Q3 2022 Xencor Inc Earnings Call
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[music].
Yeah.
Good day, and thank you for standing by welcome.
Welcome to the <unk> Q3, 2022 conference call at this time all participants are in listen only mode. After the speaker's presentation. There will be a question and answer session to ask a question. During the session you will need to press star one on your telephone you will then hear an automated message.
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Please be advised that today's conference is being recorded.
I'd now like to hand, the conference over to your first speaker today Charles Liles. Please go ahead.
Thank you and good afternoon earlier today, we issued two press releases, which outlines the topics we plan to discuss today. The press releases are available at Www Dot <unk> Dot com with me on the call are battle that yet President and Chief Executive Officer, John Desjarlais, H pick officer, John Kush, Chief Financial Officer.
Chief Medical Officer.
<unk> executive medical director and head of autoimmune will join us for Q&A.
On our agenda, we will first review recent business and financial results followed by the presentation of results from the phase one single dose study of <unk> 564 in healthy volunteers the slides should be visible on the webcast and are also available for download on the events and presentations page of our website.
We will then open up the call for your questions. After the prepared remarks and presentation.
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 primary 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.
As described in these forward looking statements are subject to known and unknown risks uncertainties and other factors that could cause actual results to differ materially from the results anticipated by these forward looking statements.
Yes.
Section of our most recently filed annual report on Form 10-K, and quarterly report on Form 10-Q.
I'll pass the call over to Beth Thanks Charles.
We will focus today on our just released <unk> 564 data and comment briefly on other topics to frame discussion. We've used our array of modular protein engineering tools to create a broad internal development portfolio in oncology and autoimmune disease and take multiple simultaneous shots on goal in the clinic.
<unk> 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 use our resources on programs with the greatest potential for success and make really our portfolio for the next wave of <unk> bus specifics in engineered cytokines.
Excited to share with you an important step along this journey very promising biomarker data for $5 six for our second engineered cytokine program.
First we will briefly review upcoming data presentations for other programs and some business highlights.
First <unk>, our phase II PD, one by <unk> four dual checkpoint bispecific antibody, it's enrolling a phase III study for patients with metastatic castration resistant prostate cancer. After two prior lines of therapy in combination with chemotherapy or a PARP inhibitor, depending on molecular subset, it's an indication with high unmet need.
<unk> is currently without let's checkpoint inhibitor to use beyond MSI high tumors, even though small studies a combination PD one and <unk> four in addition shed promise.
Later this week at the society for immunotherapy of cancer meeting, we will present some data from the first few handfuls of patients in the safety running portion of the study with a focus on patients receiving the combination to be down at a taxane and platinum agents.
We're also conducting a second phase II study with a more convenient every three week dosing schedule in patients with clinically defined high risk metastatic castrate resistant prostate cancer, which will allow us to study the Dow that monotherapy in a specific population of aggressive prostate cancer, where we saw confirmed partial response in our phase one study we're also enrolling cohorts.
For the desk oncologic tumor.
Now for promote a mab or CD 20 by CD three by specific as you probably saw at abstracts accepted for presentation at the American Society of Hematology annual meeting in December .
Updated clinical results, we expansion cohorts in a phase one study in patients with non Hodgkin's lymphoma.
We've observed the promoter map has remained generally well tolerated with encouraging monotherapy activity. In addition, we've initiated a cohort study subcutaneous dose.
We also continue to enroll patients in our phase II combination study with <unk> and Lenalidomide.
That I will turn it over to John to provide a brief financial update.
Thank you Pavel.
<unk> portfolio of collaborations and licenses with partners provides ongoing revenue streams to support investments in our research activities and our expanding pipeline of Bispecific and cytokine candidates.
These partnerships right upfront payments milestones cost sharing arrangements for development programs and royalty payments, including royalties from three marketed products.
Total revenue for third quarter and the first nine months of 2022 was $27 3 million and $143 million respectively.
Reported revenue was primary royalty revenue from our <unk> and lexan, our partnerships related to their sales of <unk> and altamira, respectively.
Total revenue proceeds that we received for the first nine months of 2022, largely funded our operations during the period.
Total cash cash equivalents receivables and marketable debt securities at September 30 totaled $564 6 million, which is just slightly less than the $664 1 million balance at the beginning of the year.
We are updating our year end cash position guidance and now estimate we will end 2022 with between $575 million and $600 million in cash cash equivalents receivables and marketable debt securities.
We continue to guide that we have sufficient cash and cash equivalents in marketable debt securities to fund, our R&D programs and operations through the end of 2025.
I refer you to our press release this afternoon and to our SEC filings for further details about our financial results.
With that I'd like to hand, the call back to baffle. Thanks, Sean.
I'd ask the audience to advance to slide five so.
So the rest of today's comments will be presenting the topline data from the phase one study for <unk> 56 for a reduced potency cytokine targeting regulatory T cells with the goal of treating autoimmune disease.
On slide six.
<unk> was designed like all of our <unk> cytokines using the full range of our protein engineering tools first we engineered cytokines receptor binding profile the aimed selectively for the particular receptor desired in this case <unk> 25, and at the same time reduced the potency of the molecule potency significantly up at a 100 fold or more to improve two feet.
<unk>.
Yes.
By avoiding over activation of the immune system that results from hyper potent net native cytokine administration and second is to reduce how rapidly the cytokines clear due to receptor binding internalization.
