Agios Pharmaceuticals Inc., the sponsor of two drugs that may change the outcomes for a subset of acute myelogenous leukemia patients, is focused on more than AML.
The company is pursuing research on isocitrate dehydrogenase mutations, which are present in multiple cancers, said David Schenkein, CEO of Agios.
“We started with AML, because it’s easy to measure activity in the blood, and you get an answer much more quickly than you can in solid tumors,” Schenkein said. “So, we’re not an AML company. We’re a precision medicine drug development company with a focus in metabolism. And that’s how we got into AML.”
Schenkein spoke with Paul Goldberg, editor and publisher of The Cancer Letter.
Paul Goldberg: You have established your track record at Genentech. What was it that got you interested in AML?
David Schenkein: My first exposure to the industry side of drug development was actually running the oncology development group at Millennium, and we developed one of the first new drugs for multiple myeloma called Velcade back in 2003. It was approved.
And then I moved to Genentech early 2006. I think what I learned at Genentech is the power of precision medicine. I’m a hematologist, so I’ve been taking care of AML patients for over 30 years.
But when we started Agios, and even today, we didn’t set out to make new drugs for AML. We set out to make important novel precision medicine drugs, and we would let the science take us to whatever cancer it made sense.
And again, Agios was started based on the concept of dysregulated metabolism. And so, when we discovered the IDH mutation’s function, we saw that the mutation occurred in multiple cancers—AML and several solid tumors.
We are pursuing all of them. We started with AML, because it’s easy to measure activity in the blood, and you get an answer much more quickly than you can in solid tumors.
So, we’re not an AML company. We’re a precision medicine drug development company with a focus in metabolism. And that’s how we got into AML.
People in the field are talking about a revolution in AML. What I’m seeing is not so much a revolution as a strategic approach to the disease. I think it may be analogous to lung cancer, but not much else. Do you think the AML situation is unique in oncology right now?
DS: I don’t think it’s a question of unique. We went through close to 40 years in AML without any novel new ways of treating patients other than chemotherapy, where the other blood cancers, multiple myeloma, CLL, lymphoma have seen a variety of different and novel drugs, most of them precision targeted drugs, but some just totally novel ways of treating the disease.
It’s a question of the biology getting to the point where we understand now that AML, like many other cancers, is a very heterogeneous disease. No two AMLs are alike. And understanding the molecular driver of the disease allows one to come up with medicines that are precisely targeting that driver.
The 20 percent of AML patients who carry the IDH mutation, either IDH2 or IDH1 are very different biologically than the patients who carry a FLT3 mutation or another different type of mutation.
I do think there is revolutionary change in that, like in other blood cancers, we’re moving away from nonspecific cytotoxic chemotherapy to much safer and more effective precision medicines.
Now, we’re just at the beginning. 2017 saw four drug approvals in AML, two of them targeted. One was our first one, IDHIFA, an IDH2 inhibitor, and the other was Rydapt, from Novartis, which is a FLT3 inhibitor.
Now, we have our IDH1 inhibitor, Tibsovo approved last week. So, it’s beginning, and I think over the next five years, you are going to see change in the way we treat patients with AML.
Well, let’s talk about FDA for a minute. What’s their role in advancing this? Are they present at all the right meetings?
DS: They are. Rick Pazdur [director of the FDA Oncology Center of Excellence] and the oncology group—and that’s the group I work with the most–have really been enlightened for a long time.
That group has been leading the charge on advancing medicines as quickly as possible that appear to be safe and effective. So, no roadblocks at all coming from the FDA.
And in AML, I think, the change that is happening that will really facilitate approvals in newly diagnosed AML patients is historically the FDA was really looking for overall survival for large phase III studies.
And as novel therapies become available, just like we’ve seen in other cancers, it really gets harder and harder from an ethical position to do studies where overall survival is the primary endpoint.
So, the FDA is beginning to show an openness to other endpoints such as event-free survival, and they talked about that at a recent session at the American Society of Hematology.
They are present at all the major meetings. They are at ASH, they are at ASCO. They are excited about what’s happening in AML, and they’re helping to facilitate it.
Well, actually, it’s interesting that your company’s two drugs are approved based on an unusual endpoint—decrease in transfusions. And that’s regarded as a patient benefit, which actually gave you two full approvals based on single arm trials.
DS: Yeah.
I think that says quite a bit about the FDA’s flexibility here.
DS: I think it speaks to where the FDA is, but I think it also speaks to the compelling data we’ve been able to demonstrate.
The primary endpoint for both our studies, which led to the two approvals was the percentage of patients who achieve a complete remission. In this setting, one would expect the complete remission rate with chemotherapy to be about 10 percent.
We’re seeing with Tibsovo a little over 33 percent complete remissions. So, that’s the primary endpoint. But the secondary endpoint, because of the way the drug works, such a novel way of differentiating or repairing the leukemic cell, led to these transfusion benefits.
The FDA has historically always believed that a reduction in the need of transfusions is a direct measure of clinical benefit. So, the combination of the compelling, a complete remission rate, together with the transfusion improvement data, and safety profile, is what led to the full approvals, which is unusual, based on a non-randomized trial.
So, we were very pleased about that.
I don’t believe I’ve seen that before.
DS: It has happened, but it’s unusual.
I’ve seen a decrease in transfusion as a primary endpoint once, and that was the ESAs [erythropoiesis stimulating agents], but that’s the only times I’ve really seen it. I guess that’s a sign that you and the agency are having fruitful discussions. Were they open to this idea?
