Amgen Inc. (NASDAQ:AMGN) 60th American Society of Hematology Annual Meeting December 3, 2018 11:00 PM ET
Arvind Sood - VP, IR
Dr. David Reese - Head of R&D
Dr. Greg Friberg - VP, Global Development and Therapeutic Area Head for Oncology
Dr. Max Topp - Head of Hematology at University Hospital Wnrzburg, Germany
Geoff Porges - Leerink
Ying Huang - Bank of America-Merrill Lynch
Ronny Gal - Bernstein
Mike Yee - Jefferies
Kennen Mackay - RBC Capital
Terence Flynn - Goldman
Alethia Young - Cantor
Yaron Werber - Cowen and Company
Matt Phipps - William Blair
Evan Seigerman - Credit Suisse
Chris Richard - Tekla
Brian Skorney - Baird
Carter Gould - UBS
Okay, so we'll go on and get started. Good evening, everybody. I'd like to welcome you to our event this evening. And I know there are a lot of other events ongoing at the same time, but I think you made the right choice. So it's a great opportunity for us to, of course, talk about AMG 420 and other data that has been represented in the scientific sessions here at ASH, but it's also an opportunity for us to talk about the broader oncology portfolio.
So the presenters from the Amgen side are Dr. David Reese, he's our Head of Research and Development; and we also have Dr. Greg Friberg, who is our Vice President of Global Development and the Therapeutic Area Head for Oncology. I'm really delighted to have with us one of the lead investigators for AMG 420, Dr. Max Topp. He is also the Head of Hematology at the University Hospital in Wnrzburg, Germany.
So with that, David, I'd like to ask you to come up and make a few comments.
Dr. David Reese
Thanks Arvind and good evening everyone. Tonight, we will talk briefly at the beginning about our oncology portfolio and then of course we will spend most of the evening talking about the BiTE platform and some of the presentations that you saw in the last few days here at ASH including just a short while ago in one of the myeloma sessions. I've been at Amgen for 13 years. I'm a medical oncologist by way of background. I've never been more excited about our oncology portfolio across a range of modalities and we'd like to share a little bit of that excitement with you tonight.
So, we’re taking what we feel is a differentiated approach in oncology. In the last quarter, in the third quarter, we introduced seven first-in-class molecules into human testing. Six of those were in oncology really an unprecedented stretch of time and year for us at Amgen. We are pursuing multiple modalities. It’s our belief that the extraordinary range of new drugs that are coming online and you saw great examples of that over the course of this meeting will coexist.
We believe that the assets in our portfolio are going to play an important role in a number of these diseases and we are aggressively prosecuting our development programs. In fact, I they don't think our execution has ever been any better. Almost all of the programs that you will see tonight are enrolling on or ahead of schedule and whether in general quite aggressive development timelines, and we expected in the coming year we will generate a wealth of data, we will give you a sense of what sort of data you can expect in the coming 12 months from this portfolio.
Let me start with our framework for how we think about oncology. It's my belief that the future of oncology is really going to be the marriage of precision oncology, or targeted therapy with immuno-oncology. Precision oncology agents are will be used often to debulk tumors, to reduce the burden of cancer cells followed by immuno-oncology agents that will be used in an attempt to eradicate disease. Immuno-oncology agents themselves can be fought broadly in a couple flavors. There agents that inflamed tumors and what that means is that they are designed to attract either cytotoxic T cells or other effector cells to the tumor microenvironment. And then there are agents that are designed to enhance that activity, checkpoint inhibitors would be a classic example of enhancing agents.
Within this paradigm which is how we organize our research efforts and our approach in the clinic, we have taken the approach to debulking agents to say, we're going to go after very high value targets, holy grail targets, I would call them in many cases, and we will show you a few examples of those tonight. In immuno-oncology of course we have focused on the bispecific T cell engaging platform, oncolytic viruses as well as a variety of combination approaches. This is a snapshot of our current portfolio there at least 20 unique assets as you can see targeting a range of hematologic malignancies and solid tumors. About half of the program here bispecific T cell engagers or BiTEs and the rest represent a range of modalities.
I would like to call attention before we move to the BiTE platform specifically to a few of these agents. If you look at the bottom of the multiple myeloma column, you will see AMG 176 and AMG 397 also in the leukemia column. These are MCL1 inhibitors 176 is an IV inhibitor and 397 is an oral inhibitor. Both of these are moving rapidly through first in human dose escalation studies. This is a verify value targets in myeloma and leukemia its one of the principal pro-survival factors in those disorders. We are seeing interesting early signs of clinical activity and those are agents that we intend to aggressively develop.