We represent this on the right panel of this slide show that reduce toxicity activity peak, but a significantly extended duration, which we believe has the potential to create greatly improved therapeutic profile.
We then use our <unk> FC domain to serve as a stable scaffold into east manufacturing plus extend half life further.
Slide seven.
Moving onto the phase one trial, it's a single ascending dose study in healthy volunteers that showed subcutaneous X amount 564 is well tolerated and selectively expanded regulatory T cells, starting at lower doses and reaching the highest reported levels. We're aware of at the high dose, particularly notable was the exceptional durability, we observed with <unk>.
The highest levels of T. Regs after three weeks that we're aware of being reported.
We're looking forward to exploring multi week dosing schedules and are already started phase <unk> multiple ascending dose study and believe that longer dosing intervals or a potentially important differentiator for <unk> targeting agents in an autoimmune disease generally.
We're also pleased that five six for the second <unk> cytokine to show remarkable target cell expansion in the clinic last year, we reported data from the phase one study of <unk> 306 are reduced potency I'll see fusion in oncology, where we also saw expansion of target cells in that case, NK cells and notably significantly.
An accumulation of NK cells upon repeat dosing across a range of dose levels, we will be monitoring for similar pharmacokinetics in a multi dose trial of $5 64, and if present assessing how that could potentially benefit dosing frequency.
I'll turn the call over now to John Deja lay to describe in more detail the T. Reg targeting rationale and design of X that 564.
Thanks, Pavel let's move on to slide eight.
Now it is well established with T. Regs play an important role in preserving immune homeostasis and there is growing evidence that this balances perturbed in autoimmune diseases.
There have been tremendous effort to utilize low dose recombinant IL two for autoimmune disease treatment, we believe our potent they reduced long acting <unk> FC fusion can promote superior T Reg expansion and selectivity, providing more robust and durable T Rex expansion with better Tolerability.
On slide nine the fundamental problem with IL two itself was that while preferentially interact with T. Reg.
Perfectly afflicted with higher doses that will also expand conventional T cells and other local players.
Intrinsic preference for T. Reg, it's because T. Reg constitutively expressed CD 25, the IL two receptor alpha that expression provides the highest affinity receptor complex for IL two.
So our engineering strategy here is twofold first we increased binding affinity to CD 25.
Second we decreased affinity to the IL two receptor beta.
With this strategy will not only improve productivity for T. Reg significantly. We also achieved the overall reduction and we're looking for to create a long acting intolerable IL two.
The next slide slide 10 here.
Here, we show some of our preclinical characterization of X fab 564.
The two plots on the left show the potency and selectivity profile Thats five six for the plot on the pop versus the wildfire policy.
Note that due to our engineering ex map classics fourth not only more selective for activation of T. Reg compared to wildfire file too. There's also adhere note the difference on the scale on the X axis. It's also considerably less potent as intended.
And as predicted from our reduced potency hypothesis, we saw a nice extended PK profile for <unk>, perhaps explore in non human primates.
Now I'll turn things over to Allen Yang our Chief Medical Officer for a brief summary of our phase <unk> study.
Thanks, John .
I'll begin with slide 11, I would like to recognize the X Mab 506, <unk> thousand 14, we started this healthy volunteer study in 2021 during a time when the pandemic was creating many logistical hurdles and we had already and we have already completed the study and have started dosing in our phase <unk> study in atopic dermatitis and psoriasis patients.
The phase <unk> study was a randomized double blind study of subcutaneous ex Mad 564 that enrolled 48 healthy volunteers.
Across six dose levels from 0.03 milligrams per kilogram to 0.065 milligrams per kilogram.
Patients were randomized <unk> to <unk> 564 to placebo respectively.
The clinical primary outcome measures, where safety and Tolerability. In addition, PK and biomarkers such as expansion of T cell populations like T regs were examined.
Important data that will inform our dosing strategy is moving forward.
Next on slide 12.
Overall, the <unk> 564 was well tolerated across all dose levels all advanced at the adverse events were grade one or two and self limited that is they resolved without intervention. The most common AE was injection site reactions. There were no serious aes no dose limiting toxicities or early discontinuation due to aes.
There were also no clinically significant abnormalities in laboratory values vital signs or <unk>.
Some subjects had transit increases in eosinophils don't know eosinophil related Aes were observed we believe this laboratory increase might be related to the mechanism of action of CD 25 targeted IL twos.
Finally, the terminal half life is estimated to be 9% to 10 days at the lower doses and 6% to seven days at the highest dose. This is consistent with the increase in <unk> 'twenty five target mediated clearance from the expanding T Reg cells.
Now I'll turn things back over to John to review the Pharmacodynamic data.
Thanks, Alan let's move on to slide 13.
Okay on slide 13, let's start with a look at the $3 25 bright T. Reg population thought to be the most suppressive T Reg population.
On the left we show a time course of the absolute <unk> dollars 25, bright T rig counts over time for each dosing cohort.
The placebo in Red as expected shows a very low level of CD 25, bright T. Reg that is consistent throughout the 20 days.
Then most noticeably notably on this plot you see starting with cohort three in the dashed Green line and at higher doses are very robust expansion of this T. Reg population, but strikingly high level of expansion for cohort six and magenta, peaking at about 150 cells per microliter.
