Good afternoon, and welcome to the Xencor Second Quarter 2019 Financial Results Conference Call. At this time, all participants are in a listen-only mode. Following the formal remarks, we will open the call up for your questions. Please be advised that this call is being recorded at the Company's request.

At this time, I would like to past the call to Charles Liles, Associate Director and Head of Corporate Communications and Investor Relations at Xencor. Please proceed..

Thank you, Stephanie. Good afternoon. Welcome to Xencor second quarter 2019 financial results conference call. Earlier this afternoon, we issued a press release, which outlines the topics we plan to discuss today. The press release is available at www.xencor.com.

Today, on our call Bassil Dahiyat, President and Chief Executive Officer will provide a business overview and review our pipeline and licensing partnerships and John Kuch, Senior Vice President of Finance and Chief Financial Officer will review the financial results from the second quarter and first half of 2019.

Then we'll open up the call for your questions.

Before we begin, I would like to remind you that during the course of this conference call, Xencor 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 for future operations, the company's partnering efforts, capital requirements, future product offerings, and research and development programs.

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.

The outcome of the events described in these forward-looking statements is 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, 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, let me pass the call over to Bassil..

Thanks, Charles, and good afternoon everyone. The core of Xencor's approach to creating antibody and cytokine therapeutics is our XmAb engineering platform. By making small changes to an antibody structure, specifically it's Fc domain, we can improve its natural functions and performance and create new mechanisms of therapeutic action.

The plug and play nature of the suite of XmAb Fc domains we've created allows us to engineer nearly any antibody to have improved potency, longer half-life or bispecific structure.

This flexibility and portability enables us to take multiple shots on goal simultaneously, and generate proof-of-concept data to guide which programs will independently advance, which we will partner and which we would terminate. Bulk of our R&D is the expansion and use of XmAb bispecific platform.

Over the two years we've initiated six Phase 1 clinical studies evaluating XmAb bispecific antibodies. Our plug and play approach engineering enables the rapid design and simplify development of antibodies and other protein structures like cytokine that combine two or more different targets simultaneously.

Bispecifics are rapidly emerging area of therapeutic development particularly on oncology and emerging step to forefront of innovation in the space who is our engineered heterodimer Fc domain is robust scaffolds rapidly develop new candidates.

We group these drugs candidate to ease our XmAb bispecific Fc domain into three classes; T cell engagers, tumor microenvironment or TME activators in cytokine.

The first and most advances is T cell engagers class, these are tumor targeted antibodies that contain both the tumor antigen binding domain and a cytotoxic T-cell binding domain specifically a CD3 binding domain. They activate T cells at the side of the tumor in order to potently kill malignant cells.

XmAb14045 is our CD123 by CD3 bispecific antibody that's being developed in collaboration with our partner Novartis.

It's an open label Phase 1 dose escalation study to assess its safety, tolerability and preliminary anti-tumor activity in patients with relapsed to refractory -- relapse or refractory acute myeloid leukemia, as well as other CD123 expressing hematologic malignancies.

Now in the second quarter, we work with investigational sites to resume enrolment following the lifting with the partial clinical hold that have been placed on the study and in early July we dose the first patient under this amended protocol which included more prescriptive guidance on the monitoring and management of cytokine release syndrome.

As we continue dose escalation we are working with our partner to plan the next phase of clinical development. Our next program, XmAb13676, a CD20 by CD3 bispecific antibody is also in Phase 1, but for patients with advanced B-cell malignancies like non-Hodgkin lymphoma and chronic lymphocytic leukemia.

We started dosing patients about a year after XmAb14045 in February 2017. Later this year we expect to present initial safety and clinical activity data from this study. XmAb18087 is our third CD3 targeting antibody and targets as well SSTR2 or Somatostatin Receptor 2 in antigen highly expressed on some solid tumors.

In February 2018, we started dosing patients in a Phase 1 dose escalation study to assess safety, tolerability and preliminary anti-tumor activity in patients with neuroendocrine tumors and gastrointestinal stromal tumors. We're now expecting to present initial data from the study in the first half of 2020.

Our second group of bispecific antibodies is our Tumor Microenvironment activators. Rather than directly bridging a T-cell or tumor cell, our TME activators seek to more effectively reactivate tumor reactive T cells than existing therapies by engaging multiple T-cell target simultaneously, such as checkpoints or agonists.

