Q4 2022 Xencor Inc Earnings Call
The conference will begin shortly to raise and lower Johan during Q&A, you can dial star one one.
[music].
Yeah.
Good afternoon. Thank you for standing by and welcome to <unk> fourth quarter and year end 2022 conference calls.
At this time all participants are in a listen only mode. After the speaker's presentation there'll be a question and answer session.
Please be advised that this call is being recorded at the company's request.
Now I would like to turn the call to your speaker today, Charles Liles head of corporate Communications and Investor Relations. Sir. Please go ahead.
Thank you and good afternoon earlier today, we issued a press release, which outlines the topics we plan to discuss today. The press release is available at Www Dot <unk> Dot Com with me on the call are battling back yet President and Chief Executive Officer, Allen Yang Chief Medical Officer, John <unk>, Chief Scientific Officer, and John <unk>, Chief Financial Officer.
After we make a few comments we will then open up the call for your questions before we begin I would like to remind you that during the course of this conference call <unk> management may make forward looking statements, including statements regarding the company's future financial and operating results future market conditions, the plans and objectives of management future operations, the company's partnering efforts capital requirements future product offerings and research and development program.
These forward looking statements are not historical facts, but rather are based on our current expectations and beliefs and are based on information currently available to us.
All of the events described in these forward looking statements are subject to risks uncertainties and other factors that could cause actual results to differ materially from the results anticipated by these forward looking statements, including but not limited to those factors contained in the risk factors section of our most recently filed annual report on Form 10-K, and quarterly report on Form 10-Q with that ill pass the call over to Pascal.
Thanks, Charles and good afternoon, everyone. We've used our array of modular approach and engineering tool to create our internal development portfolio in oncology and autoimmune disease.
And we use the breadth of this portfolio to take multiple simultaneous shots on goal in the clinic.
<unk> to us proof of concept data from our early stage studies to guide, which programs, we advance, which we terminate in which we partner so that we can use our resources on programs with the greatest potential for success and make room in our portfolio for the next wave backstopped by specifics in engineered cytokines.
We use revenues from our partnership portfolio to support our development.
Here's a few pipeline highlights from 2022 <unk>.
<unk>, we continued our phase II study in metastatic castration resistant prostate cancer in combination with standard chemotherapy or PARP inhibitor, and we initiated a monotherapy phase III in <unk> and in gynecologic tumors, which are just some of the tumor types, where PD, one and <unk> four bi specifics out potential and in November we reported encouraging single ascending dose.
As stated for <unk> $5 64, a regulatory T cell targeted IL two for autoimmune disease, particularly the strong durability of T. Reg expansion as a consequence, we've started the multiple ascending dose study in atopic dermatitis and psoriasis patients to explore extended dosing regiments, we hope to have the psoriasis arms of the study finished by early 2024.
And we started phase one studies for two novel T cell engaging by specifics first with extra added one nine which targets CD, three and <unk> III and antigen in renal cell carcinoma that was built with our.
And we built them out with you on our two plus one format for improved tumor selectivity.
We believe <unk> offers a new mechanism against a barely explored targets of high unmet need in second and later line RCC.
Second key cell and get you to start clinical studies with <unk> <unk>, our first CD 28 targeting by specific.
At co stimulate T cells was bound to the tumor target <unk> III, a widely expressed solid tumor antigen exciting early data for CD 28 by specifics has increased our already high enthusiasm.
This new class of Immunotherapies.
And we're continually building the next wave of drug candidates with our engineering tools and tried to tackle new work hard to address biology with them.
Two such programs are advancing this year led by the expected phase one initiation for our third reduced potency cytokines, except 66 to an engineered IL 12.
Followed by IND filing for <unk> 500 for one or two plus one CD three by specific targeting cloud six for ovarian cancer.
The well balanced portfolio of late and early stage programs in development that we can potentially advance to approval and ultimately the market if the data supports it.
Our development pipeline gets strong support from our <unk> portfolio not just from the revenue that generates but also from the resources of our co development partners those programs that we have partnered.
Now the last of my remarks is that we are in the midst of completing our laboratory and office relocation to Pasadena, where a new facility can accommodate our expanded R&D efforts and will help keep us at the cutting edge of protein engineering.
That I will turn over turn the call over to Allen Yang Our Chief Medical Officer, who will review recent updates from a few of our ongoing clinical studies for wholly owned programs.
Thanks, Basel with Allomap is our most advanced check dual checkpoint inhibitor. We've designed the classify specific to bind T cells that express both targets in this case PD, one and <unk> four with the intent to limit the exposure of the molecule to control and improve tolerability and yet still hit the cells that are going to be the most active against the tumor.