We believe that these agents where we used in combination with a variety of other agents that are intended to induce cell death or apoptosis. I would also like to call your attention to AMG 510, which is a KRAS G12C inhibitor. KRAS as many of you know is the most frequently mutated oncogene in human cancer is about 25% of all human tumors have RAS mutations KRAS G12C is one of those suites of mutations can occur in human tumors. It is present in about 15% to 25% of lung adenocarcinomas and 2% to 4% of a wide range of other solid tumors, including cancers such as pancreatic cancer and colorectal cancer. It's been a 35 year quest in the field to actually develop KRAS inhibitors. The chemistry is extraordinarily challenging. We were the first in the clinic with AMG 510. This is now moving through dose escalation. We are seeing interesting signs of clinical activity and we will look forward to sharing results from this program we believe sometime in 2019.
Finally let’s not forget IMLYGIC. Several months ago, we completed enrollment in the Phase 3 combination trial with KEYTRUDA so those patients continue to be are treated and followed and over the course of next year will have a better sense as we see how the event rates are tracking in that trial is so when we can expect final data. Another element of our strategy in particular with the BiTE programs is predicated on the belief that these agents will be used either in combinations or sequentially and so as you can see illustrated here in both solid tumors and some of the hematologic malignancies we have developed BiTE that target different antigens on a tumor cell.
One of the mechanisms of resistance to T cell directed therapies such as bispecifics or CART T that is clearly emerging as loss of the target antigen, the target on the tumor cells and being able to go in either a sequential alternating or combination fashion after more than one target will be core part of our strategy and our development programs are designed to then take an early look at combinations of these agents moving forward. The goal is disease eradication.
I think reflecting the pipeline that developed this is one of our biggest years ever at ASH with 45 abstracts with nine oral presentations quite a large number. We will focus the rest of the evening in Greg's talk on AMG 420, BCMA BiTE and AMG 330 a CD33 BiTE for acute myelogenous leukemia or AML. I am pleased to announce that we just received fast track designation from the FDA for AMG 420 based on that data package and we will be having discussions with regulators in the near term about the development program for that molecule.
So with that, I'll turn things over to Greg, who will take you through some of our data.
Dr. Greg Friberg
It’s a pleasure to be back at ASH and seek you all again this year. Not to belabor the point, but for those who are not quite a familiar with what the BiTE is, it stands for bispecific T cell engagers, which of course is an off-the-shelf technology. It takes two variable regions from antibodies, one targeting CD3 and the other targeting a tumor selected antigen. And it creates a pharmaceutical that we can then infuse into patients and when that comes across both the T cell as well as the antigen, there is activation, lysis, and proliferation of those T cells.
Of course, the prototype molecule that we've often spoke about is blinatumomab targeting CD19 and that’s really provided much of the clinical validation for the platform in a lot of the learning’s that we’re trying to apply as we move into other targets. We most recently received FDA as well as a CHMP positive-opinion approval for MRD-positive ALL in that case. And we think that again blinatumomab serves as a template by which we can think about applying some of these other BiTEs.
We now seem activity across a variety of different tumor types, five different tumors ALL, lymphoma, myeloma. We’re going to talk a bit about and AML today and some early data in prostate cancer. We are hoping as we build upon this data set that these can become a very meaning part of patients. The hypothesis behind the basis that they provide in an off-the-shelf manner like I mentioned a pharmaceutical that can get the patient and really won’t need the type of lymphodepleting chemotherapy or the wait time that some of the cellular therapeutics are required.
We've been developing this platform beyond just the first generation canonical BiTEs. We now have half light extended BiTEs in the clinic and we are continuing to work in the research space that try to evolve the platform even further. We’re also quite cognizant of the fact that resistance is developing out there and as data sets are evolving as Dave mentioned antigen loss is of concern. We’re also looking to combine the BiTEs with agent like PD1 inhibitors to make sure that other mechanisms of escape aren’t taking over.
Those studies are ongoing, and of course with the new BiTEs and new indications, this is really an essential part of the research plan as they are being laid out. We think we’re in a competitive position across a variety of new indications, and as Dave mentioned we have about 12 different bispecific against high-value targets that are either in the clinical or in the preclinical space peri-first in human. To our 2 BCMA-targeting molecules from multiple myeloma that were currently developing, we’re going to talk a little bit about AMG 420 that Dr. Topp presented today and of course that study has established a ready for Phase 2 dose in 400 micrograms per day.
