Q4 2023 Kymera Therapeutics Inc Earnings Call

Justine E. Koenigsberg: Good morning and welcome to Kymera Squadron. All part of it, after today's presentation. Ian Oppenheimer, And now, turn the conference... Good morning, and welcome to Kymera's Investor Update. Joining me this morning are Nello Manolfi, President and CEO, Jared Golub, our Chief Medical Officer, and Bruce Jacobs, our Chief Financial Officer. Following our prepared remarks, we will open the call to questions. We ask that you limit your questions to one and a relevant follow-up to allow enough time to address everyone's questions. Before we begin, today's discussion will include forward-looking statements about our future expectations, plans, and processes. Statements are subject to risk and uncertainty that may cause actual results to differ materially from those projected. A description of these risks can be found in our most recent 10-K filed with the FCC. Any forward-looking statements speak only as of today's date, and we assume no obligation to update any forward-looking statements made on today's call. With that, I will now turn the call over to Nellie. Thank you, Justine.

Good morning, and welcome to the Premier ought to trade up Iridex fourth quarter 'twenty.

Three years, let's call it.

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I now turn the conference over to Justin.

Thank you.

Please go ahead.

And welcome to kind of Arris Investor update joining me. This morning are <unk>, President and CEO, Jerry Colella, our Chief Medical Officer, and Bruce Jacobs, Our Chief Financial Officer.

In our prepared remarks, we will open the call to questions. We ask that you limit your questions to one and a relevant follow up to allow enough time to address everyone's questions.

Before we begin today's discussion will include forward looking statements about our future expectations plans and prospects. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected a description of these risks can be found in our most recent 10-K filed with the SEC any forward looking statements speak only as.

As of today's date, and we assume no obligation to update any forward looking statements made on today's call with that I will now turn the call over to yellow.

Thank you Justine and as always we appreciate everyone joining us for our quarterly call today.

Nello Manolfi: As always, we appreciate everyone joining us for our quarterly call today. This is a particularly exciting call for us in that we're reporting from our new corporate headquarters in Weathertown, Massachusetts, just down the road from our previous office. Our new building provides added space for a growing team, enabling us to maintain a strong on-site presence as we enhance and scale critical capabilities for our R&D organization, especially in areas like CNC as well as other development functions. We look forward to the opportunity to welcome those of you who would like to visit us at our offices in the future. As many of you know, we're on the job five days a week.

Particularly exciting call for us and that we're reporting from our new corporate headquarters in Watertown, Massachusetts, just down the road from our previous office, our New building provides other states, where a growing team, enabling us to maintain a strong on site presence as we enhance and scale critical capabilities for our R&D organization, especially in areas like Seattle.

C as well as other development function.

We look forward to the opportunity to welcome those of you who like to visit us at our offices in the future as many of you know were onsite five days a week.

Nello Manolfi: During our prepared remarks, we'll cover three main topics today. First, I'll provide an update on our strategy to build the best oral immunology pipeline in the industry. Next, Jared will provide an update on our clinical and newly disclosed immunology programs, as well as our two clinical oncology programs. And before we open the call for questions, Bruce will review our financial results.

Our prepared remarks will cover three main topics today first I'll provide an update on our strategy to build the best in the industry oral immunology pipeline next Jared will provide an update on our clinical and newly disclosed immunology programs as well as our two clinical oncology programs.

And before we open the call for questions Bruce will review our financial results.

Nello Manolfi: At our Immunology R&D Day in early January, you heard us discuss our strategy for building a best-in-industry oral immunology pipeline of first-in-class, highly valuable programs. We believe we're uniquely positioned to change existing treatment paradigms for immune-mediated diseases with our innovative and differentiated oral degrader medicine. As we reported this morning, with $745 million in cash and a runway into the first half of 2027, we're well capitalized to continue to support these very ambitious goals.

And our immunology R&D day in early January you heard us discuss our strategy for building a best in the industry overall immunology pipeline of first in class highly valuable programs. We believe we're uniquely positioned to change existing treatment paradigms for immune mediated diseases with our innovative and differentiated oral degree their medicine.

As we reported this morning with $745 million in cash and the runway into the first half of 'twenty seven we're well capitalized to continue to support these very ambitious goals.