Two ongoing phase III studies are looking for clinical signals that would prompt us to invest in Registrational studies at the <unk> meeting in November we reported the first data coming from our first phase III study in combination with chemotherapy in patients with late line metastatic castrate resistant prostate cancer, a very high unmet need population.
Given the changing treatment landscape in prostate cancer, we designed the study to address several groups of prostate cancer patients, including aggressive variant.
Actionable PARP inhibitor relapse.
MSI and biomarker negative group.
We designed each arm to receive with Allomap and in combination with the standard therapy, if warranted for chemotherapy eligible subjects. We originally designed the study to use taxane or platinum doublet.
Based on our previously reported study that showed a high response rate in order to maximize potential efficacy.
And the first patients we saw multiple PSA 50 drops and three of eight patients and one of these eight patients had a durable partial response, we also saw toxicity related to the intensive chemotherapy combination, but without a consistent type of AE. Among all of the patients. However, we modified the chemotherapy dosing regimens keeping boot allomap.
Dosing as planned and we're rolling again into the chemotherapy combination cohorts of the study.
The second phase III study is a value with allomap monotherapy and additional high risk populations of prostate cancer as we continue this.
Search for a defined subpopulation that we could advance quickly towards registration. This study is also enrolling patients with gynecological tumors, where we also saw good activity and finally this study introduces a flat dosing and more convenient schedule.
Now as we continue to enroll these patients we see a lot of opportunity for the program as emerging data across the class provides us science for a broad utility across additional solid tumor types.
Now secondly, ex map.
Presents a new class of bi specific antibody targeting the <unk> pathway and then quarters among the first companies to enter the clinic with a molecule in this space.
Clinical data beginning to emerge have indicated dramatically enhanced activity of a checkpoint inhibitor in prostate cancer, where previously checkpoint inhibitors have had limited activity.
We're seeing the case that a targeted CD 28 by specific in this case PSM may markedly increase the activity of the checkpoint inhibitor and serves as an important validation for the class.
We find the data encouraging enough to accelerate our own program targeting BC <unk> III and Energid heavily expressed in multiple tumor types, including prostate cancer renal cancer lung cancer and many others as <unk> III is also expressed at low levels on some healthy tissues, we've incorporated our two plus one by specific.
<unk> technology.
<unk> eight O eight to potentially increase the therapeutic window.
And we're moving rapidly with X map eight O eight the first patient in our phase one dose escalation study was dose last year and following initial doses of <unk> <unk>. We add <unk> is combination therapy. We believe we are well positioned to the CD 28 by specific space, especially as there becomes increasing recognition that.
This class holds a lot of opportunity and is really starting to heat up not only with our ex map eight O eight but as a research teams advance more CD 28 programs through preclinical development, we hope to share more in the coming months.
With that I'll now hand over the call to John <unk>, Our Chief Scientific Officer to review two programs, we plan to bring forward in the clinical development. This year into clinical development. This year, our IL 12, cytokine <unk> and cloud and six by CD three by specific ex map 504, one.
Thanks Alan.
So the key to all of our <unk> programs, including Xbox that seeks to reduce the potency dialing down the receptor binding affinity you can smooth out the activity profile observed in wild type product lines, which are natively very hot.
Minutes here.
Systemically can generate a lot of immune toxicity easy to get cleared.
Now I'll 12 is a different kind of cytokines compared to IL 15, and IL two.
Instead of expanding T cells, and NK cells, all to promote high levels of interferon gamma secretion, which increasingly society of toxicity of T cells, and NK cells will make tumor antigens more visible that we mentioned.
So <unk> two we can reduce potency all 12 engineered with an X five slavik FC domain enhanced with our extend technology to further duration of action.
And in preclinical testing reduced potency FC fusion compared to native IL 12 FC fusion demonstrated an improved pharmacokinetic profile of therapeutic window here.
Here your exposure a more gradual dose response and more sustained and free gambles.
Our R&D application was recently submitted an allowed by the FDA and we look forward to initiating a phase one study in patients with advanced solid tumors.
Finally X map by four one.
Cloud and <unk> by <unk> Bispecific antibody built with our <unk> two plus one format for improved tumor selectivity and we're developing the molecule for patients with ovarian cancer.
We are wrapping up our IND, enabling studies.
Yes.
Yes.
We plan to submit an IDE later this year.
Now a quick refresher on the ex Mab, two plus one format, where we build a bispecific or multi specific using two tumor binding arms at once you saw body.
The approach we use to address a frequent observation with tumor targets.
There are also expressed on normal tissue.