What I won’t be able to show you date on today which is actively evolving story is the AMG 701 program. This is a BCMA-targeting bispecifics that has the half life extension technology I mentioned, this is in currently in its first in human study, it's rapidly recruiting and we’re starting to see the kind of pharmacokinetic and pharmacodynamic activity that we would expect to see gives us a lot of excitement moving forward. We were hoping that will be able to buy a year from now at perhaps at this conference be able to show you some data regarding that program.
Shifting to AMG 420 several you may have just seen this presentation its hot off the presses from Dr. Topp and as a reminder, this was sponsored by Boehringer Ingelheim, and the molecule a short while ago reacquired by Amgen. Now putting the study in context, this is a dose escalation Phase 1 study a variety of doses even under a microgram per day all the way up to 800 micrograms per day. It enrolled patients that were essentially all comers an off-the-shelf therapy.
So after the patient finds consent, most of them are coming on within a matter of days to the study. This study in particular identified the 400 microgram dose as the highest tolerable dose. So when we talk about efficacy, we're going to focus on that but again the four-week continuous infusion two weeks off. Therefore, patients when they needed and it enrolled a variety of myeloma patients really from that standpoint 42 patients really all comers. This is therefore an intent-to-treat analysis.
This is a group of patients that was highly pretreated a median of four prior therapies, but up to 10 in terms of examples. And as you can see here, many of them have been exposed to the agents that we know are available and great majority of them had a prior autologous stem cell transplant. In fact vast majority of those were tandem transplant. So, these are folks that had a variety of prior agents and you can see the refractoriness to the immediate prior agent level.
We presented a spider plot, looking at patients serologic markers and so what you see here is each line represents an individual patient. Over time you can see what happens to that measure of the bulk of their disease and I want you to focus on two factors when you look at this. First and foremost, if you look at the blue star and the green star here, you can see as the does goes up there was a nice dose-response relationship. As patient got higher doses in the study, again it's an escalation study. They got higher doses we saw faster, deeper and longer lasting responses.
The second factor I want you to focus on is a little more subtle here. What you see is there is a group of patients actually almost immediately on the study who weren’t doing so well. These are patients who really within weeks unfortunately were progressing. These are not the kind of patients who could have sat around and waited for say a CART therapy. We enrolled these patients. It is all comers study therefore. And what you're looking at here is a real world intent to treat analysis of the kind of myeloma patients that are out there that are walking on the Phase 1 study.
We presented individual information on the patients who did respond. What I want you to really focus on here is that a majority of the responses happen at higher doses. But it wasn't exclusively of the higher doses. We have patients that are still on study this is an ongoing Phase 1 but you get a sense for the fact that particularly with the four patients in the 400 microgram dose we’re hopeful that that something quite durable is occurring in those individual patients, we will have a change to talk at the top of the end to go to more detail.
If you look across the entire cohort at the responding patients, again you see this strong trend that higher doses were seeing more activity but when you look at these patients for example, look at the patient who receives 400 micrograms per day. Many of these patients had MRD negative complete responses in these were not patients who look in different I think as Dr. Topp put very nicely than the totality of the population, this wasn't reflective of say a more well group, they would add anywhere up to six prior therapies most of them had two prior stem cell transplant and a host of them had quite a bit of narrow involvement as well.
In terms of duration of treatment you see that again it's an ongoing study. Some of these patients received up to a year of therapy, it’s a very potent molecule so just to put that in perspective a year of therapy 400 micrograms per day with the schedule we mentioned, its only about a 110 milligram of drug total. And the reason I bring this up is because we think this will be a differentiating factor for the molecules fairly a 110 milligram for a whole year of dosing something that we think is quite manufacturable and we will be feather in account of this molecule.
The side effect profile was quite managed when the skim of the patient here again this is CTCAE criteria and the CRS, the cytokine release syndrome that was seen was quite manageable. One of the benefits of having the continuous infusion of course if you run into these toxicities we’re able to turn the pump off the growth washers out and we can use that as one of the management tools here to be able to continue to treat the patient. Otherwise I think Dr. Topp very nicely in this presentation described the two reversible polyneuropathy and of course infection, which is a variety of different terms. It was seen on some of these patients and this is probably a combination of their underlying disease, as well as that being on the study.
In conclusion, AMG 420 had a 70% response rate at the target dose we saw. There were 10 patients treated at 400 micrograms per day, and of that those 10 patients 40% of them had MRD negative complete responses. We think this compares quite favorably, so other BCMA-targeting agent particularly when you put this in the context of who these patients were, there was no pre-selection we didn't select for the ability to expand T cells or wait a month every patient who signed a consent went on to the study. And again that intention to treat real-world evidence is somewhat of a different way to look at the data than perhaps other presentations of analogous and parallel technology.