Nello Manolfi: I thought I'd start with a few comments reflecting on what has led Kymera to our current strategic positioning with an innovative immunology pipeline of oral degraders with potential biologic-like activity. Those of you that have been following us for a long time know we have been driven by our unique target selection strategy. We're focused on first or best-in-class opportunities and, in particular, undrug or poorly drug targets for which protein degradation is either the best or the only solution. We're also dedicated to pathways that have strong clinical and genetic validation, where there is a clear path to early clinical differentiation. And, of course, our focus is on those indications that represent large clinical and commercial opportunities that create significant value for patients and shareholders. As you all know, we pioneered the first protein degrader program in immunology with our RF4 program, which, in addition to STAT3, were the initial targets at Kinera when it was founded in 2016.

I thought I'd start with a few comments, reflecting on what has led to our current strategic positioning. We then innovative immunology pipeline of oral degree theirs with biologic like activities potential.

As those of you that have been following us for a long time, though we have been driven by our unique target selection strategy. We're focused on there is the best in class opportunities any particular undrawn.

Poorly drug targets for which protein degradation is either the best or the only solution.

We're also dedicated to pathways that have been that have.

Strong clinical and genetic validation, where there is a clear part early clinical differentiation and of course, our focus is on those indications that represent large clinical and commercial opportunities that create significant value for patients and shareholders. As you. All know we pioneered the first protein.

You can read a program in immunology with our RF Port program, which in addition to start three where the initial targets that came in when he was founded in 2016.

Nello Manolfi: And it was the early clinical results with the IREC-IV program, with KT474, the deep and well-tolerated degradation, and the early signs of clinical efficacy that helped us inspire us to increase our focus on immunology. Additionally, we believe the activity and fidelity of translation of our TPD platform in the KT474 Phase 1 trial serve as an important read through and informs the probability of success of our new STAT6 and TIK One aspect of the current landscape in immunology that is particularly notable and creates a significant opportunity for canaries is the dominance in the market of injectable biology. These antibody-based therapies have transformed and revolutionized the treatment of immune-inflammatory disease with what, in many cases, have been great clinical outcomes for patients. At the same time, monoclonal antibodies, as you know, are injected. However, they can be costly to manufacture and can be inconvenient for patients.

And he was the early clinical results with the Aric for program with KC 47 for the deep well tolerated degradation. The early signs of clinical efficacy, which had this inspire.

To.

Inquiries are focusing immunology. Additionally, we believe the activity and see that'd be a translation of activity D block four indicate T 474 phase one trials serves as an important breakthrough and informs the probability of success of our new starts seeks into two oral immunology programs.

One spot one aspect of the current landscape in immunology that is particularly notable and creates a significant opportunity for canaries the dominance in the market of injectable biologics.

The antibody based therapies have transformed and revolutionize the treatment there'll be muting pharma the abcs.

We bought in many cases, it's been great clinical outcomes for patients at the same time monoclonal antibodies. As you know are injected there can be costly to manufacture and can be inconvenient for patients to put it in context in a recent industry survey, 75% of patients taking biologics said they would switch the board.

Nello Manolfi: To put this in context, in a recent industry survey, 75% of patients taking biologics said that they would switch to orals with an equivalent profile. We believe this creates a significant opportunity for effective and well-tolerated oral medicines and, in particular, protein degraders. In fact, while traditional small molecules offer convenience benefits, they frequently cannot match the powerful pharmacology of biology, as they don't have the ability to block these pathways at the same time. We believe and have shown with preclinical and early clinical data that protein degraders have the potential to provide a unique solution with biologics-like specificity and activity, but with the flexibility of our own small models.

We didnt Cleveland profile.

We believe this creates a significant opportunity for effective and well tolerated oral medicine and in particular for protein Degraders in fact, why traditional small molecule offer convenience benefits they frequently.

Cannot match, the powerful pharmacology of biologics and they don't have the ability to block. These pathways at the same level, we believe and have shown preclinical and early clinical data their protein degraders and the potential to provide a unique solution with biologics like specificity and activity.

But with the flexibility of oral small molecules importantly, because of this profile, we believe that they can potentially reach much broader patient populations, creating significant opportunities for the modality broadly and for <unk> specifically.

Nello Manolfi: Importantly, because of this profile, we believe that they can potentially reach much broader patient populations, creating significant opportunities for the modality, broadly, and for Kymera specifically. So as you think about our immunology pipeline, if we can build a portfolio of molecules that provide comparable pathway inhibition to biologics, as we believe we can, but one with the convenience of oral dosing, we believe the potential is enormous. We have a lot going on across our pipeline, including plenty of activities in that early pipeline that we haven't yet disclosed. We're really at the cutting edge of protein degradation and using this technology to address fundamental clinical and commercial needs and opportunities. I believe our unique approach has resulted in one of the most robust, high-value pipelines in the industry.