Okay therapies intended to address solid tumors off target effects can lead to high toxicity by having two antigen binding domains, we continually affinity for tumor antigen and bias the molecules themselves to have a lot of the energy and expressed over normal cells that have lower antigen expression, where it's just hard to wrestle with.
We believe that it's about a two plus one can be generally applicable to bispecific antibodies against solid tumor targets, hoping opens the doors to bringing more stages III cytotoxic.
848 stimulators into development.
With that I'd like to hand, the call over to John question, Our CFO to review our financial results John .
Thank you Jan <unk> broad portfolio of partnerships collaborations and licenses continue to generate strong cash flows support our operations.
In 2022, we received $198 $7 million in royalties and milestone payments, which helped fund our investments in our portfolio of Bispecific and cytokine drug candidates.
Proceeds received in 2022, offset a substantial amount of our operating expenses and we ended up 2022 with cash cash equivalents receivables and marketable debt securities of $613 5 million compared to $664 1 million at the end of 2021.
Based on current operating plans, we expect to have cash to fund research and development programs and operations through the end of 2025.
And we currently estimate we will end 2023 with between 425 and $475 million cash cash equivalents receivables for marketable debt securities.
I refer to you I refer you to our press release. This afternoon now 2022 Form 10-K filing for further information about our recent finished.
With that we would now like to open up the call for questions operator.
Thank you.
As a reminder to ask a question. Please press star one one on your phone and wait for your name to be announced to withdraw your question. Please press star one again.
One moment please for our first question.
Our first question will come from Mara Goldstein.
So as you hoped.
Your line is open.
Great. Thanks for taking the question.
To ask a question on 564 and.
The program, there and and I'm really trying to understand I guess, maybe when in looking at atopic dermatitis and psoriasis.
What you think the benchmarks for success are going to be in terms of being able to advance.
That product forward.
Yes, Thanks Bart.
For US right now Theres two goals from this phase.
Phase one be multiple ascending dose study that we're doing first and foremost is establish a dosing regimen that.
We can move forward with and that means someone that's safe and one that gives us good coverage of the target or a rather good biomarker movement of the T. Regs for the duration of our dosing interval. So that's step one and I think those two indications are great indications for that because you can see looking at skin, how the disease readouts doing in parallel with your biomarker. So so that's cool.
One I think the second goal addresses your question was what's the benchmarks for success I would say in both of those indications there.
Generally high I will say that the thing we're going to be keying off of is looking at how.
How durable and how long of an effect we can have.
With the agent does this have new biology by attacking T. Regs that you can extend response time, even beyond beyond dosing duration that was seen with some competitive programs glimmers of it and how long of a dosing can.
Can we get can we build the best in class.
Dosing intervals extending beyond every two weeks that a lot of the competing programs seem to have settled into.
I think those are the questions that we want to address with this early study and then I think after that there is there's good benchmarks for chassis and for for easy scores.
And if I can just ask onto the dial on that.
The discussion around <unk>.
Gauging the trial now that you've finished modifying the proto.
Protocol can you talk a little bit about just the enrolment characteristics for that program.
Okay.
You mean, how well.
<unk> have been yeah, what that what those dynamics like well you can expect going forward do you think you'll go back to sort of baseline where you were.
I don't know Alan do you want to comment on that yes. So just to be clear we have two phase II, we have a monotherapy phase III, which explores the sort of new flat dosing and schedule and that we've clinically defined sort of an aggressive type of prostate cancer and then we have the.
First phase II, which actually molecularly defined different subgroups of prostate cancer and this data is available, but we have an aggressive variant subtype. We have a PARP in April sort of a PARP actionable subtype of <unk>.
<unk> inhibitor sort of relapsed refractory group.
Microsatellite unstable group and then finally everybody else.
And I guess, what Youre asking is how they're enrolling now that we've.
We had to pause to adjust the chemotherapy groups and that was three of the groups, but the other groups continue to enroll and now we've opened up.
The other arms with chemotherapy and we've modified the chemotherapy for two of those groups.
Alright, thanks, so much.
Yes.
Thank you.
One moment please for our next question.
Our next question will come from Edward Penthouse of Piper Sandler Your line is open.
Thank you very much I appreciate it.
The question I wanted to get a sense.
Again to the extent you can.
Sure.
Sort of how the profile of the CD 28.
<unk>.
From CD, three and as you sort of.
Advanced on the pipeline how do you see.
Prioritizing.
One mechanism versus the other or other places, where one may make more sense.
There's multiple facets to that one John why don't you take the point about refreshing on the differential biology, <unk> <unk> thousand eight <unk> three and what we can do with that and maybe I'll jump in on the second one.