I want to shift gears a little bit and reflect a bit on our AMG 330 targeting CD33 for AML, again a very difficult to treat disease. This is unlike myeloma. Unfortunately, these patients probably only have weeks or couple of months to live, when they have relapses and are quite feel requiring immediate treatment. Of the 40 patients were enrolled on this study again I think it highlights just how 50 folks were meeting a poor prior therapies many had prior autologous stem cell transplant and of course they came on to the study having quite low neutrophil counts to begin with. This is Grade 4 neutropenia, walking in the door because of the burden of their illness.
We completed 12 escalation cohort this is been quite diligent work to get to where we are. We've been able to through the course of these escalations overcome what we saw on the way which was cytokine release syndrome, we implemented step dosing first it was one step now we’re using a two-step method. We have also introduce dexamethasone all the way and the short story here is that as we gotten up to higher doses we seen increase target coverage and were starting to see the kind of activity that gives us confidence that there is more to come. Initially, those CRS were incomplete in the logic discovery as we gotten up higher, we’re seeing true hymnologic recovery after we been able to hit the blast and get them below level that meet that criteria.
What I want you to absolutely be left with today is we think this is really the precipice of activity, it’s the beginning for this agent, we’re continuing to intensify it, we’re continuing to look at duration of therapy and long get the infusion. We’re also taking a look at where this drug will be used in the treatment paradigm thinking again about the debulking inflaming and enhancements, whether or not we should be perhaps using this in combination or in sequence with other approaches. We think this is just the beginning of activity and there's more work to come.
So the study continued, we’re not only continuing to enroll of the dose were actually trying to go up higher still. But what you see here, this is a waterfall plot again each line is an individual patient you will see that looking at the bone marrow looking at last count on patient when we got up to higher doses. There was a greater response. So, there was a clear dose relationship as I mentioned and we continuing to intensify any long gain in the schedule. The durability of the responses we saw in these four patients was not as long as we like it to be and again I think this gets back to my point, before which is we do think there's more work to do more escalation more intensification with this agent to come.
Just highlighting those patients who did have responses if you look at the bottom of this graph here, those were the two that had two CRS, these were not patients that for example that had low intensity induction chemo therapy and then just came on to study, they had multiple cytotoxic induction agents you see here and one even that had mix and cell transplant and of course there bone marrow blast were significant. The side effect profile was what we thought would be quite there. It was quite manageable on this patient population. And really I think I've highlighted the cytokine release, we've been able to dose through that using the methods that I described.
Just o summarize AMG 330 again we’re pleased by what we've seen, we have been able to get through cytokine release as a potential limiting toxicity and we’re hopeful again we’re at the beginning of the kind of efficacy that this drug can afford to be. If we take a step back and look at the whole platform we really been working quite diligently over the last several years to industrialize its platform as we mentioned before 12 molecules against high-value targets are moving into the clinic, limiting that remains the first and only approved BiTE, that’s on the market right now we are pursuing a sister molecule AMG 562 a half life extended CD19 molecule and we’re going to be focusing that molecules efforts more on the lymphoma side than the ALL side.
In terms of BCMA and CD33 we talked about AMG 420 and AMG330 respectively for myeloma and AML. I don’t want you to forget though that there are sister programs for both of these molecules that have the half life extension technology that’s we call that AMG 701 and AMG 673 and were hoping to be able to show you over the course of the next year data involving those programs. Advancing the BiTE platform for a variety of diseases glioblastoma AML, small cell we haven’t talked about prostate today. Again, were hopeful that over the course of the next year we will have some data to share and I will come back to that in a moment.
We see encouraging activity and pharmacokinetics with the half-life extended BiTE again its early days, but those studies really across all the indications are enrolling quite rapidly and we will have more to talk about. So getting back to the menu of molecules that Dr. Reese showed before we want to be transparent about the data that's coming give you an idea of what were expecting over the course of the next 12 months. In addition to having continued and longer follow-up with AMG 420 and AMG 330 we would expect this have data to share over the next year with the half-life extended sister programs similarly were hoping to have some of the first data with our CD38 targeting myeloma CD3 bispecific.
As Dave have highlighted before of course there are solid tumors that are quite interest to us both MCL one inhibitors as well as the KRAT C12 inhibitor data over the next year and we’re even hopeful that our prostate cancer and small cell programs might have data to share. These are all Phase 1 studies they’re adaptive, we continue to go through dose escalation, we want to make sure that when we do share data that we have something meaningful to share but all signs point to being able to have meaningful information to share over the course of the next 12 months and it’s full steam ahead.