This approach not only reduces the need for multiple antibodies typically used in combination therapy, but allows for more selective targeting of T-cells with high checkpoint expression, and multiple checkpoint expression which are typically sound more in the tumor micro environment than in the prefere.

In the second quarter we started dosing the first patients in Phase 1 dose escalation studies of both XmAb 22841 and XmAb 23104, including the ongoing Phase 1 study of XmAb 20717 these three studies are enrolling advanced patients with the number of different solid tumor types.

As I mentioned, each candidates simultaneously engages multiple different target for T-cell activation. For 20717 is the most validated checkpoint combination, PD-1 and CTLA-4. For 22841 it's CTLA-4 and the checkpoint LAG-3.

And while we will conduct initial dose escalation as a monotherapy we design this molecule to be developed along with the PD-1 inhibitor to create a triple checkpoint blockade. Finally, for 23104, it's a PD-1 and the costimulatory T-cell agonist receptor ICOS targeting bispecific antibody.

We focused on enrolling patients to all three – all of these studies and I hope is to be able to drive stronger anti-tumor response in monotherapy with improved tolerability for patients.

For XmAb 20717, we'll begin enrolling patients in the Phase 1 study 12 months ago and we anticipate initial does escalation of biomarker data in the first half 2020. Finally, we're developing a suite of cytokine which are immune signaling proteins that are built on the XmAb bispecific Fc domain.

Using our Fc domain to build the molecule, provides more durgable versions of cytokines with potentially superior tolerability, slower receptor mediated clearance and a prolonged half life. Our first cytokine program and the lead in our collaboration with Genentech is XmAb 24306.

It's an IL15 and IL15 receptor alpha subunit fuses with the bispecific Fc domain. As noted, it contains both the cytokine and its receptor domain in order to expand and active immune cells that can be retreated against tumor specifically T-cells and natural killer cells.

24306 is intended for development with a wide range of combination agents and importantly, we can form our own clinical trials with both our own pipeline asset and non-Genentech agents within this collaboration and subject to some conditions.

We look forward to planning a number of these combination studies pending completion of the initial dose escalation study and we will support Genentech's IND application in multiple oncology indications in the second half of 2019.

The next program in our cytokine class; XmAb 27564 is an engineered IL2 fused to an XmAb bispecific Fc domain and is intended for autoimmune indications. Later we filed two regimens of demonstrating promising results since they were first approved in the early 1990s.

However, the drug IL2 suffers from fast in vivo clearance and a narrow therapeutic index. A variety of technologies are pursued to improve the drugability of IL2. At Xencor, we've tune the IL2 to increase the preference for regulatory T cells and to have a longer half life by reducing its potency.

We also incorporated Xtend technology in the Fc domain, again to increase the half life of the molecule. Preclinical data were presented in opposed to the American Society of Hematology Annual Meeting last December. The program is currently in IND enabling studies.

We'd anticipate submitting an IND in the second half of 2020 and then enrolling healthy volunteers in the first-in-human study. I'll now spend a moment reviewing some updates from our licensing partnerships which provide us with revenues that help fund development of our own internal pipeline candidates.

Most of these partnerships usually require very limited resources and effort from us.

So we previously discussed our newest collaboration with Astellas we're applying our bispecific technology to create multiple drug candidates against a target specified by Astellas, then Astellas will conduct all preclinical and clinical development as well as regulatory and commercial activities. Now, shifting to Alexion.

In 2013 we licensed Xtend Fc technology to them to create Ultomiris , the complement inhibitor with improved half-life which last for less frequent dosing regimens compared with Solaris. With Ultomiris's approval in United States last December it became the first antibody to incorporate an XmAb technology to be marketed.

Ultomiris has now received multiple global marketing authorizations in Japan this past year, in Europe just last month for the treatment of adult patients with PNH. We are receiving milestone payments for each of these approvals and low single digit royalty of net sales.

Another partner, MorphoSys license from Tafasitamab, which was previously known as MOR208 and as XmAb 5574 before that. It’s a anti- CD19 antibody that we built ourselves and incorporated our cytotoxic Fc domain for high ADCC function.

We're first just recently have reaffirmed that they intend to complete a BLA submission by the end of 2019 for tafasitamabd. If approved we will receive royalties in the high single digit to low double-digit percentage rate as well as additional milestones.

Finally, I'd like to thank our Chief Medical Officer, Paul Foster who will be retiring from Xencor at the end of October. His contribution and leadership at Xencor over the past decade enabled us to build an internal clinical development organization as well as launch nearly 10 clinical programs.