So as you think about our immunology pipeline, if we can build a portfolio of molecules that provides comparable pathway inhibition to biologics as we believe we can.

But one with the convenience and oral dosing, we believe the potential is enormous.

We have a lot Anthony and go cross sell pipeline, including plenty of activities in that early pipeline that we haven't yet disclosed.

We're really at the cutting edge of protein degradation and using this technology to address fundamental clinical and commercial needs and opportunities I believe our unique approach has resulted in one of the most robust high volume pipeline in the industry.

Jared Golub: I'm very proud of the continued execution and innovation by our team to support our future growth. I will now pass it to Jared to walk you through in more detail our clinical and soon-to-be clinical pipeline.

I'm very proud of the continued execution and innovation by our team to support our future growth I'll now pass it to Jerry to walk you through a more detailed.

Our clinical and soon to be clinical pipeline Gerry.

Jared Golub: Thanks, Phyllis, starting with our IRAC-IV program. In the fourth quarter, our partner Sanofi initiated two KT474 Phase II trials, one in hydradenitis opertiva and one in atopic dermatitis. Enrollment in both trials is ongoing, with top-line data expected to be reported in the first half of 2025. And importantly, with the start of these trials and the dosing of the first HS and AD patients, which we disclosed late last year, we collectively earned $55 million in development milestones from Sanofi, which we have already received. We in Sanofi are enthusiastic about the potential for this.

Thanks Paolo.

Starting with our Iraq War program.

In the fourth quarter, our partner Sanofi initiated to keep people or seven four phase two trials, one in hidradenitis Suppurativa and one in atopic dermatitis.

Enrollment in both trials is ongoing with topline data expected to be reported in the first half of 2025.

Importantly, we started these trials and the dosing of the first H S 80 patients that we disclosed late last year, we collectively earned $55 million in development milestones from Sanofi, which we have already received.

We entered into as you asked about the potential for this program in.

Jared Golub: In addition to the two initial indications, we continue to discuss and explore additional potential indications, and we will plan to share more details as we are able to. Moving now to our two recently announced preclinical immunology programs. KT621, our once-daily oral spastic degrader, is slated to enter the clinic later this year. What makes this program particularly exciting is that the IL-4, IL-13 pathway has been exceptionally well validated. AT621 Target Stat 6, which is an essential transcription factor for the IL-4, IL-13 signaling pathway and the Central Driver of Type 2 Inflammation in Allergic... By degrading STAT6, we believe we can selectively block this pathway fully and, importantly, this pathway only, potentially phenocopying upstream biologics such as dupilamide. At our R&D day, we shared what we believe is a very compelling set of pre Specifically, in our preclinical studies, we have demonstrated full inhibition of the IL-4, IL-13 pathway in all relevant human cells, with picomolar potency superior to dipilomab and exquisite selectivity.

In addition to the two initial indications we continue to discuss and explore additional potential indications and we will plan to share more details as we are able in the future.

Moving now to our two recently announced preclinical immunology programs.

<unk> 86 to one our once daily oral stat, six or greater is slated to enter the clinic later this year.

What makes this program, particularly exciting is that the IL four IL 13 pathway has been exceptionally well validated.

C. P 61 targets that six which is an essential transcription factor to the IL four IL 13.

The pathway and the central driver of type two inflammation allergic diseases.

And the greatest ethics, we believe we can selectively block this pathway fully and importantly, this pathway only potentially being a copying upstream biologics such as diplomat.

At our R&D day, we shared what we believe is a very compelling set of preclinical data that supports a high level of enthusiasm and confidence we have in this program.

Specifically in our preclinical studies, we have demonstrated full inhibition of IL four IL 13 pathway in all relevant human cell contacts with Tyco moment potency superior to diplomat and exquisite selectivity.

Jared Golub: We also demonstrated very high levels of activity in multiple well-established preclinical models, which gives us confidence in the potential of KT621 to deliver biological activity as we advance this program into clinical trials later this year. If we are able to replicate our strong preclinical data in the clinical setting, which is something we have accomplished with our clinical stage programs, we believe KT621 would be poised to be a best-in-class therapeutic option for multiple indications, representing a multi-billion dollar opportunity. We are currently in the midst of IND-enabling studies and expect to advance KT621 into Phase I testing in the second half of 2024, with data from that study in 2025. We also recently unveiled KT294, our potential first-in-class oral TIC-2 inhibitor. We believe KT294 also has a potential biologics-like profile, creating an opportunity to treat a range of autoimmune and inflammatory diseases. We believe degradation of TIK2 has the potential to overcome the challenges of small molecule TIK2 inhibitors, which have limitations due to lack of selectivity, limited target engagement, and or lack of potent activity against type 1 interferon.