Now these are averages shown here, but on the right hand plot, we showed the T. Reg fold increase for each subject across all dose levels.
Here again, you see a consistent and statistically significant fold increase across all the dose cohorts.
These are clearly significant increases in T Reg with tenfold larger boots, starting at the 15 microgram per kilogram dose, culminating in the dramatic 170, <unk> fold increase with the highest dose cohort.
You'll also notice the very large chunk going from some of the intermediate doses to the high 65 microgram per kilogram dose.
This is nicely consistent with our in vitro dose response curves, whereas the serum concentrations. We have for these doses in vitro dose response is just beginning to climb up rapidly toward the EC 50.
Finally, while there was clearly an overall dose dependent trend you'll notice a lower calculated fold increase for cohort five.
Digging into this we find that these bolt calculation can be prone to large variations that baseline values has normalizing to create the full values can involve dividing by very low numbers of T. Reg observed at baseline.
Let's move on to slide 14.
One way of avoiding these baseline variability to simply look at the T. Reg T con ratios.
So here, we're showing the time course in peak values for the ratio of CD 20, quite bright T. Reg conventional CD four T cells.
Again, we see a nice dose dependent increase peaking around days eight to 10.
On the right plot you can see the individual subjects and now we see the consistent dose dependent behavior more clearly.
Notably the ratio moves from almost zero to an impressive T. Reg E con ratio of 0.14 at the highest dose.
I'd like to particularly readout as it is generally thought that the T. Reg T con ratios the most functionally important metric for immunosuppression.
And again, you'll see here that they couldnt collection from cohort five to cohort six once again consistent with our expectations for in vitro analysis.
What we expect for the way, we designed our molecule to be low potency and promote strong pharmacology near the bottom of the dose correct.
Now the other thing I want to emphasize in this data is the durability of this expansion effect.
The high dose cohort you can see that our T. Reg counts are still well above baseline value at the last time 0.3 weeks after dosing.
Now on slide 15, let's take a look at the total T Reg population.
On the left again, its the time course, where again you see convincing increases in the absolute key rig counts from cohort six to four 4% to six.
And with the plot on the right showing fold expansion.
Again muddied by the baseline variability that contributes to the fold calculation ucs.
Do you see a strong April boost for the highest dose cohort. We believe this April boost and Paul T. Reg is as high as anything reported elsewhere.
Once again like we saw for the 25 bright population you can see on the time course that we'd still have elevated total T. Reg three weeks after dosing.
Okay. So now moving on to slide 16, let's take a closer look at the durability. We show here the remarkable day 21 T. Reg counts for each subject with the <unk> 25 bright subset on the left the bulk T regs on the right.
We believe this maintenance of elevated T. Reg on day 21 holds potential for more convenient dosing and we look forward to exploring a range of multi week dosing schedules in our phase <unk>.
Finally on slide 17, taking a look at non T. Reg cell expansion, we see some evidence of a minimal increase in conventional T cells, but it's unclear at this point, whether there was a real expansion of the NK cell population.
I'll also note that the increases in the conventional T cells are generally not statistically significant but will of course be tracking this as we progress through additional studies.
Moreover, recall as I showed you earlier that our <unk> ratios are also very nicely increased for all of our dose cohort.
Now I'll turn things back over to Basel to wrap up the presentation to review, our ongoing clinical progress and plans.
Okay.
Thanks, John .
Moving on to slide 18.
To sum up the phase one study of <unk> six four showed that a single dose was tolerable and gave a large and selective increases in T cell populations, which max or exceed previously reported engineered IL two programs with particularly notable durability of these increases in our high dose group.
<unk> already started our phase <unk> multiple ascending dose study in atopic dermatitis and psoriasis, having recently dosed the first patient and we'll use it to explore multi dose safety and also assess the potential for multi week dosing intervals by assessing T cell populations as well as looking at disease modifying activity.
We designed this study and selected the indications with the goal of advancing quickly and I want to Echo Alan's. Thanks to the entire 564 program team from the molecule designers during the clinical team.
Now advancing to slide <unk>.
Zoom out and look at our entire expat cytokine platform 564 is the second clinical program, but it will soon be followed by excess 662.
Reduced IL <unk> IL 12 for oncology and we expect to start phase one studies for 2023.
We're pleased that our approach to producing externally that resulted.
<unk> program, showing reduced toxicity compared to <unk>.
<unk> cytokines.
Notable novelty and duration of immune cell expansion.
We are working on a number of additional cytokines and look forward to discussing our cytokine programs during future updates.
We'd be happy to take questions now operator.
Okay.
Thank you at this time, we will conduct a question and answer session.
As a reminder.
To ask a question you will need to press star one on your telephone and wait for your name to be announced.
Please standby as we compile our first questions.
Okay.
Our first question comes from Edward <unk> with Piper Sandler.
Great. Thank you very much and congrats on the exciting.
Six four data really appreciate the way youre laying out this entire telecom.
That's emerging.
I wanted to get a sense.
<unk>.
What kind of duration of dosing should we expect.
The atopic derm and psoriasis patients.
After 16 weeks are you able to dose a long yet.
And is this something where we could have expected in the back half of the.
Next year and then just following up on that.
Outside of your oncology.
Area of expertise is five six for a potential partnering opportunity or do you ultimately have aspirations to really be in both oncology and autoimmune. Thanks apologize.
Thanks Ted.