Sure Yeah. Thanks for the question Ken So.
The way, we think about the <unk> 2018.
With the phase III.
More of an artificial immunity or youre, just taking advantage of any any T cell around engaging it through CD three an recruiter to get to attack the tumor cells.
With the CD 28, because it's just providing signal too.
That's equally intriguing biology, because now you have that signal has to build off of an endogenous signal one.
Which pumps rolling new antigen.
T cell recognition by the T cells and of course, when you're applying the CD 28 in order to fully open up that signal one you're generally going to be combining a PD one checkpoint blockade.
And then the third arm of that as well.
We also see really interesting opportunity for combining <unk> with the <unk> 28, and Thats one of the reasons. We chose B 783 is our flagship seen 28 program because it's expressed in so many different histology that could be sort of a one size fits all combination partner for <unk>.
<unk> or other People's seizures.
Great. That's very helpful. Thank you.
Alright.
Go ahead, Ted did you did you get all your answers you need me to address your other point.
Please go.
Thanks.
Yes, so regarding how we view the different <unk>.
Thinking about them in different indications some of it depends on target availability.
Yes.
<unk> is is there an opportunity to improve.
Response for targets that have been tried to have promising biology, but it didn't work out I think thats the case, where the combination of a CD 28 with a checkpoint inhibitor could be very attractive I think we've seen that from competitive programs in prostate cancer with that early glimmer of data and then philosophically on.
Targets that you can.
You have a good nice differential of expression healthy to normal tissue hitting it with that direct attack on a CD three could make sense more right. So that's generally how we think about it as we explore the initial biology.
CD 28 over the next year or two.
Great. Thanks, guys et cetera for more data this year.
Thank you.
Thank you.
And one moment please for our next question.
Our next question will come from Dane Leone.
Raymond James Your line is open.
Hi, Congrats on all the progress and thank you for taking our questions.
I was just.
Wanted to get your take on maybe some of the earlier programs that you have.
<unk>.
Emerging now and.
Firstly, maybe would like to hear your updated thoughts on the IL 12 approach.
There seems like there's been maybe a few more discontinuation from from peer programs.
Curious to your thoughts on how you are differentiating.
To create it.
Therapeutic index essentially out of a difficult cytokine.
And then maybe on targeting with the 783 versus.
Maybe another emergent approach of you that would be 784.
It would be interesting as well thank you.
So on the IL 12, I think it comes down to a reduced potency design is something that has given us.
<unk>.
Significantly improved tolerability profiles versus wild type level activity cytokines for IL 15, and IL two programs.
So I think that's what we're banking on maybe John if you want to touch briefly on the preclinical profile and nonhuman primate data we have for.
$600 to and how that we believe differentiates it.
Yes, yes.
Thanks for the question David.
We actually compare to wild type IL 12 FC fusion, two or <unk> $6, two which again is around 100 fold potency reduced.
And recall the problem with these cytokines as when they signal they actually get cleared through the receptors and so when we look at monkeys that a wild type IL 12 FC.
We dose it.
As high as we can in terms of Tolerability, and it's gone and about one or two days.
In contrast that snaps skewed because of its potency reduction actually has it looks incredibly like an antibody. It's got a half life of 40% to 20 days in the monkeys.
That's likely to extend out even further.
So thats one aspect Basil also mentioned that when you have the pumps to reduce version you have much greater Tolerability and then the thing in the Monkey studies that kind of inspired me. The most is when.
We put in the wild type IL 12 at a rate.
30 fold differential dose range.
And every one of those doses dose levels gave the same exact initial peak of interferon gamma responses irrespective of the dose the only thing that changed when you're just more was because you get a little more exposure.
Rod and out that peak in terms of time, Inc.
<unk> was 66, two we actually saw a really nice gradual increase of the dose response as we up the dose and that I think that is going to give us a lot more flexibility thats really zero in on the optimal dose and therefore therapeutic index.
And regarding the <unk> III versus the 700, <unk>, where I think we will focus on what we find attractive about <unk> III. It's expressed in multiple tumor types. It has.
A good differential across multiple tissues for tumor versus normal tissue.
It is absent.
Very undetectable and scratching I should say in certain problematic tissues like the central nervous system brain.
<unk> I think that makes it very attractive.
<unk> for US is it target I am starting to see pop up and I think there's very little data to comment on it.
Do you view do you view <unk> three in a different way when using our coast them approach like <unk> 28 versus the past at times I've used adcs.
I think it could be very very different in immunotherapy approach versus delivering a direct direct sealy delivering a cytotoxic.
It could be profoundly different and so I don't know how much read through we get other than that you have.