So, in summary, I think Dave had gone over this before really we’re hopeful that these molecules represent first in class opportunities, and that we will be able to do the fine-tuning work to find out where again they offer patients most value; the studies that we’ve shown today were all monotherapy studies. So of course they represent beginning of the fine work that we’re doing but we’re hopeful that rolling these into rational combinations, trying to prevent resistance as well as picking patients who are undeniably need more therapy, the MRD-positive ALL cases is a nice prototype for that we’re hopeful that these will offer something quite significant in the coming years.
A - Arvind Sood
Okay, thanks very much, Greg. Look forward to getting your questions now. So, we’ll open it up for Q&A. Before we do that, let me just mention that these slides are going to be posted on our website, so you will be able to access those. For the Q&A, if I can make one request if you can just raise your hand and then if you can state your name and company affiliation. Why don’t we take the first question from Geoff Porges of Leerink.
Just a couple of questions on 420 and really particularly about the platform, I think we’re all impressed with the responses that you saw, the MRD-negative cases are pretty impressive in such highly pretreated patients, but I think we all struggle with the dosing schedule and clearly from infection risk associated with the permanent catheters as well that probably other treated modalities don’t have. So could you be relatively specific, David, about the change in the half life that you’re getting to with the HLE formulations of both the BCMA and the other most advanced bit beyond blinatumomab? And then, can you get away from the permanent catheter, so that you don't have the risk in these highly immunosuppressed individuals for those infections?
Dr. David Reese
Quite good questions, so I’d make a couple of points. First in regards to AMG 420, this is obviously a patient population with very advanced relapsed refractory disease. One of our intent here is to also move this drug up in line of therapy for example, in a consolidation setting where you have now clearly regimens that are -- will have extraordinary induction affects and then we believe two or four cycles of a BiTE consolidation can, our goal will be to drive MRD remissions that last hopefully years. So, there will be different setting. Your point is well taken regarding the half life extended BiTEs, our goal in developing that platform was to generate drugs that could be delivered weekly or less frequently in a short IV infusion, the pharmacokinetic data that we’ve seen to date suggests that we should be able to achieve that and I am actually quite confident about the sort of dosing regimens and schedules that we will be able to achieve with half life extended platforms.
Let’s take a question from this side of the room. Ying, why don’t you go ahead and then we will go to back.
Ying Huang with Bank of America Merrill Lynch. I'd like to ask you about the durability, so we didn’t get enough durability data, but beyond what you were presenting today at ASH. What do we know about durability of those responses among the patients were treated with AMG 520?
Dr. Greg Friberg
I’m going to let Dr. Topp comment, but of course the challenge with durability is we need to wait long enough to see the responses. I think Max, you have the longest experience with patient from the study, IF you want to comment about at least on an anecdotal level.
Dr. Max Topp
I mean, I only can herald what Greg's just said. This is still ongoing study. We still need follow up. We have patients who actually are in remission and all receiving therapy. We also have one or two patients who came off the clinical trial either because they actually had a DLT, but we're still following those patients or the patient had four cycles and is still they came off due to patient wish. We're still following those patients, but I can say that the vast majority of patients that are in remission have not relapsed so far. So what that means in long-term, we will see.
Dr. Greg Friberg
And the data cut you saw today are relatively up-to-date, so we're continuing to treat and follow many of those patients.
And then maybe for David quickly, are you developing also potentially a subcutaneous formulation of these BiTEs or it will be only IV?
Dr. David Reese
We’re looking at different formulation and methods of administration. So I am quite confident between the half life extended format and other approaches such as subcu administration. For example, that that will be able to ultimately move away from continues infusion. Now there are some settings where we wish to have continuous infusion you saw, for example, glioblastoma BiTE listed there in the central nervous system you want to be able to turn off an infusion. If there is an exuberant immune reaction and so we in fact purposefully developed a first generation continues infusion by in that setting. But moving forward with the overwhelming majority almost all of the new BiTEs that we introduce will be half-life extended or have others some other mode of administration that’s not continuous infusion.
Let’s take a question from Ronny Gal in the back.
Ronny Gal from Bernstein. My comment, my question is on the bispecific CD33 molecule. When I speak to doctors, they kind suggest that suggest indication of this anti CD33 compartment leads to significant myeloid depletion, and therefore need to see very decent duration of the fact in order to justify use of drug of that sort. What we’re not seeing in this trial is a durable effect that even patient response seems to be relapsing relatively quickly. In your mind, what kind of duration of the fact would justify using therapy like this?