We've initiated a search for a successor to Paul and we hope would build on the foundation Paul's created and carry us through the advancement of our pipeline. In addition, we are continuing to expand our senior leadership. In the second quarter we announce the appointment of Jeremy Grunstein as Vice President of Business Development.

Jeremy spent more than 15 years in Business Development at Amgen sourcing and executing a wide range of transactions. We also appointed Kirk Rosemark as Vice President Regulatory Affairs and Quality Assurance to lead our regulatory strategy.

He joined just most recently from Beijing and brings nearly 25 years experience in biopharmaceutical regulatory affairs. We're happy to have both Jeremy and Krik join our team and look forward to their leadership and contributions. With that, I'll turn the call over to John Kuch to review our second quarter 2019 financial results..

Thank you, Bassil. In the first half of 2019 Xencor continues to build a strong financial position which enables us to support a broad pipeline of development and research programs. Our cash, cash equivalent and marketable securities totaled $626.1 million at June 30, 2019 compared to $503.5 million at December 31, 2018.

The increase reflects upfront proceeds of a $135 million received in the first half the 2019 from our Genentech and Astellas collaborations offset by cash used to fund operating activities at first of 2019.

Total revenue for the second quarter ended June 30, 2019 was $19.5 million which reflects revenue recognized from our Astellas collaboration and from our Alexion collaboration which includes $5.5 million in milestones and royalties received.

Total revenue for the six months ended June 30, 2019 was $131.4 million and includes revenue earned from our Genentech collaboration in addition to Astellas and Alexion revenue, though revenue was reported for similar periods in 2018.

Research and development expenses for second quarter were $33.3 million compared to $23.3 million for the same period in 2018. Total R&D expenses for the six months ended June 30, 2019 were $61.5 million compared to $49.4 million for the same period in 2018.

The increase spending on R&D for the three and six months ended June 30, 2019 reflects increased stock-based compensation charges and additional spending on our CD3 bispecific antibody and cytokine development candidates and technologies.

General and administrative expenses for the second quarter were $5.8 million compared to $5 million in the same period 2018. Total G&A expenses for the six months ended June 30, 2019 were $11.3 million compared to $9.5 million for the same period in 2018.

The increase spending on G&A expenses for three and six months ended June 30, 2019 reflect additional spending on intellectual property which includes patents and licenses and additional expenses related to personal and professional services.

Non-cash stock-based compensation expense for six months ended June 30, 2019 was $15.2 million compared to $9.4 million for the same period in 2018.

Net loss for the second quarter was $16 million or $0.28 on a fully diluted per-share basis, compared to a net loss of $25.9 million or $0.46 on a fully diluted per share basis for the same period in 2019.

The Lower net loss reports for the second quarter over the net loss for same period in 2018 is primary due to revenue recognize from our Astellas and Alexion collaborations in 2019.

For the six months ended June 30, 2019 net income was $64 million or $1.10 on a fully dilutive per share basis compared to a net loss of $55.4 million or $1.07 on a per dilutive per share basis.

The net income report for the six months ended June 30, 2019 over the loss report for the same period in 2019 to 2018 is primary due to revenue recognize from our Genentech collaboration. The total shares outstanding were 56,529,390 as of June 30, 2019 compared to 55,821,310 as of June 30, 2018.

Based on current operating plans we expect to have cash upon research and development programs and operations beyond 2024 and 2019 with between $575 million to $600 million in cash, cash equivalents and marketable securities. With that, we would now like to open up the call for your questions.

Operator?.

Thank you. [Operator Instructions] Our first question comes from Ed Tenthoff with Piper Jaffray. Please proceed..

Great. Thank you very much and thanks for the update.

I'm wondering if you could provide some Ultomiris royalties are presently and whether or not you'll be breaking those out in the second line of the Q?.

Hey, Ted, you kind of broke up for a second in the beginning of your question. Could you just repeat? We couldn't hear your first few words..

I was wondering if you could provide some color on what the Ultomiris royalties are and when that you'll be breaking them out in the Q?.

Yes. We will be breaking them up for the Q for the six months we reported royalty of 1.1 million. It is low single-digit royalties and it's an estimate based on the sales reported by Alexion..

Right.

And that's for the first six months of the year?.

Yes..

And just a quick question, I'm just seeing, is there push out in the expectations from the tumor micro environment data readouts. I was thinking we might get something this year, but it now looks like we'll getting data in 2020. Is there any push up there or is it just the desire to have a fuller data set to reporting? Thanks so much..