We also demonstrated very high levels of activity in multiple well established preclinical models.

I have confidence in the potential okay T 61 to deliver biologic like activity as we advance this program into clinical trials later this year.

If we are able to replicate our strong preclinical data in the clinical setting which is something we've accomplished with our clinical stage programs. We believe K T 621 would be poised to be a best in class therapeutic option for multiple indications representing a multibillion dollar opportunity.

We are currently in the midst of R&D, enabling studies and expect to advance K T. Six two months into phase one testing in the second half of 'twenty 'twenty four with data from that study in 2025.

We also recently unveiled Katy two nine for our potential first in class world kick to the greater we believe K T. 294 also has a potential biologics like profile, creating an opportunity to treat a range of autoimmune and inflammatory diseases.

We believe degradation of take two has the potential to overcome the challenges of small molecule <unk>, two inhibitors, which have limitations due to lack of selectivity limited target engagement and a lack of potent activity against type one interferon.

Jared Golub: Importantly, we believe TIK2 degradation could allow us to recapitulate the human loss-of-function biology of near-full pathway inhibition of type 1 interferon, IL-12, and IL-23, while also sparing IL-10, representing a best-in-class TIK2 agent. Our plan is to move this program into first in human studies in 2020. Across our immunology portfolio, we intend to present preclinical data from the SAT-6 and TIK-2 programs at multiple scientific and medical meetings, starting with the American Academy of Dermatology annual meeting next month. We also expect multiple clinical data readouts from these programs. To summarize, in the first half of 2025, we plan to share top-line data from the KT474 Phase 2 trials, as well as data from the KT621 Phase 1 study, which, as mentioned, is planned to start later in 2024.

Importantly, we believe kick to degradation could allow us to recapitulate, the human loss of function biology of near full pathway inhibition of type one interferon IL 12, and IL 23, well also sparing IL 10, representing a best in class stick to agents.

Our plan is to move this program into first in human studies in 2025.

Across our immunology portfolio, we intend to present preclinical data from the SGR fix it took two programs at multiple scientific and medical meetings. This year, starting with the American Academy of Dermatology annual meeting next month.

We also expect multiple clinical data readouts from these programs next year.

To summarize in the first half of 2025, we plan to share top line data from the K T. Four separate four phase two trials as well as data from the K T 61 Phase one study, which as mentioned is planned to start later in 2024.

Jared Golub: Switching gears to our oncology portfolio, we expect additional proof-of-concept data readouts for both KT333 and KT253 this year. Both programs have demonstrated initial encouraging anti-tumor activity in liquid and solid tumors and are progressing through dose escalation in line with our expectations. For KT333, our STAT3 degrader, we shared data at ASH in December demonstrating early signs of antitumor activity at doses that were generally well-tolerated and associated with substantial STAT3 knockdown in blood and tumor. Our preclinical-to-clinical translation showed strong, objective responses in both CTCL and in Hodgkin's as well as induction of a gamma response in tumor and blood that preclinically was shown to enhance the response of solid tumors to anti-PD-1 drugs.

So switching gears to our oncology portfolio, we expect additional proof of concept data readouts for both K T 333, and Katie 253 this year.

Both programs have demonstrated initial encouraging anti tumor activity in liquid and solid tumors and are progressing through dose escalation in line with our expectations.

For Kt 333, our stats, we had a greater we shared data at ash in December demonstrating early signs of anti tumor activity at doses that were generally well tolerated and associated with substantial scatter three knocked down in blood and tumor.

Our preclinical to clinical translation showed strong objective responses in both C. T C L and in Hodgkin's lymphoma, as well as induction of interferon gamma responses in tumor and blood that pre clinically was shown to enhance the response of solid tumors to anti PD one drugs.

We believe this supports KC 300, three's potential to address both Hematological malignancies, as a single agent and solid tumors as a potential novel combination therapy with anti PD, one or other targeted therapies.

Our intent is to complete dose escalation in the phase one study in 2024.

Which point, we will share the trial results and disclose our plans for the next phase of development for the program.