Dr. David Reese
I'll start and we may ask Max who has got tremendous experience in this area with BiTEs across hematologic malignancies to comment as well. We certainly want to see remissions that would be in the general range of 4 to 6 months, but I think one of the other concepts that I introduced this evening is also important, which is having our BiTEs directed against additional targets such as FLT3 and FLT3 BiTEs are now in the clinic as well. And being able to approach the -- for example leukemia stem cell compartment after you debulked with AMG 330 with the FLT3 directed by -- is the strategy that we will take going forward. Max, do you want to add some?
Dr. Max Topp
Well, at least, with leukemia patients, we have always allogeneic transplantation. So, this therapy leads to substantial portions patients going to complete remission with even MRD response that would be then a trigger to take them to transplant, so even duration of just three months will be meaningful in that situation in getting that endpoint. And secondly, I think what is also very important is that new drug on chemotherapy so the patients going to transplant without actually having infectious complications while they actually have time to resolve these infectious complications even in a burst of just eight weeks is the basically the game changer for patient going from ECOG 2 to an ECOG 0. And so the TRM rate then in the transplantation situation would drop and hence that’d be a combination of therapy definitely for the acute leuks.
Okay let’s take the next question from Mike Yee in the second row.
Thanks, Mike Yee from Jefferies. Dr. Topp, you made some comments about the value proposition of particularly in off-the-shelf therapy and that obviously makes a lot of sense particularly for patients who can’t wait until real world population. Maybe you could describe or quantify, how you think about that population who can’t wait versus those who could consider CAR T and the salvage therapies? And then as you go upstream, does that value proposition change if off-the-shelf is related in picture?
Dr. Max Topp
I think it depends on the disease that you’re tackling, so if you’re tackling AML, AML is really explosive disease. So -- and if there's someone's failure on a 3 plus 8 in that situation, the options are actually quite limited for those patients. So that context does do CAR T therapy to develop that leukapheresis is going to be almost impossible to get T cells that you need to make that. So with my -- not much of a difference you may have agents, there’s much more armamentary there to debulk to keep that, and actually thinking that all have do with myeloma is a disease of patients who are 60 plus. And so, we’re dealing with patients who have a lot of cardiovascular problems, in my mind those patients are not suitable for ECOG therapy. It is actually lot of shelf population to be treated, but just because of all the probability that we’ve to deal with. Of course, the outpatients will have a very explosive myeloma, very fast flowing myeloma and that will be very advantageous. Those are to have the off-the-shelf product might be not even feasible to get the leukapheresis done with a substantial amount of T cells to make a CAR product.
Should we have to think about that's the half the population in later lines that we just can’t read?
Dr. Max Topp
It’s about half the population in salvage therapies and you think about in CAR T that that there’s self select?
Dr. Max Topp
If you look in myeloma, so 80% of the patients like this myeloma is 60 years and plus. So let’s say about half of those patients have cardiovascular problems, diabetes, anything like that I would not think that’d be suitable for ECOG therapy. So, that’s a really a big population to look at.
Terence, for fair balance, let me take one question on this side of the room then I’ll come back to you. Kennen, why don’t you go ahead?
Maybe just as it relates to 701 versus 420 obviously a very substantially extended half life there and some quite elegant biology doing that. But maybe elaborate as to how the predictive toxicity and efficacy from mouse models or what we see in humans compare there as we think about dose escalation i.e., if we're linearly increasing dose each of these drugs that the onset of tox sort come in the same fashion between 701 and 420 and similarly with would be onset of efficacy?
Dr. Max Topp
So, this develop now when you compare blinatumomab SLE product and now looking at 420 toxicity profile, we're seeing, we have to deal with blin, we had to deal with neurotoxicity, which is the most common toxicity, Grade 4. Cytokine release syndrome just being in trial and about 5% great free. Now we having a 420, we don’t have any really severe neurotoxicity, neurotoxicity meaning central neurotoxicity. What I was looking to that we’re talking about, we’re seeing peripheral neuropathia. It's something very different. So into which degree now the 420 versus 701 will have a very similar profile we have to be seen. We do different trial. We have to look at the dots as it comes alone.
Dr. David Reese
Thank you, Max. I mean we’re early in the 701 dose escalation trial. I think what you’re alluding to is that, for example, pharmacokinetics curves may look different Max and the exposure curves, and that's something that we've looked out in animal models which are imperfect here. But my sense is that based on the large amount of experience we generated with blinatumomab and now multiple agents, we become quite good at recognizing patterns of adverse events. And my sense is that we shouldn't see anything that's dramatically qualitatively different with the half-life extended molecules but of course we need to generate those data.
Okay, let’s take the next question from Terrence. Terence, I assume you still had a question.
Terence Flynn, Goldman. Maybe the first one was just a follow-up on Mike question. If you were to look at the percentage of myeloma patients in Europe for 20 study what percent what would have been eligible for CAR T trial and where they get the same kind of question? And then I have one more.