Yes. It sort of the balance and desired to have a fuller data sets we reported in the resource allocation it takes to generate the data cut, data cleaning and reporting as we balance it across launching two other programs a couple months before and it rapidly advancing the 717 program itself. So everything is on track.

It just more of a resource allocation balance weight with wanted to have fuller data..

Great. I appreciate that and I'll wait patiently for it. Thanks so much, guys..

Thank you. And our next question comes from Arlinda Lee with Canaccord Genuity. Please proceed..

Hi, guys. Congrats on all the progress. I had a couple of questions on the IL15 partner with Genentech. Can you maybe provide additional color on how the collaborations are working today? It seems like the time to IND is accelerated. And then also the timing of when we might see two, and three and four data sets? Thanks..

There has been no shift in any other timing for the program. It really was fairly seamless with regard to the collaboration. I think Genentech is a company with an enormous amount of skill and history in developing biologic, so we're happy to have as a partner. In addition, we have a really deep and robust oncology pipeline.

So again, there are really ideal partner in that regard. With regard to the due at three and four, we haven't really guided on timing for data yet. We just started dose dosing of patients a couple months ago. We'll be able to give more clearly probably later in this year as that ball gets rolling..

Okay. And then I guess you had talked about – maybe just a follow-up, a triple combination. Can you talk about how that dose escalation would work? Thanks..

Yes. Sure. So you're probably referring to XmAb 22841 which is our CTLA-4 and LAG-3 dual checkpoint inhibitor bispecific.

So the way that the clinical trial constructed is to run dose escalation cohorts with the monotherapy and after a few of those cohorts to add a parallel set of dose escalation cohorts that treat patients with 22841 on top of Pembrolizumab.

So you'd have a little bit head in dose, the monotherapy and upheld of sort of cohorts, a dose behind in the combination..

Great. Thank you very much..

Thank you. And our next question comes from Jonathan Chang with SVB Leerink. Plese proceed..

Hi. Thanks for taking my questions.

First question, can you hopes expectations to have the initial Phase 1 data for XmAb 13676 in the fourth quarter?.

Yes. We expect to have data that shows given where we have the dose escalation. What we see in terms of safety as well as efficacy in our patients which all have advanced B-cell malignancy.

So it’s really that that combination of safety efficacy profile as we proceed through dose escalation, where we certainly made good progress, but we're not expecting to be completely done by the data report. But that's sort of the picture of efficacy safety.

And then, we are certainly right now thinking very hard about what next steps in development would be. But the next phase of development would look like not sure we'll able to guide on that this year whether we'd want to push that a little bit. But those are the – that sort of the expectations we want to set.

So, how we stack up and how we of course look relative to the competitive landscape in B-cells. .

Got it.

And just a follow up on that, how do you see the competitive landscape for this program and how you thinking about not just next test [ph], but potentially we're partnering this asset?.

Yes. So – and I think this kind of landscape for B-cell malignancies one of the densest in the industry. I think you've got this baseline of long-established use of Rituxan and combination with chemo that sort of sets the bar and that there is a number of different emerging modalities people are trying.

I think CD3 bispecifics are going to be a very compelling approach there. I think early data from some of the competitive programs that have CD20. CD3 looks promising and I hope that we can we can fit very well within that.

We designed our molecule -- really would be eye towards -- B-cell malignancy being really treated by combination therapy, monotherapies are unlikely to carry the day and therefore we design our molecule with that sort of mix of tolerability and dosing convenience along with the potency.

As for partnering it, I think we're driven by the strategy of the development of the molecule which is, we want to advance it quickly, we want to advance it for as many patients as possible and being thoughtful and aggressive about using combination with different agents.

And so that would really drive our partnering strategy not the need for cash or the need for anything like that. So we're open to it. And I think that we will also give a very strong eye towards maintaining significant commercial rights. You could never predict the precise structure so talking about it doesn't make sense.

But we would also look towards preserving significant commercial rights. And that said, we're happily running along and happy to develop this molecule for a while without any part. We think there's a lot of avenues to do that..

Got it. Thanks for taking my questions..

Thank you..

And our next question comes from Shanshan Xu with Berenberg Capital. Please proceed..

Hi. Good afternoon. This is Shanshan Xu from Burma Berenberg Capital Markets. I think with the XmAb Fc engineering technology especially with functions to increase a half life and it enhanced ADCC you potentially create a next generation Solaris and next generation rituximab.