So I guess with regard duration of dosing, where it is going to have to follow the data. We just don't know we know there is some bogeys out there.
We're the market leader depicts it in atopic dermatitis is every two weeks and its pretty firmly fixed there. It doesn't look like it will ever be able to extend but we know that debt in autoimmune disease, and particularly Dermot along a bit better. So we're just going to follow the biomarker data as we go through this steady look to see if we observe accumulation like we saw with our IL 15 cytokine program in the clinic.
<unk> and.
And do the best we can so too early to say anything there yet.
I'm, sorry, I should have been more clear I meant in terms of follow up.
How long will you be dosing peso I apologize.
Oh, I'm, sorry, I'm, sorry, we'll be dosing patients for eight weeks as the study is designed currently.
And I suppose we can amend as we observe the pharmacodynamic data and look at duration I apologize for that.
No no no no worse and do you think we should be able to do efficacy measures or is it still mostly going to be biomarker data.
I think as designed right now this is mostly about the biomarkers, but we can observe the data we see in the early cohorts and go from there right.
Say that certainly top of mind for us is thinking about how.
Standing cohorts and using expansion of patients.
Select cohorts is something that we do a lot of oncology and I know that some of our competitors have done that in autoimmune disease. So we're very much aware of those approaches.
Absolutely B b.
I'd be thinking about this and.
To be clear we are following efficacy in those patients yes, yes, yes.
Zero efficacy measures.
These scores and easy scores.
Sure.
Well I think more than my first question.
Okay.
That's great. Thanks, Ted So I will address in though we'll guide a little bit later on as to our data timing expectations, but we are trying to move this program very quickly.
For partnering in the overall indication strategy, we want to chase the molecules that can be truly differentiated and offer Zen core something thats best in class.
To move forward.
If a partnership is something that can really accelerate the program in makeup reach patients faster and more broadly obviously, that's something we would we have done in the past. So we would consider doing but for now I think we've got the right plan and we are going to aggressively pursue it for a while.
Next question.
Our next question comes from Mara Goldstein with Mizuho.
Oh, great. Thanks, so much.
Thank you actually for the slides I appreciate that.
You could.
Spend a couple of minutes just talking about.
Just talking about 564 in relation to maybe raise peg, which is the other which is another drug in development.
Not inconsistent mechanism of action and then I'm also just wanted to get an update on that promote a mab combination trials with lenalidomide and <unk> sentiment and just what that recruitment looks like.
So ill address quickly the question on <unk> phase III, we are recruiting patients and now we've got the study opened up in a number of countries beyond just the U S, which is where we started.
And.
We're moving forward, we don't have any more granularity that we're offering on that.
Now going up to $5 six floor. There's so many ways to answer that question. So are you referring to a pegylated IL two that is CD 25.
Biased I will point out that our half life of nine to 10 days and then shifting to six to seven days that you build up that antigen sink is very competitive with that with Pegylated IL two.
I'll also say that our.
Our dose response and the magnitude of both.
Total T regs and $3 25, bright T regs and most immunosuppressive populations and I think the whole field is really focusing on now.
I think our magnitudes are.
Look look really good in comparison.
An interesting metric that I know is out there.
That the multi dose study in atopic dermatitis and psoriasis that were reported on earlier this year.
For that compound had about a 50 cell CD 25 high 50 cells per microliter, CD 25 high T Reg count at about steady state right.
And note that we are single dose we.
Approach that certainly with our lower doses greatly exceeded even at 21 days for our highest dose. So we think there's a lot of room for us to operate and potentially have.
Okay.
Durability as well as magnitude of increases that could exceed couldnt exceed competitive programs too early to say, but I think that the ground late with the SAP <unk>.
<unk>.
Is very promising.
Okay.
Maybe you can just indulge me for a quick zac.
The company has really talked a lot and so a lot of effort behind those cytokine pipeline, but clearly on the oncology side thats been very very heavy lifting as it relates to sort of IL, two and even some of the other programs, which are still early Steve. So can you talk about sort of the risk reward and <unk>.
How youre feeling about making those decisions.
We again go back to we follow the data that the risk reward I think comes down to how differentiated of a profile do you think you might have for any given compound.
As you say in oncology, it's a heavy lift because you are.
We're treating patients that are seeing the layers of immunotherapy typically and then the cytokine case in oncology, you're you're essentially maybe not entirely every case, but the vast preponderance of those of us making cytokines are across the industry are looking at them as ways to complement other immunotherapies to increase NK cell counts increase T.
Cell activation et cetera, and so combination studies inherently or what's more challenging larger more complex and slower I think in the case of autoimmune disease. The situations that flipped on its head where where there you've got monotherapy activity that you would be looking at it right out of the gate right and Theres Nishi in flight.
As a patient population even naive to biologics that are that are there and they have still a high unmet need so it's a very different situation, but in all cases, we've got look objectively at can we put our resources behind something Thats got the best shot of being differentiated because an undifferentiated compound is one that is.
Going to bite a small biotech.
On the behind if you put so much resource behind it.
Alright, Thanks I appreciate it.
One moment for our next question.
Our next question comes from Jonathan Chang with SBB Securities.
Hi, guys congrats on the progress and thanks for taking my questions.
First question on 564 can provide any additional color on the details of the newly initiated phase <unk> study.
Sure. So maybe I don't know Alan do you want to.
Do you want to take that.