Clearly enough of that target around tumors that an ADC can provide activity.
Beyond that theres, such different mechanisms that I don't know if anything we can glean.
Excellent. Thank you.
Thank you.
One moment for our next question.
Our next question will come from Dara <unk> of BMO capital markets. Your line is open.
Great. Thanks for taking the questions first one is a few things going on in prostate just wanted to know if you had any.
Any updates on AMG 509, the steep.
One two plus one.
Any updates here from from Amgen under development in.
Italy, just wondered for that program.
<unk>.
<unk> of the sort of a combo trial with <unk> is that just kind of based on literature.
Samples in or sort of.
Clinical data on the synergies or if thats, something where you're seeing something in the clinic that sort of prompted the combination with Pembroke. Thank you.
Great regarding <unk>.
<unk>, 5% or nine program, which is licensed.
They license all of the tools and technologies from us to build it.
The only information we can share is what they publicly announced I think they did it at the earnings last month and is that they expect to have any.
Initial data presentation in the second half of this year and that they are pursuing a quite broad phase one program looking at both combinations monotherapy, they've got a subcutaneous formulation and in addition to their IV, so they're putting a lot of resource behind it thats. All we can share publicly but we're certainly encouraged by the by the by the effort and by the initial data.
We saw a year ago.
For Ada wait I think that there is a very strong theoretical reason in fact, the fundamental basis for why you want to use a CD 20 by specific for combining it with either a checkpoint inhibitor or SaaS CD three by specific because that completes the circle of getting the CD 28 to give you that potent signal.
<unk>.
Activation and maintenance of activation, while the other side signal one.
Initiate that T cell movement in and September is based on very strong theoretical data that combo for why you want to combine a checkpoint inhibitor with a <unk> 28 for that 628 to put the checkpoint inhibitor over the hump when it's in a nominally cold tumor.
And Basil just to put a finer point on that.
There are some pretty strong literature that the dominant mechanism of action of PD. One checkpoint itself is to directly inhibit CD 28 signaling and most people also think it inhibits the single woman so.
The idea is that the b seven years to receive 28 by itself.
Hi.
It is going to be hindered unless you can also block PD one at the same time.
Great. Thank you.
Thank you.
Please go to our next question.
And our next question will come from David Dye of SMB <unk>. Your line is open.
Great. Thanks for taking my questions and congrats on the progress.
So I have two questions are first it's a solid with gallium I, we have seen some competitors showing PD one <unk> four.
If anybody has some pretty interesting data.
In the metastatic prostate cancer at <unk> Gi could you maybe compare and contrast, your gallium abstract profile versus the competitor <unk> antibody.
Sure So I guess.
For starters I guess ill say there is a lot of movement in the PD one <unk> four class Thats starting to happen also based on very early studies.
<unk>.
And we're very encouraged by how that is reflecting on that the potential for the dual checkpoint as we start to sort out how to use them.
I'll start off by saying that the relevant comparison is the monotherapy data from our phase one expansion cohorts that we presented a while back.
Compared to what was presented at <unk>. So it is that monotherapy monotherapy comparison.
So I don't know Alan did you want to touch on that.
Sure if I will be happy to.
I think the the day.
Data at <unk> sort of validates the class in prostate cancer, and it's difficult to compare the data between our data and Theres. What we reported is PSA response rate of about 20% in a heavily pretreated U S population use only population where the median number of therapies was five.
<unk>.
The other data that was reported at <unk> you reported a response rate of PSA response rate in the high 20%.
But a less pretreated population, where the median number of treatments was only two so again I think it's interesting data. It supports the idea of doing these PD one <unk> four is in prostate cancer and we already believe that and that's why we've started two phase III programs and are moving aggressively to try to figure out a registration pathway.
Got it that's really helpful. And then just another question on the <unk> I know you're currently developing a sub Q version of the drug could you maybe talk a little more about the status of the sub Q formulation and when should we expect to see data from that program.
So we initiated clinical studies that is dose patients.
With the sub Q formulation last quarter end.
That is a dose escalation study so we can figure out the sub Q regimen priming dose.
Step up doses, we of course have all the information we have from the IV that we think is going to greatly accelerate that process relative to what we had to learn from the IV and of course, we're doing this in collaboration with our partner Janssen.
Thats going forward as part of the whole package of our B cell collaboration with Janssen, which also incorporates our CD 28 by specifics, where we just this quarter announced that we have achieved the candidate selection milestone. So we delivered the FERC the b cell targeted CD 28 net.
Ultimately when it gets to the clinic would be combined with <unk> sorry.
Alright with that plateau will know demands.