Jared Golub: We believe this supports KT333's potential to address both hematological malignancies as a single agent and solid tumors as a potential novel combination therapy with anti-PD-1 or other targeted therapies. Our intent is to complete dose escalation in the Phase 1a study in 2024, at which point we will share the trial results and disclose our plans for the next phase of development for the program. And lastly, KTEA-253, our MDM-2 degree. This is another really exciting one. Arm A of the Phase 1a trial in solid tumors and lymphomas is ongoing, and in November, we reported clinical data demonstrating evidence of target engagement in p53 pathway activation, as well as initial anti-tumor activity, and a lack of the traditional hematological toxicity seen with small molecule inhibitors.

And lastly, K T 253, our MTM tutor greater this is another really exciting program.

Arm a of the phase one study in solid tumors and lymphomas is ongoing and in November we reported clinical data demonstrating evidence of target engagement and P 53 pathway activation as well as initial anti tumor activity and a lack of that traditional hematological toxicity seen with small molecule inhibitors.

We also announced that we commenced enrollment in arm b for patients with high grade myeloid malignancies, including AML.

For both arms of the study enrollment is progressing in line with our expectations.

Microstat three we expect to complete dose escalation in 'twenty 'twenty four at which point, we will disclose our plans for the next phase of development for the program.

As part of our development plans later this year. We also expect to present comprehensive preclinical and clinical translational data across liquid and solid tumors that will inform our patient selection strategy for kt to five three and ongoing and future clinical studies.

I'll now turn the presentation over to Bruce for a review of the Q4 financials.

Bruce Jacobs: We also announced that we commenced enrollment in Arm B for patients with high-grade myeloid malignancies, including AMI. For both arms of the study, enrollment is progressing in line with our expectations. Like with FAT-3, we expect to complete dose escalation in 2024, at which point we will disclose our plans for the next phase of development for the program. As part of our development plans, later this year, we also expect to present comprehensive preclinical and clinical translational data across liquid and solid tumors that will inform a patient selection strategy for KT253, an ongoing and future. I'll now turn the presentation over to Bruce for a review Thanks, Jared.

Thanks, Sharon I'll quickly review the fourth quarter financial results and you can certainly referenced the tables in the back of the press release today as Noel mentioned with the basket of 474 into the phase III trials in HSA D. We earned $55 million in milestones from Abbvie, we received $40 million of that in the fourth quarter or the other.

$15 million, which is recorded as receivable at year end that payment was received in the in the early part of 'twenty 'twenty. Four are these milestones were added to the total consideration received under the collaboration with the poorest portion recognized as revenue in the fourth quarter and the remaining in deferred revenue at the end of the quarter, our deferred revenue balance.

Total on the balance sheet was approximately $54 7 million at.

That reflects partnership revenue that we expect to receive over the next several years, excluding the receipt of any potential future milestones and then quickly with respect to operating expenses R&D for the quarter totaled $53 million of that about $5 3 million was noncash stock based compensation the adjusted cash R&D spend of 47.

Bruce Jacobs: I'll quickly review the fourth quarter financial results, and you can certainly reference the tables in the back of the press release today. As Nelo mentioned, with the advancement of 474 into the Phase II trials in HS and AD, we earned $55 million in milestones from Sanofi. We received $40 million of that in the fourth quarter. The other $15 million, which was recorded as receivable at year-end, that payment was received in the early part of 2024. These milestones were added to the total consideration received under the Sanofi collaboration, with a portion recognized as revenue in the fourth quarter and the remaining amount in deferred revenue. At the end of the quarter, our deferred revenue balance total on the balance sheet was approximately $54.7 million.

7 million, excluding stock based comp was up 13% from the comparable quarter a year ago.

Bruce Jacobs: That reflects partnership revenue that we expect to receive over the next several years, excluding the receipt of any potential future milestones. And then quickly, with respect to operating expenses, R&D for the quarter totaled $53 million. Of that, about $5.3 million was non-cash stock-based compensation.

Operator: The adjusted cash R&D spend of $47.7 million, excluding that stock-based comp, was up 13% from the comparable quarter a year ago. On the G&A side, our spending for the quarter was $14.2 million, of which $5.6 million was non-cash and the non-cash stock-based comp. And that adjusted G&A spend of $8.6 million, again, excluding stock-based comp, is a 5% And then finishing up with our cash balance, as stated earlier, at the end of 2023, it was $436 million, including the $300 million of net proceeds from our equity offering last month and the $15 million that I referenced from Sanofi that was received early this year. That brought our unaudited cash and equivalent balance as of January 9th to approximately $745 million.

In terms of our prepared remarks, and now we'd be happy to answer any questions.

