David Bearss, PhD, CEO of Tolero Pharmaceuticals discusses a new drug that could possibly help patients with acute myeloid leukemia.
Interview conducted by Ivanhoe Broadcast News in August 2017.
Tell me a little bit about the drug, there are not a lot of treatments for AML?
Bearss: We have been developing this drug alvocidib to treat patients with acute myeloid leukemia. We have treated over four hundred patients now with this drug, and we have discovered something pretty exciting things. What we discovered was that a certain percentage of patients, about twenty-five percent, have a mechanism in place that this drug targets. We found that those patients do well when we treat them with this drug.
How does it affect them?
Bearss: The drug affects a particular protein that these AML cells like to express. It’s a survival protein; it’s a protein that helps them not die. It is one of the things cancer cells learn how to do pretty early on in response to a lot of different signals. So this survival protein is critical for their growth and development in these cancer cells. What we’ve discovered is that our drug inhibits the expression of that protein. It blocks the ability of the cells to express the protein, and it kills those cells. So that’s how it targets them.
So the protein in simple terms is it food for the cells and you’re cutting off food supply or different?
Bearss: It’s more of a mechanism of how they live or how they survive. The protein is not necessarily helping the cancer cells grow, but it’s helping the cancer cells stay alive. One of the interesting things about our bodies is we have built-in mechanisms to make sure that things don’t go wrong. Especially in our immune system, our blood cells have mechanisms to get rid of cells that aren’t doing correct things. It’s one of the ways that we can stay healthy over our lifetime; by selectively getting rid of certain types of cells that have mistakes and aren’t functioning normally. What this protein allows the cancer cell to do is to not listen to any of those signals that tell the cell it’s time for it to die. Thus, the cancer cells can grow in the absence of, or even in the presence of these signals. It’s an escape mechanism that these leukemia cells can figure out how to turn on.
Side effects?
Bearss: One of the things that we discovered about alvocidib is that it targets a family of proteins, but the dominant activity is inhibiting in one protein called CDK9. CDK9 stands for the cyclin-dependent kinase. It’s a family of proteins that we initially thought regulated cell growth, how fast a cell was growing. We discovered later that CDK9, specifically, is involved in regulating expression of different genes. In various tissues, it regulates different types of genes. So one of the things that we know is that when we treat cells with our drug, it turns off the gene expression of many different genes and some of those can happen in healthy cells. One of the things that we see is a drop in white blood cells in patients that are treated. If you have leukemia, that’s great, because that’s what we want to happen. In patients that don’t have leukemia, it can be a side effect that isn’t something you want. We do see some diarrhea in patients, some you know just general fatigue, and other types of common side effects that we see with a lot of these newer cancer agents.
So it’s not an immunotherapy you consider it a targeted therapy?
Bearss: Yes, it definitely is a targeted therapy. It targets a particular protein or a family of proteins, and in our case, we are trying to target CDK9.
Is there any way to tell before you give the drug to somebody that it’s going to work on them or not?
Bearss: That’s a great question. We’ve spent a lot of time trying to figure out how some patients will benefit from the treatment and how other patients don’t benefit as much. As a scientist, that’s the most intriguing question is why do some patients do well and other patients don’t do as well. When we started treating AML patients, we got to work right away to try to understand who was going to benefit the most. We discovered that we could predict patient’s ability to respond to the drug using a brand new test. It’s a relatively straightforward test; we take cells from the patient. For instance, leukemia patients have a lot of cancer cells circulating in their blood, and so we can draw blood, or we can take it from their bone marrow, and then we run the test. The test tells us whether the patient’s cancer cells are using this survival protein, for survival. It asks the question what the mechanism is of cells using to live and if it’s using this particular protein, then we know the drug will work. In retrospective, we tried to figure out if we could use this test to find patients that we already have treated and we figured out a way where we could find a hundred percent of patients that would respond to our drug using this test. It is pretty exciting to us to be able to find a way that we can screen patients and identify if those patients had a response. We are testing that now in a clinical study where we’re asking the question what if we only treat those patients that are positive for this test. That’s what we’re exploring now with the drug, and previous experience tells us that we should have a very high response rate.
So is this a separate trial than the one that you’re doing with the drug?
Bearss: We are testing the test and the drug at the same time.
Same trial?
Bearss: Well, the present and the future of oncology; even the future of medicine, is being able to find the right patients to treat. To only treat the patients that really are going to benefit. This is an exciting concept for us, is to be able to go out and screen and find the right patient and only treat those patients.
So what has the response been in your four hundred?