Yes, it will be a randomized double blind placebo controlled study in atopic dermatitis and psoriasis.
I'll start at a higher dose than we started in their phase one.
And the study will allow us to go higher than we've dosed in the phase one as well since these are patient if needed.
Started four doses given every two weeks and assessed the PK and Pharmacodynamic data as we go and optimize the potential longer dosing intervals.
As the data presents itself.
Yes.
Got it thank you.
Second question on <unk>.
Or would you highlight as key things to look for the upcoming <unk> presentation.
Okay.
Go ahead al.
Yes, so we will have updated data at <unk> as I said, we have an abstract there.
<unk> mentioned that we'll have a couple of handfuls of patients. This is the first time, we've combined with Allomap with chemotherapy. So I think we will have the safety and.
The ability of those chemo combinations.
Yeah.
Got it thanks for taking my questions.
Thanks, Jonathan.
One moment for our next question.
Okay.
And our next question comes from Brian Chen with JP Morgan.
Hey, Pathilon guys. Thanks for taking my call.
So a couple on five sixth floor just following up on your comment regarding the magnitude of T Rex expansion.
Do you have any insight and in terms of the correlation of the magnitude of T rack that you need to see.
<unk> improved mannion, atopic derm and plaque psoriasis and then.
I have a follow up thanks.
So there are two directions of data you can take at this point only two I think there is the.
Ample data from the historic use of low dose IL two.
That I believe increased T. Reg counts bulk T. Rex total T regs on the order of about two fold, maybe a touch higher.
And in open label small study showed disease modifying activity across a range of indications from lupus to term to even.
To even Gi autoimmune disease. So there's that's one bucket.
Uncontrolled data small studies open label academic academic studies than the other bucket. We have is the data we referred to from a competitor data or a pegylated IL two presented in.
In September at the AAD conference in both psoriasis, and atopic dermatitis, where multi dose study relatively short I believe 12 week treatment.
Showed that when you increase the CD 25, Bryce around to about <unk>.
40% to 54, I think more like 44, 40 cells per micro liter absolute and no <unk>.
<unk> you are talking.
Zero to three or four cells right. So you can glean sort of the magnitude of fold improvement.
And in total T regs around 60, or 70 absolute cells that was sufficient to have pretty promising activity certainly in atopic dermatitis with a remarkable durability post end of treatment.
Those are the two metrics that give us a feeling.
And a pretty good range right now with what we saw in the single ascending dose to come up with a potentially very attractive dosing schedule in our Ma.
Work is cut out for us we have to do really careful work great.
Great.
Just a follow up so we went back to your presentation I think.
2018 2019.
This molecule I presented <unk> data.
Couple of questions on this one so I think the.
The impact on U S. NFL, it's pretty much in line with what you're expecting and also the class at the hall.
Just one quick question is whether you saw any impact on.
Basal cell any impact on albumin that we stop.
That we saw back into NXP model and how do you think about whether these observations could probably come into whether how whether that would impact those.
Selection moving forward. Thank you.
So we didn't see the Brexit Nick.
We did not see anything in.
Sure.
Yes.
<unk> fills or anything like that nothing to yourselves.
Okay.
Great. Thank you guys.
Thank you our next question.
Yeah.
And our next question comes from Dane Leone with Raymond James.
Yes.
Congrats on the.
Yes.
The data.
Sure.
So that program will.
I actually wanted to ask just because of that.
So it can't go to the website to work but.
Are you guys able to disclose what's in the abstract but all of that at.
At this point.
Given the issues the technical issues.
As far as as far as we know we're not I will say that our ability to communicate with did see has not been any better than anybody else's that we've been aware of that apologize for that.
All good.
Do you guys have any idea why.
And that the issues might get resolved.
We don't but I will say that our.
<unk> is is.
The data is almost entirely in our poster presentation, which I believe is coming out on Thursday, AAM and the abstract is really the setup of the study for the most part so our abstract we're a little less concerned about this bit of a.
The perennial city snap views on data releases for that for that society.
Okay.
That's actually Super helpful. So, it's basically that attracted just like CIP and annual actually out of the data on the poser essentially essentially.
Okay, that's great.
On 564.
Did you guys.
<unk>.
Atopic derm and psoriasis, just as a way of getting.
Early clinical proof of concept is that necessarily indicative of what you wanted to you from.
Longer term drug development or what areas you want to go into.
Yes, let me flavor, that's both Korea, and you look at the landscape of auto immune and inflammatory disorders.
Where do you rank.
A topic term in psoriasis and kind of.
Disorders that could be mediated by dysfunction of T regs like notably in RA.
There has been good.
Good evidence of T regs dysfunction.
But does that necessarily hold true in some of these other indications.
Maybe I'll address the strategic question and I don't know if John wants to comment on the literature linking T. Regs. It is youre right about the raw data being maybe the clearest.
So our goals for this phase <unk> b for the indication selection with first and foremost how can we move fast getting a clear set of biomarker data that can help us understand schedule and dose.
As well as have the potential to look for disease modifying activity.
It relatively easily I think in particular psoriasis psoriasis fits that bill for both atopic dermatitis is really honestly something we added because there could be potential in particular, if you see this long term remitted function that was observed with the peg related IL two from relatively small number of patients.
There is absolute unmet need and potential there. So so I'll say, it's a maybe on atopic dermatitis and then we're.
