are drugs that, you know, do prolong survival and they do knock down cancer. And so physicians aren’t going to stop using those drugs. You know, they’re not going to stop using this drugs because they’re effective and yeah, they definitely have side effects and chemotherapeutics are difficult for the patients to tolerate in many cases, but they still in many cases will prolong their life and you know, given the option of prolonging your life versus not taking anything at all, you know, I think, I don’t want to speak for patients, but I think, historically patients have opted to take the drugs that will prolong their life even though they have side effects. And then our sort of value proposition for our product is you can add our drug in and you’re not, giving anything up. You know, you’re not sort of replacing the efficacy of the chemotherapeutic agents. But what we’re hoping to do is turbo boost them, you know, sort of add incremental efficacy to what the baseline drugs are offering them. And so I think we would all agree with you, Richard, that we wish that there were drugs that patients could get to, didn’t have any side effects and that, you know, just cured their disease. But we haven’t found those drugs, we’re still trying to discover those drugs in certain cancer types, you know, certain types of leukemia they have figured out how to cure certain types of cancer. But the ones that we are sort of trying to help out with, our first sort of foray as a resistant ovarian cancer, I don’t think the world has discovered drugs that are cured of yet. So what you’re left with then is can something be added in to existing drugs that will have a incrementally beneficial effect to the patients? And we believe, although we haven’t proven it yet, we believe that our drug has the potential to really help those existing drugs out. But you wouldn’t want to take those drugs away, unless you found something that could sort of just, cure the disease. And I’m afraid at this moment we don’t have evidence that our drug by itself will cure it. So, and I don’t think there’s really any drugs out there that have been able to show that yet. So again, the hypothesis or the hope is that and the prayers that we will be additive to the drugs that are already getting them a beneficial effect in terms of efficacy.
Richard Jacobs: So how would you prove it? That your drug may have positive effects on its own. You know, let’s say you do it and hopefully the trial works and works well. How would you ever then say, well when I just tried the drug alone, maybe it’ll work so well that we will need chemo or is that just not allowed?
Jay Shepard: I think it’s, you know, drug development is sort of always a stepwise sort of process, you know, if you think about any therapeutic area, you know, you take it to step by step. And so typically what you do is you develop your drug and you test it in patients who are, you know, really having a hard time or are not responding to conventional drugs. And you start there and then as the drug sort of shows that it, it can slow down or reverse or stop disease progression, then you start using it earlier and earlier, meaning you know, first line, second line therapy versus say the second or third line. Does that, does that make sense?
Richard Jacobs: Yeah, I just believe that. I’m just wondering whether, you know, okay. The amazing the sense is as far as it can go, but, okay. So what’s the timeline as you said by the middle of this year you’re going to be in phase two B or you know, what’s the timeline for phase two, three and then I don’t know if there’s a four and until it actually comes to the market.
Jay Shepard: So, the timeline would be that it, you know, phase two would start sometime in the second half of this year. So, sometime between July and December of this year, we would start our phase two trial and then we expect to see results of that trial sometime toward the end of 2020 and then after you’re done with your phase two trial, then you go to your pivotal trial or your phase three trial, which would be sort of, you know, a larger, it would also be a randomized trial, that, you know, we would then take that data and submit that to the FTA to try and get them to approve this drug. So it could be used, you know, in the resistant ovarian cancer population. It would be available what you say commercially. So, that’s more or less the timing in so far as, the resistant ovarian cancer setting.
Richard Jacobs: So, if things work out well. The drug shows good efficacy, how long would it be ballpark do you think until it’s available as a therapy to the general public? You know, we haven’t really given the public, I mean, we don’t know exactly what the timeline looks like in terms of the completion of the phase three trial because that’s obviously a larger trial. But, you know, it could be, it’d be sometime before 2025. So, 2025 it would be sometime before then, probably. Hopefully, you know, several years or a couple of years before that, but we haven’t disclosed exactly when that would be, and the phase two trial has to start accruing and then we have to complete it. Then we have to sort of assess what the data and the results, you know, how the data looks, and then you start your phase three trials and then that takes a year or two to accrue, meaning enroll patient, getting the results of that. So you know, if you can imagine, that would be in the early 2020s.
Richard Jacobs: Okay. Very good. So what’s the best way for folks to find out more, you know, getting in contact, ask questions, etc.
Jay Shepard: I think, you know, they can go on our website, they can also look up, it’s called clinicaltrials.gov, is, you know, sort of the standard place where you can find information on clinical trials on all kinds of therapeutic trials that are undergoing. So they can contact the company directly by looking at, you know, aravive.com or they can go on clinicaltrials.gov and on the web in general. And I think the website, there’s obviously contact information for the company and they can ask any questions folks would have into the appropriate scientific and medical folks.
Richard Jacobs: That’s great. Well, Jay, thank you for coming, I really appreciate it.
Jay Shepard: Ok Richard. Thank you for your time and your questions and hopefully, the information was helpful.
Podcast: Play in new window | Download