Bearss: When we look back at historical data of patients that have been treated, what we discovered was that there were about twenty-five percent of patients that had very long, durable responses. Unfortunately for acute myeloid leukemia patients, their five-year survival rate for patients newly diagnosed is only about twenty-six percent. This means that twenty-six percent of people will be alive after five years, but seventy-five percent are not going to be alive. When we treat these patients, we found out quickly whether the drug works or not, whether it extends peoples life. That’s what we’re looking at; looking back in time what patients were benefitting from the most and how long they were living. Unfortunately, what we usually see in treating high-risk AML patients is that after three or four years you have a lot of patients that have passed on. We saw this flattening of the survival curve, as in, patients living a lot longer than what we expected. That’s actually how we discovered this test. We were asking, what is different about those people, then the people that are dying early?
Any way to be able to quantify that?
Bearss: When we apply this test, one of the things that we did was we collected samples from the patients that we treated before we had the test. We saved those samples so that we could go back and check them in the future. When we look back, what we see is that patients that are positive in the collection of patients we’ve tested. The important end point for us is how long fifty percent of the people lived. The median survival is what we’re looking for. When we look backward, we have not reached the median survival in that population of patients, even projecting out four or five years now in follow-up, so that’s very exciting. That means that we’re having not only an impact on these patients responding to the drug but those responses are durable, and they’re affecting survival at least in this retrospective analysis. Now to prove what we are doing in this prospective study, we’re only enrolling patients that are positive for this test, and then we’ll be able to answer the question; how long does that extend the lives of people?
No real way to say it’s a month; it’s two months at this point?
Bearss: At this point, the data that we have looks very encouraging. But until we do this prospective study, we really can’t conclude what the data means moving forward. It is about new information to the field. In this population of patients, unfortunately, they have such bad prognosis that if we can extend their life for six months or a year, I mean that’s a big, big impact for these patients.
Where are you in the trial right now?
Bearss: The trial is designed to be what we call a two-stage study. We’re first enrolling everybody who’s positive for this marker; we’re just treating those patients now. As soon as we hit a certain number of patients that will trigger what we call a randomized study which means that we’ll test those people that are positive with our drug versus just the standard of care. Our drug combined with the standard of care versus the standard of care. We’re getting ready to trigger that now. We’ve been refining and improving this test in a way that we can really expand. We’re just poised right now to open up this study and in fact, we’re opening this study up all across the United States. It’s been at a very select few centers so far, but we’re open up new sites all over the United States. We are starting to open sites internationally as well in Canada as well as in Europe.
So it is launching into a Phase II or Phase III?
Bearss: It will be a randomized Phase II, but if the results are what we expect them to be, then this data could be used to move and accelerate an approval for this drug. It could act like a pivotal study or a Phase III study.
So there’s really so far off that this would be available to Joe on the street?
Bearss: The approval could come pretty rapidly because the response rates in these patients are so bad right now. If we see a dramatic improvement, that could trigger an accelerated type of review with the regulatory agencies such as FDA and the European medicines, EMA. We expect that we would be able to take this data and have a discussion with them about making this medicine available as fast as we possibly can.
What haven’t I asked you that you think that I need to put in this story?
Bearss: The test that we have now is run in a reference laboratory; we collect samples from the patient. In fact, what we’ve decided is the bone marrow from leukemia patients is the best sample because it’s really full of these leukemia cells. We take a bone marrow aspirate and it’s a standard procedure that these patients are already getting so it’s at the time of diagnoses. We take these cells from the patient; we put them in a FedEx box and ship them off to the lab. The lab right now is in Boston, and we get a turnaround of just one day. The physician has the results. In fact, it comes back a lot of times faster than other labs that they have, that they’re running on the same patient. The doctor, their treating physician, will know whether the patient is positive or not for the study and so they can be enrolled in the study. It’s a very simple procedure. It’s a diagnostic that’s already being run on these patients where they’re taking this bone marrow and so we just use the same sample to run this test.
Is it something people can ask to participate in now or not?
Bearss: At the selected sites that we have opened now it’s available for patients that qualify and there are other qualifying criteria, the inclusion and exclusion criteria. We’re trying to look for patients that have failed prior therapy. These are patients that are relapsed after frontline therapy. Typically, after they were newly diagnosed, they were treated had a response and relapsed. We’re looking for patients that had a short duration of their first response. People that didn’t enjoy a very good benefit from the first therapy, or patients that never responded to the upfront therapy so relapsed, and refractory patients with AML. We’re selecting younger patients right now. The median age of diagnosis in the U.S. for adults with AML is around sixty five so we’re trying to treat patients sixty five and younger. That is the reason why is we’re combining our drug with the standard of care drugs. Unfortunately for patients, the standard of care for AML hasn’t changed in forty years. We’re still using pretty old chemotherapy and it’s really hard on the patients. It can make them susceptible to infections and lots of other complications that are tough. Normally, we treat younger patients with AML with the high dose chemotherapy regiments and because we’re combining it with that, we’re selecting those patients. Now we have some new studies that are planned that we’ll target different populations but right now that’s the focus of this study.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
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David Bearss
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