Actively both looking at our competitors' clinical work I think theres lupus data coming shortly from some competitors within the next 12 months.
And then there is also work in ulcerative colitis is still ongoing we are of course looking at a number of other indications that we'll disclose in due time, we just finished our phase one a.
So psoriasis for speed atopic dermatitis, because there could be potential there.
And we will brief you more on that later I don't know John I don't know if you want to comment on quality of data supporting indication choice.
Yes.
<unk>.
Ralph feel free to jump in here too I mean, it's basically.
There seems to be an overall consensus that for most of the autoimmune diseases.
Greg.
So these are the deficit either in ratio or absolute pounds of T regs or in function of the T regs and so that's.
That's why it's really encouraging to see.
25, bright population as the various press the population we see other markers of <unk>.
Activation of the functional marketing to that population.
So super Super encouraging and potentially applicable to a wide array of bottom Rob.
Ralph do you have any more specifics you want to add to that.
We're waiting to hear from Amgen and Lilly.
John has a big phase III program coming in and literally is going to present their data you are in the spring.
Really interesting to us.
We're going to have a good.
Data in the spring and the athlete.
Yes.
Programs, the Osha with quite a show.
Some of them are canceled and some of them are continuing but that's a real good indication as well are the only one that we've heard about was.
John .
A lot of trouble.
Akshay is going to be but I think lupus ulcerative colitis.
Dermatologists are probably our best.
That's.
At the moment there is still so much to be discovered about this.
This mechanism and class of drug and what we want to do is make sure. We established the most competitive hopefully highly differentiated.
Dosing regimen and.
The biomarker activity that is the measure of how much immune modulation of this drug really Darrin, we think our design might really put us in the driver's seat there and so we wanted to exploit it.
As best as possible.
Excellent thanks, guys.
Thanks, David next question.
One moment for that question.
Yeah.
And our next question comes from Caveri Pullman with BT IAG.
Yes. Good afternoon, thanks for the updates and congratulations on the progress for.
Five six for any insight into antidrug antibodies are you testing those.
Yes, Alan I guess, you want to touch on this one yes, we didn't see any evidence of 88 and the PK data do not suggest any evidence of it as well.
We are still early in the process analyze this data.
Got it and my second question is with all the math chemo combination heart prostate cancer can you tell us what drove your encrusting choosing kebab textile over other chemo agents like does the tax law, which is also used for earlier lines of treatment at least in a subset of patients.
Yeah.
Yes.
Current study allows both capacitor taxol and taxol and I think what we're doing is we're exploring both <unk>.
Physicians seem to have a preference depending whether it's for foot, whether they've seen taxane and payers make them use the taxane and they go to the tactful second line. So we are interested in understanding the activity in combination with both of those agents either alone or in combination with a platinum.
Got it.
Yes, yes, I believe at your side on clinical trials Gov.
But yes.
Really helpful and maybe a last one on slim modem app so the upfront.
Data cutoff date of July I believe.
Will you be providing updated data at ash and also if you could just tell us about how you plan to introduce the subcutaneous formulation.
Do you plan to incorporate it into the ongoing pivotal trial.
So a couple of questions. So we will have incremental data more data at the time of the presentation in December .
The plans for the sub Q is not incorporated into the pivotal study, which is our phase II, but our current phase one so that was probably the most convenient and fastest way to accelerate the sub Q development. So we have established group of investigators who have been working on this for a while it's a phase one study that's open.
And so it will be incorporated into the current phase one so there'll be additional cohorts, where we're studying our optimal IV dose expansion cohorts and then there'll be a cohort of sub acute patients.
Got it thank you for taking my questions.
Sure.
One moment for our next question.
Yeah.
And our next question comes from the route with BMO capital markets.
Great. Thanks for taking the question and congrats on the plastics where progress just.
Yes.
On the some of the variability, we see Atlas III or higher doses.
But obviously really robust and compelling expansion at these doses just wondering if this was just a phenomenon of small and then how much confidence or wait you put on the high dose data and then I guess secondly, you mentioned.
The Mad study just wondering how many patients youll dose in each of the indications atopic derm and psoriasis.
And whether or not sort of the placebo two drug arm ratios will be the same as we saw for the single Istent.
<unk>.
Maybe I'll have Alan of Ralph touch on the phase one b patient allocation.
Okay, alright patients in psoriasis and.
One two and 16 patients and 12 four.
It's going to double the PD patients, yes, and thats per cohort per cohort EMCORE is depends on the number of cohorts, we do will be dependent on the data we see.
So it could be a few cohorts or it could be several cohorts yep.
And we are doubling the end on the atopic derm of course to see if there is to have a better shot at looking at a signal right now going back to the variability question.
There are a lot of confidence in the data, even though it's relatively small number six patients on study.
On study drug.
For the in the Sad study because of the consistency across multiple measures in particular looking at T. Reg T con ratios that don't involve that that baseline variability when you look at fault measurements as well as the consistency and just looking at absolute T. Reg counts right the real data not the full data so those.
There is there is choppiness in the data because of the small numbers I think the trend is quite clear.
We're really replicating a dose response curve like we saw in vitro pretty nicely as John said, So I think that all of those things points were pretty high confidence in the data and you can see the individual.
Data points those are individual subjects on those box plots and so you can see that the clustering is actually fairly consistent as.
As well as the absolute sell talent.
Hardcore traces are very nicely.