The investors ask did Xencor actually find a skeleton key to upgrading entire clause of therapeutic antibodies. I think this is a complicated question to answer.

But can you please help us to understand a little bit better whether which subclasses of therapeutic antibodies are candidates within when operate by XmAb Fc technology? And then I have two follow-ups..

I would say that there's a set of different XmAb Fc domains that we've created each that has a different purpose. The primary are the half life extension one of the Xtend and I think in that case there's a very wide range of therapeutics that could benefit from that.

I think it really more fits to that question of what instances is the extension of half-Life for reducing dosing frequency or dose amount going to be a compelling competitive edge where it might not matter.

So I think it's a wide range of therapeutics and we certainly expect and we have been seeing a lot more interest in it as the Alexion programs advanced. I think for cytotoxic Fc, it's a narrow range.

I think it's in slices of indication where the really compelling balance of tolerability and heightened potency of tumor killing that was seen with Tafasitamab considerable use.

I don't want to get into the weeds of different oncology drug target -- drug targets and there are various merits, but I think that agents, agents with that kind of scope really there's a broad range but perhaps not as broad as the half life extension ones.

I think our bispecific Fc domains, that's one where the future for multi specific antibodies is so wide open and unclear the world doesn't know.

And I think what we're really talking about there is creating new therapeutic classes and I think that's just going to be limited by the imagination that approach and engineers have whether it's the Xencor tools or other people's tools that we use.

It's a vast array of opportunities in bispecific antibodies and I think we're just trying to scratch the surface of. And I think, yes, is that kind of get it what you asking..

Yes, absolutely. Actually you read my mind for my next question that I actually saw success with the Fc engineering technology applied to the monoclonal antibody and I was just about to ask how is that applied, I mean just educate us a little bit more about how actually engineering is applied to different franchises of your bispecific antibodies.

I know for the cytokines you probably have extended half life and maybe four others immune cells maybe elaborate a little bit on this front, please?.

Sure. I think you know you want to combine different feature sets in any protein therapeutic and in particular with Fc engineered antibodies suited to purpose when it makes sense. It's nice having these plug and play tools. You can mix and match and add together.

For example, all of our tumor microenvironment activators and cytokines Fc fusions have on top of their head are a dimeric FC domain or extended half life variants just to that made sense for all of those to have longer dosing interval and higher exposure, so at goals at least, right? So, I think again it's all suit to purpose and it's hard to be overly specific about it when the number of opportunities is so broad and we're just learning how to use these drugs.

But I would say that in general for the field which is using these Fc containing IDG like platforms for creating bispecific antibodies and certainly Xencor build it's playing an important role there. That the field is about as rapidly as you can plugging in different biology and testing them.

And I think that's why we specifically made our platform as robust and sort of reusable as possible in the standard antibody manufacturing processes. Just to simplify the engineering part so we can focus on what's important which is the biology.

I think once we can start ignoring the nuts and bolts of the engineering tools and focus on making good drugs and studying the biology that's where you really get the advances like what happened with monoclonal antibodies being humanized twenty years ago..

Absolutely. So the last one for me is a very specific question for XmAb 13673, should we think about that ASH data release? And what is the bar for efficacy and safety to constitute a gold position? Thank you..

Yes. I think we're looking at a Q4 data release hopefully at a medical conference until you know where you're going to present you don't. I never liked a front runner, but we're targeting Q4 for sure.

And I think a go no go it really depends on having clarity on you completed your dose selection and escalation and then you can start looking at your numbers relative to the competition. Not sure we're going to be all the way there yet at this at this data release. We might or might not be.

But I think we should be able to see given the different subtypes of B-cell malignancies that have been studied with bispecifics recently. Though again the data sets are not large. There were just one or two data released we're talking about.

We know we have to have pretty robust activity against different NHL subtypes multiple different NHL subtypes really feel compelled. And again I wouldn't want to get into the numbers just yet without having numbers to talk -- specifics to talk about..

Thank you so much for our time..

Thank you. And our next question comes from Dane Leone with Raymond James. Please proceed..

All right. Thanks for the call. Congratulations. On 14045, we just kind of your updated thoughts in terms of the clinical algorithm has now evolved.

What that kind of means for treatment protocol and kind of the next steps and what you need to see how the program in itself clinically?.

Yes. I think what it really means is the monitoring and treatment of CRS cytokine Release Syndrome is getting more specific.