Operator.

Thank you.

We will now begin the question and answer session.

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At this time, we were the boss momentarily to assemble it also.

The first question comes from.

From Morgan Stanley.

Please go ahead.

Hi, good morning, Thanks for taking our questions we had to both on immunology first so you alluded to in your prepared remarks.

Potential pipeline expansion 4474.

To the extent possible I was wondering if you could speak a bit about what's going to feed into that decision and.

How the datasets, we get in the first half of next year for H as in a D might be related to how you think about with San iffy.

Operator: That is expected to provide a runway into the first half of 2027, and it will enable us to deliver the next stage of growth in data readouts, including, as Jared mentioned, the KT474 Phase 2 data, our oncology proof of concept results this year, and then several critical and clinical inflection points for our STAT6 and TIC2 programs. So that's what we had for you today in terms of prepared remarks. And now, we'd be happy to answer any questions. Operator, I will now begin the question and answer session. To ask a question, you may press star and then 1 on your touch screen. If you are using a, Please pick up your handset before proceeding to draw your questions. This time.

Where to go next with this molecule and then a.

Similar question 4621294, what will you be assessing from the initial clinical data, we're gonna be getting next year to help prioritize indications for subsequent development in an ini indications. Thank you.

Thanks, Vikram, so maybe I'll start so if we posed to them for just a bit more challenging because you said you know.

Collaboration with <unk>, we're not even the liberty to disclose.

Mm several things around decision, making and timing.

In the past.

The reason why we built this program several years ago actually we we said today that Eric was that we were the first programs in 2016 17, so the I D around Iraq for the relation needed the opportunity to generate and develop it brought an anti inflammatory drug with a glint vulnerability profile.

Nello Manolfi: The first question comes from... and I'm............ Hi, good morning. Thanks for taking our questions. We had two, both on immunology. First, as you alluded to in your prepared remarks, potential pipeline expansion for 474. To the extent possible, I was wondering if you could speak a bit about what's going to feed into that decision and how the data sets we get in the first half of next year for HS and AD might be related to how you think about, with Sanofi, where to go next with this molecule. And then, for 621 and 294, what will you be assessing from the initial clinical data we're going to be getting next year to help prioritize Thank you. Thanks, Vikram.

So.

<unk>, there's always been the the possibility and high probability to move beyond skin indications.

And you know we'd be school with some of the other potential indications that one could go out to really could be respiratory could be rheumatology. It could be G. I. So I think it's <unk> I think when we're ready we with our partners NOP to disclose the path forward you know we'd be happy to do so.

Obviously.

Personally I don't believe that.

You know a <unk> an indication we'll inform necessarily the probability of success of this drug in other type of disease is that obviously confirming the.

The safety and and and.

An activity in in longer term face the studies will bolster confidence to then move into either indication maybe that tie level, how I would characterize it today for for us that fixed and and and peak too I think it's early for us to comment on the.

Nello Manolfi: So maybe I'll start. So with 474 it's just a bit more challenging because this, as you know, is in collaboration with Sanofi, so we're not at liberty to disclose several things around decision making and timing, but as we said in the past, the reason why we built this program several years ago, actually, we said today that IREC4 were the first programs in 2016-17. So the idea around IREC4 degradation is the opportunity to generate and develop a broad anti-inflammatory drug with a good tolerability profile.

Decision, making beyond early early clinical studies I mean these are you know we could spend hours talking about your question you and maybe just high level you know with that seeks that we've been seeing now for a few months.

It feels like the month, a few months, but it's actually two months. It's the the value proposition is the oral degree there. They can match the biologics like activity of upstream monoclonal antibodies such as do people a mob we've shown without preclinical data that we can match that type of.

Nello Manolfi: So in our goal, there's always been the possibility and high probability of moving beyond the skin indication. And, you know, we've disclosed some of the other potential indications that one could go after. It could be respiratory, it could be rheumatology, it could be GI.

Phenotype, Tom with argue we're more potent than it in some context that maybe we don't have to go there. So we have a pretty exciting blueprint of development plans in front of US I think we.

Nello Manolfi: So I think it's, I think when we're ready with our partner Sanofi to disclose the path forward, you know, we'll be happy to do so. Obviously, I personally, I don't believe that, you know, a skin indication will necessarily inform the probability of success of this drug in other types of diseases. But obviously, confirming the safety and activity in longer term phase two studies will bolster confidence to then move into other indications. Maybe that's high level how I would characterize it today.