And if I could add.
So I think the question was comp.
Our confidence around the data so the variability is really around the baseline because the baseline is can be so low that can have a huge effect on the actual fold increase and we've tried to be very transparent here and go above and beyond we are presenting the fold increase the absolute increase.
And then a ratio to conventional T cells. So we can be very clear on our data.
And help you compare it to other People's data.
And just to be clear the ratio the ratio is really nice because theres.
Theres no dividing by a low number in the baseline youre dividing the T.
T regs by the conventional T cells.
I think thats consistent.
Consistent with what Alan and saying that.
It's really that those low based on my numbers that give you most of that variability.
Got it. Thank you congrats again on the update.
One moment for our next question.
Okay.
And our next question comes from David Dye with SMB C.
Great. Thanks for taking my questions and congrats on the update.
No.
One question on the map.
<unk> in the renal cell carcinoma understand what we'll see.
The initial look at the data in the phase one trial data.
Next week. This week, maybe you could help to help us.
Citations ahead of a data readout.
And a efficacy bar should we be looking at here.
Yes, I just want to set expectations, we just started enrolling the <unk>.
Patients over the summer and I think you're mistaken we've never guided we would have 109 data this year at all.
Yes.
Others are trials in progress abstract at 50, though yes that just describes the trial design and high detail not data.
Thank you got it okay. That's helpful. Just wanted to get some clarification there and then you have another.
Another question on the 564 data the safety looks fantastic so far in the health volunteers, maybe just share some insights in terms of whether any differences between the healthy volunteers.
Versus any kind of all the immune patients that group actually into anything differential safety profile, we're seeing in the patients.
Any thoughts on that.
Thank you Ralph.
Hard to say normal volunteers are very different of course.
We're going to see in the psoriasis patients 80 patients.
I will say from the limited competitive data presented.
For granted CD 25, directed IL twos that are designed very developed from ours, but that limited competitive data didn't show really any new.
Signals.
Got it that's very helpful. Thank you guys.
And one moment for our next question.
And our next question comes from Gregory <unk> with RBC capital markets.
Hi, This is Neil on for Greg Congrats on the data and thanks for taking our questions.
Maybe just a follow up on 564, just wondering how does the inflation reduction act like a rolling out thinking around indication selection for this program as well as the impact on market opportunity. Thank you.
Sure. So what I will note that actually that five to six quarters, a biologic drug. So it has the longer time on market prior to being subject to Medicare.
<unk>.
Would say that we're going to chase, what we think is going to have the biggest patient impact.
And kind of it was to help establish a new class of drug with a new mechanism of action I don't think the IR re inflation Protection Act is really entering into our thinking at this point much yet at all.
Great helpful. Thank you and then.
I think the last year.
Yes.
Could have.
Coming in from Gregory Renzo, if you want to.
SAR one one to come back and we can follow up your follow up question.
Our.
And so our next question will come from Charles <unk> with Guggenheim Securities.
Hey, guys, thanks for taking them.
<unk>.
I had a quick one on the blood eosinophils not sure. It was addressed earlier, but how should we think about it.
Still seems early an extremely mild and transient but how should we think about that.
What this could look like as you go into multi ascending dose cohorts and how does that benchmark so far relative to some of the other 25 programs out there. Thank you.
From what I know about the other CD 25 premiums I don't know that we have a lot of detail from any of them in fact, we don't.
Everybody reported.
In limited ways the way they reported a transient increases.
And very limited clinical consequence, we didn't see any clinical significance, we're just going to watch out.
Great keep track of clinical signs and symptoms.
Do the lab work and just follow up.
Got it got it great and maybe one question on IL 12. It looks like you guys are starting up the phase one next year.
How should we think about the potential similarities and differences in the IL 12 program relative.
To what you guys are going through on IL 15. Thank you.
Yes, I think John is the best equipped to address that question about the different cytokine <unk>.
So let me go out that linger.
Yes, absolutely.
So first of all <unk>.
<unk> that the IL 12 FC.
We followed the same general principle that we used for the <unk> class explore that was to reduce potency pretty significantly.
Approximately 100 cold for IL 12, and in our preclinical studies we saw.
Kind of like we expect for a post to reduce product line, we saw what looks like better Tolerability, we're able to dose at a lot higher we see improvements in the half life in nonhuman primates because of the potency reduction.
I think most importantly.
What impressed me the most about the data that we saw in the nonhuman primates was that we had a much better control of the Pharmacodynamic response as we dosed.
From low dose the higher doses with the plugs a reduced version.
I think that bodes really well for getting through dose escalation.
Phase one study.
As for differences in MMA I think of the IL 12 is promoting more cytotoxicity and interferon gamma response from natural killer cells and T cells.
Whereas our 2015.
Some of that as well, but also.
Really a lot about proliferation.
Particularly the NK population.
Great. Thank you.
And one moment for our next question.
And our next question comes from Peter Lawson with Barclays.
Great. Thanks for taking my questions.
A quick clarification question initially just on.
Hi, Dennis.
Do we get initial efficacy data.
This year and kind of what's.
What's the bar for success.
And at what point do you think you have enough data to make it good comparisons.
Additional.
Data sets out there.
But we'll report efficacy data for the patients that we're reporting on safety them to the extent they have had their efficacy assessment, which I think nearly all or almost all would've had.
Okay.