Dr. Max Topp
I would say about half the patient, I mean they were not selected for that question but 62 years with the meaning of patients so with many we have patients who were 70 plus.
And then maybe for Greg you mentioned some early prostate cancer data is there anything more you can share on that front with respect to the PSA response you're seeing, these responses what type of patients are there and thanks a lot.
Dr. Greg Friberg
With a public presentation I believe that ACR this year patients treated with AMG 212, we can provide that information for you after the session.
Okay let’s take the next question from Alethia.
Alethia Young of Cantor. I just wanted to get maybe your observation, there were many, many BCMA CAR T presentations and just maybe talk about how that stacks up with how your data has been generated? And then just the second part of the question is I know you’ve something preclinical with the CAR T I believe the one that you had in your Kite portfolio. Can you just talk a little bit about what you’re trying to develop there what that and what the status is?
Dr. David Reese
About our CAR T program, so we’ve a partnership that’s public with Kite and three targets, which we’re bringing forward, it’s a case where we’re bringing both the CAR T and the BiTE on those high-value targets. We’re actually in a quite good position in that sense to be able to compare the results we see in those two Phase 1 studies we’re focusing on three diseases, AML, small cell lung cancer and prostate cancer. And again, we’re hopeful that that in these cases where the targets are of high value that we can test multiple platforms and modalities as Dave was alluding to see what the right tool is to get at that biology.
Dr. David Reese
We’ve a really hard time comparing again we don't want to inter compare various trials, but the lack of the intention to treat analysis just makes it difficult for us to comment beyond pointing to our data describing who these patients were, truly is all comers population, and we have to leave it there.
Okay, I think, there was a question in the back. Yaron, is that you? Welcome back.
Yaron Werber from Cowen and Company. I’ve a couple questions. One, give us a little bit of sense, there is a lot going on these days on the BCMA front, there’s a question of antigen expression and antigen loss over time. And then on the other side there’s a CD38 antigen with great job of showing single agent activity. So as you think about differentiating your portfolio with the two BiTEs how do you think about which one you prioritize and maybe pockets of strategy as to how do you move them up? And then I want to follow up on the XmAb technology and give us a little bit of sense of how does that differentiate within the portfolio?
Dr. David Reese
So that's a good question and I would actually not view it as a prioritization question between the BCMA and CD38 bispecific as we mentioned given that antigen loss is emerging as one of the mechanisms of resistance actually our intent will be to ultimately develop those drugs in combination or as part of alternating or sequential therapy so it's not an either or at all, and in fact we plan to take both forward quite quickly. And then you said you have a follow-up question.
Maybe just the XmAb technology results and how that differentiates over a -- just a T Cell enhancer, just a give a little bit of sense exactly what you mean by an XmAb and what’s the differentiation?
Dr. David Reese
So XmAb is a collaboration with Xencor, it is a bispecific technology that’s still basically built on the skeleton of a standard antibody that Scott, both a CD3 engaging arm as well as antitumor target engaging arm, it also has extended halfway properties, because it is antibody like and again with the XmAb agents that we are developing in collaboration with Xencor we would also be looking for intermittent short infusions of those agents.
Okay, let’s take that question in the back.
Matt Phipps, William Blair, a kind of follow-up to that question. When you think about the BiTE platform, are there specific advantages to that structure like the stoichiometry of the proteins that make it a better bispecific platform as opposed to full-length IgG? Especially not that you’re adding on FD domain it seems like a lot of work as oppose to just whole and you do have kind of a Xencor partnership.
Dr. David Reese
Yes, we do think that stoichiometry is important in their clearly some constructs and we've looked at many, many dozens of potential bispecific constructs and some simply won’t engage in the appropriate ways. I would say that after a very large amount of molecular engineering. We arrived at the choices that we made meant to optimize both the engagement in T cell activation, as well as the pharmacokinetic properties of those molecules.
If I could also add, we been able to look at this platform also from a manufacturing standpoint and try to optimize so that if these are successful we will be up to bring high-quality proteins were with the efficiency that’s required.
Evan, why don’t you go ahead?
Evan Seigerman from Credit Suisse. So back to the toxicity of 420 and potentially 701, you've mentioned that one of the ways to manage the CRS by turning off the pump given extended half way assets. How do you manage the toxicity there? And then with AMG 330 credit kind of challenging, what are you going to do to fine-tune in your next steps to potentially see better outcomes there?