As we've done for all the other programs for US is imperative that we go into human and demonstrated this beautiful translation that we've seen with other programs of Italian knockdown predictable safety predictable P. K P. D. And then we have this.

I think very arrogant biomarker strategy that will be talking about later in the year of that I think will allow us to validate the ability to match the type of pathway depiction that upstream biologics do and 42 briefly again is it well correct their eyes mechanism.

Nello Manolfi: For stat six and tick two, I think it's early for us to comment on decision-making beyond early, early clinical studies. I mean, these are, you know, we could spend hours talking about your question, maybe just high-level, you know, with statistics that we've been seeing now for a few months. It feels like two months, a few months, but it's actually two months.

We know what either take to any visitors or missing, which I would say Ah several themes sandler's till activities, all our target engagement that and Tom R ability to block all the other scaffolding functions into what good looks like for us is b.

Nello Manolfi: The value proposition is the oral degrader that can match the biologics-like activity of upstream monoclonal antibodies, such as dupilumab. We've shown with our preclinical data that we can match that type of phenotype. Some would argue we're more potent than them in some contexts, but maybe we don't have to go there.

Lots of function like phenotype, and we know where that looked like based on human genetics and that's what we Wanna confirm in phase one and then once we're there you know Jared and his team will be happy I'm sure to share more details about believe me doesn't plan.

Nello Manolfi: So we have a pretty exciting blueprint of development plans in front of us. I think we, as we've done with all the other programs, for us, it's imperative that we go into humans and demonstrate this beautiful translation that we've seen with other programs of target knockdown, predictable safety, and predictable PKPD. And then we have this...

Got it thank you.

Thank you.

The next question is from the line of Mike Schmidt.

Can I. Please go ahead.

This is Paul I'm from Michael Thanks for taking our questions minor on Kiki 333. So the first one is on on your bar for pursuing a development in solid tumors I believe that asked me to add about a third of the patients.

Nello Manolfi: I think a very elegant biomarker strategy that we'll be talking about later in the year that I think will allow us to validate the ability to match the type of pathway inhibition that upstream biologics do. And for TIK2, briefly, again, this is a well-characterized mechanism. We know what other TIK2 inhibitors are missing, which I would say are several things. Some are selectivities, all our target engagement tests, and some are the ability to block all the other scaffolding functions. And so what good looks like for us is a loss-of-function-like phenotype, and we know what that looks like based on human genetics, and that's what we want to confirm in phase one. And then once we're there, Jared and his team will be happy, I'm sure, to share more details about the late development process. Got it. Thank you. Thank you, the line of Paul and Michael.

Stable disease, so no one would hire races stable disease biomarker data would be sufficient advanced program.

Nations or would you really need to see some objection responses to sort of condition evaluation and solid tumors. In a second is just you know how does your thinking now uhm first at three and auto immune put into your your current hotline and I'm waiting for the registry data to a ball further before making it for like a minute.

<unk>.

The movie Janet you Wanna take the first one and then I'll make comments of the second one sure I think I think with regard to your question on the bar for solid tumors. As you noted and we have had some patients who have had prolonged stable disease and that of course is of interest to us and we continue as we enrolled patients onto the study. It continues to go to escalate and look for opportunities.

Jared Golub: Thanks for taking our questions. Mine are on KTEA-333. The first one is on your bar for pursuing development in solid tumors. I believe the ASH data included about a third of the patients with stable disease. So would higher rates of stable disease from biomarker data be sufficient to advance the program into combinations, or would you really need to see some objective responses to sort of commit to evaluation in solid tumors? And then second, how does your thinking now for stat 3 and autoimmune fit into your current pipeline, and are you waiting for 3-3-3 data to evolve further before making that decision? So maybe, Jerry, do you want to take the first one, and then I'll make comments on the second one?

<unk>, we're bringing on solid tumor patients that can give us a better idea as to what our activity will be as a mono therapy in solid tumors I think all along you know we've been guiding that we expect that ultimately if we move this into solid tumors would be as a combination approach, especially in a P. D. One combination of something we're very interested in based on our promising preclinical data.

And based on what we've shown with our Biomarkers that we can induce this interferon gamma responsive tumor and blood, which can actually facilitate responses to anti P. D. One. We're also looking at additional targeted agent combination Ah Ah preclinical and so I think you know what will inform moving forward with solid tumors will be a combination of what we continued to learn pre clinically with combination studies and whether we do see.