DS: Absolutely. We’ve always considered the FDA a partner, not an adversary. And I think that’s critically important when you’re doing drug development, because they are here to make sure that we develop important, safe and effective medicines.
And for us, they’ve been a great partner from day one on these programs and all of our programs.
Does this idea come from them or from you; just sort of curious?
DS: Which idea?
To use the decrease in transfusions as a justification for full approval.
DS: It was a secondary endpoint in our clinical trial, so the FDA had all of that data. The decision to go down the route of full approval or accelerated approval—that’s totally in the FDA’s domain, and they, during the review process, began to indicate to us that they were leaning towards full approval.
And so, we were very excited by that. And we gave them all the information they needed.
But the secondary endpoint of the study, among others, was looking at transfusion burden in these patients, which is such an impact on these patients’ lives. Because right now, patients with AML spend most of their time either in the hospital or in the outpatient clinic getting transfusions and chemotherapy.
And the fact that both of our medicines are pills that patients can take at home, and if their blood counts improve, which in most patients they do, they don’t need to come to the clinic to get transfusions.
So, quality of life and benefit is pretty dramatically different.
Are you moving these drugs towards the front line?
DS: Absolutely. There’s no question that we want both of these drugs to become the cornerstone of therapy for patients with IDH mutant AML, and then eventually other cancers.
So, we’ve already initiated one randomized phase III study in newly diagnosed patients. These are slightly older patients who are not young enough to get aggressive chemotherapy, but still fit enough to get standard of care. So, we’re doing a randomized study there.
Later this year, we’ll be starting a very large randomized study in the young patients who are getting aggressive chemotherapy now, and that would be with both IDH inhibitors.
Our goal in that study is to improve the cure rate, because for young patients, there is a 20 to 30 percent chance of cure, and that needs to move. It hasn’t moved in 25 years, since I was a fellow in 1986. So we want to move it…
And then, the third population that we’re studying, believe it or not, an important population, there’s a significant number of patients in the U.S. and around the world with AML who are older and who don’t get any treatment at all.
They’re sent home with hospice. And given that our medicines are well tolerated, and they’re a pill, and we’ve already shown in a small number of patients very impressive data, we’re going to continue to pursue that population as well.
Well, you mentioned one of these trials is randomized. Why randomized?
DS: Yeah, two of them. We’ll combine with standard of care therapy versus standard of care plus placebo.
Will you be doing any of this through the Beat AML trial; is that helpful to you?
DS: It is helpful. So the Leukemia and Lymphoma Society is running the Beat AML Trial, and we are participating. Both IDH inhibitors are in the Beat AML Trial. That’s not a randomized trial, but it’s an important trial in newly diagnosed patients. And so, both our drugs are participating in that trial. But in addition, we’re doing the phase III randomized studies combining with standard of care or using placebo that would hopefully lead to worldwide labels in the newly diagnosed patient, which is our ultimate goal.
So this is more of a, kind of a supplementary trial for you?
DS: It is, but important. And LLS is a great organization, and we’re excited to work with them.
If you were to blink right now and imagine what AML looks like in five years, what do you see?
DS: So, I’ll give you the analogy. But if I were to really blink and say, “What could things look like in the next five years?”
In the young patient, we’d see a significant improvement in the cure rate. We know it’s not going to be 100 percent. But a real pickup in the cure rate in the young patient.
The decision to go down the route of full approval or accelerated approval—that’s totally in the FDA’s domain, and they, during the review process, began to indicate to us that they were leaning towards full approval.
And in the older patient, today, there’s no potential for cure. So, if I’m going to dream, I’m going to dream that in that patient population, either with our drugs or other novel drugs, we’ll begin to see the potential for cure and/or long-term remission in these older patients.
And remember, in AML, the median age at diagnosis is 68. But most of the patients cannot today get cured with intense therapy. And if that could change, that would be amazing.
Now, if you remember, when I started working on multiple myeloma in 2001, the median survival in myeloma with melphalan and prednisone for any age was three years.
Today, with Velcade and Revlimid, and daratumumab, and other therapies that have been developed, overall survival in newly diagnosed myeloma is at least 10 to 12 years from the time of diagnosis, and there are some patients who are out much longer.
And that’s what I’m hoping will happen with AML.
How many drugs do you think there is room for here? Because it’s a fairly small indication.
DS: Given how dismal the current outcome is in AML, and that in the United States alone there are 20,000 new patients per year with AML, which is not all that different from some of the other blood cancers, there’s a lot of room.
Because until we move the response and survival data up in a meaningful way, it’s going to take a lot of different drugs, targeting different subsets. It’s not one disease. Just like lung cancer’s not one disease. So, we’re going to need lots of novel targets, and we’re going to have to combine them. One of the beauties of our two IDH inhibitors is how well tolerated they are, and they’re pills. So we’ve already shown so far that combining them with other therapies has been very easy. And that’s what the future will bring is to combine these new drugs together.
Well, that seems to be where Beat AML is going, right—combinations?
DS: Absolutely, but that’s just the beginning. We’re going do combination trials with our drugs as well. And there needs to be more, and more, and more–and there will be. So, there’s plenty of room. We’re nowhere near where we need to be in AML. We’re just starting. Myeloma, CLL, the other blood cancers are a decade ahead of us.
Fascinating. Is there anything we’ve missed in our conversation?
DS: I think we’ve hit the main points. Again, as a hematologist, someone who’s been taking care of AML patients for 30 years, it’s just really exciting to see light at the end of the tunnel there, and the hope that we may actually see a meaningful difference in survival in these patients over the next 5 to 10 years.
Well, thank you so much.