Dr. Greg Friberg
So, you've raised an important point. Of course, nothing for free in life if we go with the half-life extension, the ability to turn off and tune the pump goes away. But we’re hopeful is that the targets and the range will be forgiving enough but again it won’t be too hard or too cold, but will be able to recapitulate with the dosing that the lot of half life. With the long half life what we learned from the continuous infusion. We do have other ways to mitigate some of the toxicities. Of course, we learned quite a bit about steroids and in some cases tocilizumab. So again, it's absolutely complex. It will be based on the toxicity that we see the patient and the constructs.
Dr. David Reese
I would also point out that the in the acute leukemia where you have an enormous tumor burden CRS has release syndrome has been most problematic. We suspect that's going to be much less of an issue as we move for example to solid tumors and so where again that half-life extended format would be much preferred.
And in the seven on trailers is there a protocol to use tocilizumab?
Dr. Max Topp
While it's an option, patient to develop more severe grades to a grade three upfront that content.
So physicians have the option to use if it is not mandatory.
Dr. Max Topp
With the virtual question about that CD33 hope I wasn't too cryptic we’re going to try to get the infusion for longer, we’re going to try to keep going up on the dose and refining for patient population perhaps we already been debulked, these were the kind of things that were going with but we’re going up on the dose and real on getting on schedule.
Let’s take a question in the back there.
Chris Richard, Tekla. Relative to MT 201, to blinatumomab, it seems like you're going with much with both the contractor going with much higher amounts of drug that get to an active dose and for the same construct I would if it is not that different across these three agents. Dr. Topp, maybe you could comment on, do you think it’s a difference in antigen sync? I mean is there a way to kind of saturate that, maybe change the PK a bit, maybe get it weighed from at least after an induction regimen, something little more, away from the continuous infusion?
Dr. Max Topp
Well, I think is an excellent observation I mean the dose that we’re using is almost 20 fold higher, when you compare that to blinatumomab that we’ve now for ALL so yes that’s definitely a discreet proportion of the tray is exactly the same, format has with blin, but the 420 part targeting BCMA target is a different one, dissynergies there's a difference disease is different too and all that might contribute to different dosing that we use in situation. Coming back to how to maybe do this more intelligently I think we’ve an option of course of introducing step dosing in a situation, we’ve not explored that either in the 701 protocol or in the 420 protocol, currently we don’t plan to do that, in 420 because tox profile looks so great, but who knows what we’ll see in the upcoming trials.
Any other questions? There’s a question right there.
Thanks, Brian Skorney from Baird. Just a kind of follow-up a little bit on the comments about looking at the BiTEs versus some of the IgG bispecifics that maybe we’ve seen at this conference, how would you recommend as looking at the date in terms of determining whether it is true T Cell engagement versus just more of a standard like ADCC affect to the IgGs?
Dr. Max Topp
Well I think the IgGs that we’ve been seeing, IgG proportion that's usually linked to ADCC have been blunted in that context. So it's truly T Cell engagement, there’s no NKA cell activity in those construct that have been used for the full length, bispecifics have been presented here by Roche, Genentech or Regeneron.
Dr. Greg Friberg
With the CDC binders as well we didn’t present the data but across the BiTEs, we do have a set of biomarkers that we’re following closely and there’re what we call the hallmarks of BiTEs where we see T cell redistribution and certain cytokine profile. So at least behind the scenes those are things that we’re looking at very closely just try to optimize dosing, and of course we would look for the same effects with others if they were taking the same mechanism of action.
Okay, as this is almost 9 PM, let’s take one last question. Carter, I think I saw your hand up.
Great, Carter Gould, UBS, just to comeback to planned study for 420 given the focus on the HLE molecules just trying to understand again what you’re exactly trying to accomplish with that sort of immediate next steps and then just to come back to the CD33 HLE program are you still targeting the same sort of dosing regimen that you mentioned earlier getting that weekly kind of schedule. I know that there’s a competitor out there that’s seems to have a sort of a half life in between kind of your two programs?
Dr. Greg Friberg
So with AMG 420 within the course of weeks we’ll be beginning a large expansion study that IND is filed and we should be dosing that shortly and we’re actively engaging with regulators on the types of studies you could imagine, trying to use that as a tool, not just as a monotherapy in later stage patients but really in rational combinations moving in up in lines of treatments. With regard to the AMG 673, the CD33 half-life extended, our goal is to have a treatment that would be once weekly or less frequent, of course, based on the need to do step dosing and get to a safe dose it may require a loading period. But that's the kind of work in the Phase 1 study that’s been actively done. The goal is to have once weekly or less frequent.
Thanks, Greg. I would like to thank you all for your participation in our session. If we didn’t get to your question, our team will take a round for few minutes. So feel free to come and approach them individually. Thanks again.