<unk>.
So that's.
That's the sort of general context.
We'll guide on data as we go forward with the caveat that of course Janssen has to to be party to wanting to disclose data.
Got it thank you so much.
Thank you.
And one moment for our next question.
Our next question will come from Charles.
Of Guggenheim Partners. Your line is open.
Hello, everyone and thanks for taking the questions I have one question Thats essentially a follow up to something that's sort of had asked but regarding ex Smith 808, encouraging to see that you guys are combining this with Pembroke, but perhaps given do you have other pipeline assets in the clinic.
We're also going after prostate cancer with similar mechanism such as with element.
U K gauging the potential to hold too I guess co develop with food with element as opposed to an external asset and how should we think about that thank you.
We think that's a great idea and a great approach, we absolutely have it in our in our minds as we escalate with eight Oh wait we want to obviously do that very quickly and we have to start from relatively low levels because of course.
Regulators are cautious with new Immunotherapies.
As we escalate we have in our minds, how we can quickly flex in with our own pipeline agents.
Such as <unk> or perhaps even CD three by specific system of R. R.
<unk> hundred <unk> specifics that could overlap with the expression patterns that we don't hit.
Moving forward for example, <unk> hundred nine our <unk> III so absolutely.
The key here is get rolling fast.
Hi to understand data in light of a well understood standard <unk>, where enrollment frankly is greatly facilitated by its broad use and jump in once we once we have got a little further.
Got it great. Thanks for taking the question.
Thank you.
Okay.
One moment for our next question.
Our next question will come from Bill Maughan of Canaccord Genuity. Your line is open.
Hi, good afternoon. Thanks, So just looking at the cash guidance for this year and thinking through the fact that <unk> is still <unk>.
Available in some ex U S jurisdictions, how much <unk> are you expecting this year in that guidance and then I'll have a fall 'twenty three.
Yes, 23 zero.
It's been coming down since Q1, and they lost their U S.
Authorization in Q1, so it's just been ex U S. So going forward anything we get is found money, we have no expectations of future revenue.
Great and then on your two plus one T cell engaging so understanding that the different differentiated mechanism allows you to go after something like a CD 28, do you see room to improve on more more well worn targets like CD three <unk>.
Over over products that are later in development.
Kind of come in behind them and steal share with a better better version of what's already kind of making it to market.
Absolutely we have all of that that kind of consideration in mind, and we watch very carefully.
<unk> three programs that are advancing into the clinic I would say, it's still early days and the whole <unk> world. So theres not a lot of late phase <unk> work, yet outside of the heme malignancies building <unk> and Bcm ACD threes dominating.
And those don't strike us as may be fruitful avenues to use. This plan of attack is those are not solid tumors, but absolutely we look at potential fast follower approaches with the two plus one carefully.
I think the opportunity space is still just emerging so that's why we haven't declared in yet.
Great. Thank you.
Thank you.
And one moment our next question.
Okay.
Next question will come from Michael <unk> of <unk>.
Hudson.
Line is open.
Alright, Thanks, guys can you hear me okay.
Yes.
Okay.
Let me pick up where Dave left off on <unk>.
IL 12.
I, just wonder just as far as the cytokine spaces concern sort of writ large.
Im a big fan of engineered cytokines phase.
Wonder if we know enough either.
Sure.
Yes.
What.
The real correlate sort of real includes our two clinical success.
Licensing gamma interferon levels go up in response.
IL 12 can we now.
What's the meaning of that is and I think it is.
Again, especially important to think about in light of some of the recent developments and IL 12, and IL two world I just saw.
This call literally as the call started.
Nektar.
Good.
As Peg August Lukins had some activity in F. L E, but did not achieve.
Relevant Scott Big results, So do we.
That went up about this class are really.
Put them into clinic without further.
Preclinical exploration date.
There is no doubt that we don't have perfect knowledge about what it's going to take to succeed in cytokines. So I would say that's the case for pretty much almost any drug I think with cytokines. We do know that a lot of the approach that have been tried in the past tepid challenged and have not worked.
So I will say that we are taking a specific approach we are putting a bat down on reduced potency cytokines, which inherently because of that reduced potency give you longer action.
And a lower peak.
<unk>, which so far with two programs out of two has reduced tolerability has reduced tolerability issues, but still given this profound biomarker movement itself.
We think that's a great start does it answer the question fully do we are we out of the risk window, absolutely not we're optimistic our IL 12 will share those kinds of properties on the biomarkers and the tolerability, but we're going to see.