And I think also becoming more and more uniform across the field generally as people realize you need to treat it aggressively, rapidly, stabilize patients and then you can really move on, one, because if you can catch it, it doesn't create this cascade of sort of auto catalytic T cells, activating what T cells with more cytokines.

But also after initial exposure with CD3 bispecific that first exposure, the incidence in severity of CRS does go down, right, and people are seeing this. I think you want to be aggressive and catch it fast. I think that implication is now spreading around across really across the industry. That's a good thing.

I think for this program in particular we've aside from instituting this kind of CRS protocols. We are also continuing to dose escalate. We of course have to be very mindful of CRS. There's of course heightened scrutiny now just once you have the FDA has around you they're of course going to keep it on you.

But I think we also are right now planning that hopefully this been imminent, completion of our dose escalation exercise in the next phase of development both exploring earlier line in combination in the right settings as well as this current relapsed refractory line. I wish I could be more specific.

We just got the ball rolling again and we should be back on track in a few months..

Is the algorithms should probably knows? Is the new algorithm like prophylactic steroids or Tocilizumab or something?.

The use of prophylactic steroids isn't new, it's certainly been done and we've mandated it. I think it's really more how rapidly and without waiting for full blown CRS symptoms to manifest there is a number of different symptoms that can be the first ones to manifest whether it's fever, whether it's initial hypotension.

There's a variety of others there. The minute you see any of those assume CRS and start treating for it with additional steroids and/or Tocilizumab, that's the logic. Once you see that first glimmer just treat it. Because there almost certainly is that and you can really catch it and really save a lot of risk for the patient after that.

That's really what it amounts to..

Yes. Like generally speaking we haven't really seen an impact on the efficacy of the CAR-Ts once what you're resolving CRS.

Is there any reason to think that the bispecific CD3 T cell redirected antibodies would behave any differently in terms of clinical effect?.

I don't think there's any basis for expecting there'd be difference.

And I think the data that we've seen published from others that we've seen ourselves with it public or not public there doesn't seem to be a strong you know any kind of signaling you see when you when you pre treat with either steroids or Toci that it has any effect whatsoever later on.

With much larger numbers in the future we might glean something but I think so far it does not seem to be an impediment that is these aggressive CRS treatments nothing to be impediment for whatever efficacy you might be achieving..

Right.

And how many is it -- like are all the trial sites back open now and enrolling or how are things rolling this out?.

Well, we got our first patient on -- back on last month and I know there's a number that are open, I don't I don't know the full answer to that question. There's a number of sites. There's multiple open. First patient was on almost exactly a month ago. So I don't know the specifics..

Any chance we get an update on the patients, because when you had to hold you saw a patients on that were allowed to still be treated and followed.

Would we -- is there any chance we get an update on those patients at least in the back half this year?.

Not in the back half of this year. But we're targeting next year for that..

Okay. All right. Thank you..

Thank you. And our next question comes from Mara Goldstein with Mizuho Securities. Please proceed..

Great. Thanks very much. Just a quick follow-up and then another question.

On the change in protocol for CRS, is at some point is Tocilizumab mandated in the updated protocol?.

I'm trying to remember the verb that was used and I'm the wrong person to ask. I think very you can never dictate a physician's treatment decision of a patient they are caring for. They are always the final word. I think that what you can have in your algorithm is if you see this kind of symptom you will treat with this.

But of course that's all under the heading of any clinical protocol and any decision under that is up to the discretion of the physician for what they think is best for the patient. So I guess in essence we strongly sort of guide to that, but you could never really dictate what a doctor will do..

Okay. And then just actually a question on guidance because your actual expectation to end year with cash actually went up which we don't see all that often.

And I'm just curious is that more a function of just the deals in the quarter? Or in the first half of this year or just forward-looking at potential royalty revenue how should you think about that?.

Yes. We try to -- we're fairly conservative on our guidance because there's a lot of milestones and events from partners we really can't control. I mean sometimes they give us public guidance and we'll use that information for example more forces guided on submitting to BLA that's public knowledge.

But it just updated based on new information that we've had. And I said, we'd try to be a little bit conservative on these things. So when we have more information and better ideas for spending as well as milestones we'll update it..

All right. Thank you very much..

Thank you. And our next question comes from Tom Schrader with BTIG. Please proceed..

Good afternoon. Kind of related questions.

As you get into this CD20 trial are you seeing CRS at the same place or you getting confidence that you sort of know where things get tricky and maybe dosing in the future could start higher? Just can you tell us where you are there?.