So of course, we'll be completely transparent that goes without saying I think that these are relatively small numbers. We've guided a couple of handfuls as we go through the safety.
Run in period, so I don't think thats going to really be able to give you a read and any kind of quantitative way on competitive positioning against sort of what you see with with the chemo regimens, which are the standard of care here for the non PARP sensitive patients, which I think right about 30, or 40% or but durability being rather a.
<unk>.
We'll guide more on timing.
Later, but certainly nothing this year.
Okay, and then when do we see combination data for 2000.
The combination safety running data is going to be this year with whatever efficacy we have in a couple of handfuls of patients and that's the that's the study that's furthest along relative to the monotherapy. So it's really going to be about the combination with chemo platinum taxane.
Or PARP.
Got you we have enough of those.
Combination.
<unk> to kind of start telling the story or was that much.
A less common grouping so we're getting a lot more of the chemo combo and the bid the poster is going to focus.
Mostly on those.
Okay, and just to remind you Peter of the study design with the PARP. We have those that are both PARP refractory and then those who are park naive.
So in the park Refractories get the chemo combo apartment <unk> get the PARP as there is there.
Co drug with the Buda.
Thank you.
Then for promoting the triplet data.
Timing around the data set.
What do you need to see to.
I guess final positioning pretty crowded.
Nice.
Or you meant to phase III.
Yes.
The timing for that.
Go ahead, Sir yes, we haven't guided yet on timing for that I will say without getting into specific numbers. The bar for efficacy there less I think it is going to be high which is why we went after a triple regimen with.
With two completely distinct msas and different targets.
But we aren't going to be setting a high bar because we only want to pursue something if there's really potential.
Got you.
When would that kind of go no go decision would that be.
Late 'twenty three kind of event.
We'll guide on that as we move further rollout we havent, we havent chosen our guidance statements on that yet.
Okay. Thanks for taking the questions.
One moment for our next question.
And our next question comes from rising shoe with Baron Burke.
Great.
Thanks for taking the questions.
First of all on fire for us.
Four.
First one is around the dose I guess two parts first is.
Dose escalation single dose ascending dose study that you haven't seen the only seeing grade one and two and no SAE I wonder if.
If you have considered.
Those higher and explore even more potent.
Animation appear AG.
And as a part of one.
And I guess part two on the dose part.
Is when you look at the.
The full change looks like there is no clear dose dependent change.
Change, but really the highest dose most significant.
Okay.
Congratulation.
T Reg is there any.
Mechanistic explanation for this.
Yeah, So first on the <unk>.
We're not going to be going higher doses in the single ascending dose because it's in healthy volunteers and thats the limit for healthy volunteers. However, in our multiple ascending dose. We do have to go ahead and could explore higher doses in the multi dose setting because thats in patients and the risk benefit is obviously better.
So we have that option, we don't know whether were going to do that or not.
With regard to the full change as we discussed when you are normalizing each individual against their baseline number that baseline number is going to range from zero to four normalizing create a lot of scatter or we think that even so there is a clear dose dependent trend. When you look at absolute cell counts when you look at at T. Reg T counter.
<unk> and even when the full changes.
And I think in particular you should.
You should consider that as John said earlier in the call. The dose response curve. We saw in vitro now that we're seeing concentrations that are starting to climb up that curve at the top two doses youre seeing that uplift pretty much mirrored. So I think the explanation is very simple.
Let's see how the molecule was designed and the drug concentrations.
Yes, Basel ill add.
I think the colors should should.
A hard look at slide number 14, which has the peak ratio was on there, but again the ratios are not subject to this division by low baseline numbers.
Really the cleanest way to look at the data.
And there we.
See significant statistically significant increases of the T regs, starting all the way at the lowest dose level at a very nice looking dose response throughout the different doses.
Okay.
Okay, Great and then the second question is around kind of how you look at the competitive field.
A few names.
Mentioned.
They either pharma or large cap biotech.
They get the.
IL two.
In autoimmune quite early in the development and I guess for you as a small biotech is imagine.
How do you plan to compete in this in this field are you actively looking for a partnership to.
Accelerate we're not looking for partnerships right now where we have the right plan right now to build value in this program and if we feel like the time is right and that would be when you have the vision that you could greatly accelerate the program and move it faster and more broadly with a partner we would consider that we don't this partner.
Things off Willy Nilly.
Okay, great. Thank you.
One moment for our next question.
And our next question comes from Ted <unk>.
Piper Sandler.
Great. Thanks, just a quick follow up on IL 15, what kind of X, but what kind of expectation should we have for updates from you and Roche. Thanks.
That well certainly update on <unk>.
<unk> study that new studies that we're going to start in the near future. We'll guide on that one that started to kick off and I can say that.
Roche is very busy with the program and I would not be surprised to see new studies for <unk> soon.
On data from that study yet because of course, that's really at roche's discretion.
Fair enough thanks, guys.
Great. Thanks, a lot Ted.
Okay.
I would now like to turn it over to Basil for closing comments.
Great. Thank you so much and thanks, everybody for joining us today and spending the time on the call and going to our our new data update will really look forward to updating you again in the near future. Thanks and have a great <unk>.
Thank you for your participation in today's conference. This does conclude the program you may now disconnect.
Okay.
Yeah.
The conference will begin shortly to raise Johan during Q&A, you can dial star one one.
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Okay.
Yes.
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