If our preclinical data plays out in humans, we will start seeing that later this year. So we don't have the answers, but we've got a bet. That's so far is performing as it should this reduced potency and we think the opportunity is enormous if we could be among the first to crack that code. So it's absolutely a bet, we think as we're taking.
And I think the one thing we can hang our hat on is.
If you can see the immune markers of activity.
That certainly ties in better to whether youre going to have success, we know wild type IL two proleukin creates all sorts of immune <unk> activity most of the toxic but it also in a small number of patients can cure them. So I think thats, all we got and I think how we position ourselves is really strong and I will say referencing some.
The recent.
The recent <unk> news.
We'll say that lupus is an area, where many successful drugs have had unsuccessful formal trials.
It's a challenging development space, certainly then coordinates path that has experienced.
Ricky conflicted phase two data in lupus.
And so we'll dig into that more but.
It's a hard read through on our lupus phase to really tip to anything I would say.
And Bob.
Okay.
Ken I will just follow up on that question about the interferon gamma so.
The reason interferon gamma is so important as it does a couple of things.
First and foremost it it can have a direct tumor a subtle effect, we're probably more intriguingly is the most famous thing it does it does.
Hey, guys. Thanks to tumor cells that up regulates class, one MHC and Thats, what the T cell receptors are looking forward to recognize the tumor cells, but thats, a really desirable activity and then the other famous thing up regulate PD L. One well that's exactly why.
Combining <unk> IL 12, with portable as a mob or other checkpoint inhibitor makes a lot of things.
Can I ask you why did you guys choose to.
Develop an IL two agonist.
First as opposed to <unk>.
I think I'll go into autoimmune direction rather than oncology.
Well, we think that that was a great hypothesis and we already try T. Reg boosting for auto immune and we already have our IL 15, which address is much the same pathway that we think are.
Better suited natural precursor molecule for our engineering, so it would've been redundant do an IL two given.
306, and then really promising phase one data we've seen with it so far.
Okay I appreciate the answers thanks guys.
Thank you.
One moment please for our next question.
One moment.
Our next question will come from Bryan King of Jpmorgan. Your line is open.
Hi, Thanks for taking my question just going back to <unk>.
Curious if there is any strategic shift in your way of thinking around the development of a dial maps and Astra is planning to start phase III with their on site set by specific later this year.
A follow up thank you.
Yes, we're certainly aware of that data from Astra and think that it's very promising we we know that our molecule X mab.
I was about to call it <unk> 707 with Allomap.
Shares a very similar design monomeric binding to both targets.
Essentially very limited <unk> for finding without <unk>, our PD one binding so it's very conditional binding and so.
We think that's a really interesting comparison set.
We're looking very hard at that we're thinking through possible.
Game plans and hope to be able to guide on that really soon.
So yes, it's a very relevant point and I think the key element. There is there their willingness to combined with highly active chemo regimens in frontline learned where you really I think have to have chemo as part of your backbone given that the comparator is a chemo PD one combo.
I think that.
That's a really intriguing synergy with our thinking around <unk>.
Using aggressive chemo in prostate cancer and some of the experience we gained there.
More to talk about that later, but it's something we're definitely on our radar.
Great and just related to <unk> are there any learnings from other <unk> approaches.
And a path to give you a better sense of what's the low hanging fruit here for <unk> in terms of the solid tumor type.
That you think could be more sensitive to the IL two iOS plasma approach.
Hey, John do you want to tackle that one.
Yeah I mean.
It would build off of my response to a second ago about.
We expect six Institute us.
Forget.
Lot of interferon gamma up regulate class one MHC and so.
Probably the low hanging fruit as you put it would be to go after.
The more immunogenic tumor types like melanoma places, where checkpoint inhibitors are already work.
Of course, certain practical synergies with that approach as well.
But maybe the slightly higher hanging fruit would be to go after histology that have struggled a little bit shown.
Simple side.
A little bit of evidence of activity with checkpoint inhibitors, but if we can make those tumors more immunogenic with an IL 12, that's a whole new opportunity space.
Great. Thank you John Good luck. Thank you.
Thank you.
And one moment for our next question.
Okay.
Our next question will come from the line of Peter Lawson Barclays. Your line is open.
Alright, so shea on for Peter Thanks for taking our question.
We're hoping to get an update around your E&P.
Program.
Progress is there.
How are you thinking about timing for initial data.
For the recommended phase two dose whether that might be something we see in 2023.
We can just barely hear you just from a volume perspective, if you could speak up we know you are asking about 819.
Oh policies is it better now.
Yes that is.
Okay perfect that we were just hoping to get an update on your 809 programs of E&P P. Three.
And just how progress is going there.