Without getting into talking about data that we haven't pulled together to release yet, I think all of these CD3s do have CRS.

In all cases reported to date and I can say with our experiences generally that CRS is most pronounced upon the first exposure of the drug and attenuate significantly as you go to -- as you do your second dose through dose et cetera. And that's attenuation about frequency, how many patients get it versus and in severity that you see.

The tools, the trade that have emerged or in addition to management of CRS in a proactive way and as mandate as much as you can that proactive treatment.

The other real tool of the trade is that you do step dosing, you start out with a slightly lower exposure enough to get the T cells going and cause that sort of conditioning that reduces CRS upon subsequent exposures and then you step up the doses on subsequent exposures and doses. We've implemented that with our 14045 protocol.

It's been shown for CD20, CD3s from our competitors. And I think that's going to be a general that you use first exposures the most delicate sensitive one and the subsequent doses and exposures can be more confidently done. And I think that's really going to help the whole class of drugs be used more confidently.

These lessons of all emerged really over the last two three years. So the pace of learning for how to use these drugs is really rapid and I'm very optimistic for the future for this whole class..

I guess, but you're not saying that CRS sort of appears at the same level of CD3 buying drugs?.

The same amount of dose of drug you meant. I misunderstood my question. Now each drug is going to have a completely different offset so to speak of what mass of drug per body mass of patient causes CRS. It depends on the density of the antigen, right, CD123 versus CD20.

It's going to also depend on the design of the molecule, how tight of a bind did you make in terms of either the CD3 or the antigen binding, I mean both of those have an impact.

A really nice publication by our partner Amgen on their CD38, CD3 program, which was built on our tools, really nice recent publication demonstrate how you can tune those things and completely raise or lower the offset for what doses is call CRS. This was in primate model at least. So it all depends on the program.

But the Primate is a reasonable way of zeroing in on about where you're going to start seeing it. So far that we've seen with our experience and what we've seen from our partners..

Okay. And then, on the Astellas IL2 program you talked in more detail than I've heard you before.

So, what's the opportunity here? Is it hag [ph] accumulation or do you think there's more safety to be at by a tuned IL2 if you have more efficacy…?.

Our work with IL2, we have nothing to do with Astellas. It just -- we happened -- those knew each other on the phone call. Our some collaboration is for a bispecific antibody program not cytokine.

Our IL2 programs internal, the idea there is that really tuned to potency can give you benefits whether you're trying to jack up the effector T cells like with our IL15 case, so the regulatory T cells for autoimmune disease like in our IL2 cases.

So, I think that the strongest distinction we have is that we really reduce the potency, try to broaden the therapeutic window as well as slow down the expansion of that antigen sink that you create that sucks away all your drugs. You want to balance out that T cell Treg [ph] expansion with the presence of the drug for a while.

So I think that's really the opportunity. There wasn't any kind of specific counter engineering we were doing relative to other approaches like [Indiscernible] just we think that Fc domain is a great way to extend half life. And with tuned to potency you really get a double win..

All right. Got it. Thank you..

Thank you. And our next question comes from Alethia Young with Cantor Fitzgerald. Please proceed..

Hi. This is Irene on for Alethia. Thank you very much for taking the question.

Just so as these tumor microenvironment antibodies advance through the clinic, can you just discuss the safety considerations that you're most focused on particularly as we think about 20717? And then for the initial data for that asset I believe you mentioned the biomarker data that we should be expecting, but should we be thinking about this in terms of across all of the tumor types in this study or can you characterize one that may be enrolling well or showing any early advocacy that you might be able to comment on? Thanks..

Okay. So, the kind of safety signals that we're looking for really are around the pretty well characterized now immune related adverse events or IRAEs that have been seen across a class of checkpoint inhibitors.

But that also seem most pronounced when using an anti-CD4 therapy like ipilimumab and those get even more severe and pronounced and frequent when you combine CTLA-4 blockade with PD-1 blockade.

So even though in indications like mono and RCC you see really promising and usually superior activity of those that combination relative to say a PD-1 alone, the adverse event specific to the IRAEs in their severity and frequency really I think limit use and enthusiasm for those.

So how do you get that efficacy with the safety? We tried to design a molecule to be more specific and selective for double positive cells and of course have that -- those are more prevalent generally believed in the two microgram. So what we're going to look for is really kind of IRAE profile do we have.