We could see initial data maybe recommended phase two dose in 2023, and then just secondly, how we should be thinking about how this compare profile lifestyles telesis E&P P. Three ADC program any color that would be great. Thank you.
So I guess on the updates we're about six months in or seven months into the phase one dose escalation and I think the one thing we will say is that it.
Investigators in renal cell carcinoma are very enthusiastic to have the option of a CD three and therefore R.
Our <unk> have been great collaborators.
And we've been accruing patients really well so I think that's all we can say about that yet we don't we don't have a timing on data guidance. When we will do that as we advance and cohorts and understand better the the regimen. When we would when we would guide on how we're seeing just were not giving a timing update on that yet other than saying the.
Accruals been going really really well.
File of a CD three versus in particular, our two plus one CD three versus ADC. We hope would have a completely different kind of side effect profile that offers something that that physicians.
Don't have right now.
Compared to salvage chemo I mean any comment there Alan in that particular space.
Renal cancer has been one of those tumors that are traditionally immuno responsive and so we think that the immunotherapy with hopefully have an advantage, but it's still early days, but as <unk> said, we have high investigator interest that really hungry for this MLA in this disease type.
And so.
We are very excited I also will add we.
Sort of predict what our recommended phase II dose will be and how many cohorts we need to get there, but along with investigator interest trial design is fairly novel in terms of how we're escalating without disclosing our strategy. There that allows us to sort of aggressively pursue the recommended phase II dose both in the priming dose and the actual step up dose.
<unk> as well as the final highest dose as well.
Okay.
Thank you.
One moment please for our next question.
And our next question will come from Gregory Winter of RBC capital markets. Your line is open.
Yes, hi, guys. Its an issue on for Greg Congrats on the progress and thanks for taking my question just on the <unk> two plus one design for 2019, and AMG 509 being armed with the knowledge of these compounds, what's the ultimate effect on the development and future of the Oneplus one class so the future of <unk> at 968. Thanks. So.
Much.
I'll, let John handle that and give a thoughtful response, but I will just tell you what plus one has plenty of roles to play if you know if you know how to pick properly.
Yes.
Yes, I think the easiest way to think about that as you know.
One plus one work really well for <unk>, because it's very well established you could you can get rid of all your b cells.
And hopefully, including the lymphoma b cells.
And that's on target off tumor toxicity that is that is it.
It's fine to live with that when you go into the solid tumor setting.
You've got to be a little more careful and a lot depends on the target and the selectivity of the.
Selectivity profile of a target how well over expressed and selectively expressed in the tumor versus normal tissue also would you plan to some extent on which of the normal tissues are expressed in because some are a little bit more dangerous to attack than others. So.
In general we don't see a downside to using the two plus ones and so we'll likely use that.
For most of our solid tumor targets, but there could be exceptions.
Great. Thanks, so much.
Thank you.
And one moment please for our next question.
Okay.
Our next question will come from the line of Jonathan Chang of S. VP Securities. Your line is open.
Hey, guys. This is Matt count Bronco, Jonathan Chang Thanks for taking my question.
I know you said that the estimate.
<unk> created data validate the classical broadly but.
Looking at the data it didn't look like the cleanest AE profile, particularly with regards to EMEA responses. So just kind of wanted to get your thoughts on how youre thinking about the AE profiles for this class sort of in light of what we've seen with PD.
Monotherapy approaches and then sort of maybe discuss how you approach might mitigate some of these effects.
Yes, I think that the.
The choice of co target, we believe is going to be very important.
It was interesting that some of the aes. The most dangerous aes that were seeing are ones that are not typical for a PD one inhibitor alone because remember that study was done combining it with the PD one inhibitor submit lab.
And you saw particular central nervous system involvement in a couple of patients peripheral nerve involvement in a couple of patients or more patients.
And it's notable that the target choice PSNH outside of prostate has.
Among its brightest expression in brain and nerve. So I think there is a quite reasonable hypothesis, there that you're activating immune response against the.
The target.
In the tissues and have that target and in fact, I think that the sponsor of the study emphasized that they saw those aes in patients that responded very early data and it's hard to make too much of it but.
I think the.
The idea that seeded 20th greatly activate the immune system.
In cold tumors has been.
Pretty convincingly demonstrated now the question is Ken <unk>.
Choice of target, we make a great drug we're exploring that but work we're excited by the prospect.
Got it makes sense. Thanks, so much.
Thank you.
I see no further questions in the queue I would now like to turn the conference back to Basel <unk> for closing remarks.
Thanks to everyone for joining us today, and we look forward to updating you throughout the year have a great EBIT.
This concludes today's conference call. Thank you all for participating you may now disconnect and have a pleasant day.