How does it as you know grow in number patient -- how does that stack up against the sort of baseline set by the combo therapy? So it's all about IRAEs and frequency and severity and can we have this dual blockade be done in a context where it's more tolerable and easily used and better adapt -- better adopted.

And certainly we're looking at all sorts of biomarkers peripheral and when possible tumor biopsy to look at immune activation, right.

We're doing that in this initial dose escalation across a wide range of indications generally skewed towards those two that have seen activity for checkpoint inhibitors that you know the web in the clinical trials at gov entries.

I don't think there's really any guidance I can give right now on particular slices and indications of that set just yet, but we're of course characterizing for everybody.

And the kind of markers we're looking for are things like to affect your accounts CD8, also CD4 accounts looking at when possible again they're more difficult to get biopsy of tumor and T cells there when possible. So, in general how hard are we activating the immune system, efficacy data that we have, we'll obviously share.

But how hard do we activating the immune system versus how much help -- how tolerable is it. That's where we'll see whether there's anything really knew that we've got with these agents across all of them..

Okay. Thanks so much. That's helpful..

Thank you. And our next question comes from Michael Schmidt with Guggenheim Securities. Please proceed..

Hey guys this is Charles Zhu on for Michael Schmidt. Thanks for taking the questions and congrats on the quarter.

Broadly speaking how are you thinking about T cell engagers in solid cancers and how might the 18087 readout impact your thinking?.

T cell engagers we think should have significant promise. I think it's early days for that for CD3s in solid tumor. I mean it's early days everywhere but it's really early days in solid tumor. I think we've all seen glimmers of activity from some programs out there like the CD3 program from Roche.

So I think that it's early days and I think that we're going to learn a lot by how these initial set of molecules perform and what kind of design decisions we made around them. What kind of activity and tolerability we see. Obviously the issue was solid tumors. Is that those antigens tend to be expressed all over the place. It's not just in the tumor.

They tend to be a lot less restricted than hematologic malignancy targets or even in the cases where those are healthy tissue. Those around him hem cells and depleting those often can be tolerated.

So I think we've got this tolerability and selectivity issue and how we design these bispecifics whether we use balances like 1 to 1, 2 to 1 the affinities that we pick for our CD3s and how hot we make these molecules. Those are all going to be a lot of learning.

So, whatever specific learnings we see around the efficacy tolerability window for 18087 I think you're going to play into that generally. And every solid tumor is also different. I think it's really dangerous to lump these all together.

Neuroendocrine just within 18087, the neuroendocrine tumor both the way the patient presents, the way the tumors are distributed, their treatment history like in these net patients they've often been treated for many many years. It's rather indolent but it can relentlessly grind on and attempt generally unresponsive.

And then we're looking at gastrointestinal stromal tumors and these just tumors have a whole different set of behaviors.

So I don't think you can over generalize, but I think in general that selectivity and can you get efficacy against the tumors and activate that tumor, the T cells around that tumor and how pleasing and safety is going to be the big datasets we're all going to learn from all of these solid tumor programs out there..

Got it. That makes sense. And given that the dual checkpoint or co-stimulatory bispecifics have a similar design rationale where by valence interactions resulting in enhanced avidity.

How much read through would you say would the XmAb20717 readout have on 23104 and 22841?.

I wouldn't over read out anything there. I think that the targets are really quite different. And whether you can get an avidity effect for binding, that's great, but those targets are all expressed with different kinds of densities at different sort of stages of T cell exhaust and I wouldn't overstate the read through there..

Okay And our last question from me. How many patients do you think you'll have treated by the 4Q update for CD20 bispecifics? And if you could provide any incremental color around how many you would anticipate within the therapeutic doses? Thank you..

I really don't think we can we can comment on that at this time. We certainly been working through quite a number of dose escalation cohorts as is typical for a CD3 bispecific given the policy set by regulators around where you can start. So I wouldn't want to try to guide to specifically the numbers.

I think it should be enough numbers to see what's going on. That's terribly helpful. But until we're ready to really lay it out it's really -- I think it's imprudent for me to say in particular because the trials moving very rapidly..

Got it. Thanks for taking the questions..

Thank you..

Okay. And I am currently showing no further questions in queue. I'd like to turn the call back over to Bassil Dahiyat for closing remarks..

Thank operator and thank you all for joining today's call. We look forward to updating you all again later this year..

Ladies and gentlemen, thank you for your participation in today's conference. This concludes the program. You may now disconnect. Everyone have a great day..