He continued signals of some sort of activity at the amount of therapy, either stable disease or even preferably. Your major responses you know with regard to major responsibly are seeing those in hematological agencies, including Hodgkins lymphoma in Katine.

Jared Golub: Sure. I think with regarding your question on the bar for solid tumors, as you noted, we have had some patients who have had prolonged stable disease, and that, of course, is of interest to us. And we continue, as we enroll patients onto the study and continue to dose escalate, to look for opportunities for bringing on solid tumor patients that can give us a better idea as to what our activity will be as a monotherapy in solid tumors. I think all along, we've been guiding that we expect that, ultimately, if we move this into solid tumors, it would be as a combination approach, especially anti-PD-1 combination is something we're very interested in based on our promising preclinical data and based on what we've shown with our biomarkers that we can induce this interferon gamma response in tumor and blood, which can actually facilitate responses to anti-PD-1.

Can you see some former and that continues to be of interest to us and will continue to bring on patients onto the ongoing face when they studied to further explore activity there as well.

Yeah. Thanks, Yeah, that's great and and and on the <unk>, maybe I just want to go back to our strategy, which is tell me that we've talked about it during the day. We believe you know we exist to bring together the power of the technology and unmet needs that booths clinical comer.

Sure and I would see also the opportunity to do with this technology things that cannot be done with other technologies I guess another type of them that need the technological one and only I think when we married those three together.

We're gonna go all in and as you've seen with with with Iraq for which that seeks and take too and I think we have a very very easy to articulate volume for a position I Hope you guys also feel that way and these are you know complete degradation of target that lead to accept.

Jared Golub: We're also looking at additional targeted agent combinations preclinically. So I think what will inform moving forward with solid tumors will be a combination of what we continue to learn preclinically with combination studies and whether we do see continued signals of some sort of activity as a monotherapy, either stable disease or even, preferably, major responses. With regard to major responses, we are seeing those in hematologic malignancies, including Hodgkin's lymphoma and cutaneous T-cell lymphoma, and that continues to be of interest to us and will continue to bring patients onto the ongoing Phase 1a study to further explore activity. Yeah, thanks, Jared. That's great!

<unk> anti inflammatory profiles that a wet tolerate it at least in our end so far.

Until we sat three seats.

It's obviously a program that we know I I would argue better than anybody at this point, we've been working on this target for several years and the reason why you haven't seen us disclosing more details on set three ionised because we feel that at this point, we don't have all the information in hand to being able to say that.

We'll see.

The profile of the type of programs that we've articulated so far when we do when he dog and would be would be able to do so I will disclose more.

Alright, thank you.

Thank you.

The next question comes from any more from M E S.

Nello Manolfi: And on Satsriya and I, maybe I just want to go back to our strategy, which is something that we talked about at R&D Day. We believe, you know, we exist to bring together the power of technology and unmet needs that are both clinical and commercial, and I would also say the opportunity to do with this technology things that cannot be done with other technologies. So I guess another type of unmet need, the technological one. And only, I think, when we marry those three together, we're going all in. And as you've seen with IRAC-4, with STAT-6, and TIC-2, I think we have a very, very easy-to-articulate value proposition. I hope you guys also feel that way.

Oh this is Catherine <unk>. Thanks, so much for taking my question.

Hi, This is Catherine for Alley. Thanks, so much for taking our question and what's your latest thinking on whether you're gonna take.

<unk> or it comes with a dog prioritize whenever the other giving you a second and any knowledge.

With your threshold for sixth Aspie, paycheck, and I'm thinking about the Gal in yoga.

Thank you I think I felt like there were two people, but anyway I think we got the question I'm sure. There were similar questions. So so great question. So maybe I would start with saying that it has everything that we've gone. It came era you know for the past almost eight years all our decisions there.

Gonna be data driven so and that is you know for example decisions even that we've made for programs that would discontinue for example for one three Ah Ah even though the molecule was behaving well and was well tolerated was driven by Pfizer up data, obviously clinical commercial landscape.

Nello Manolfi: And these are, you know, complete degradation of targets that lead to exceptional anti-inflammatory profiles that are well-tolerated, at least in our end so far. And so with SAT-3, it's obviously a program that we know, I would argue, better than anybody at this point. We've been working on this target for several years, and the reason why you haven't seen us disclosing more details on SAT-3 INIs is that we feel that, at this point, we don't have all the information in hand to be able to say that it will fit the profile of the type of programs that we've articulated so far. When we do, when it does, and we'll be able to do so, we'll disclose more. Thank you. This question comes from... Hi, this is Jasmine from LEU. Thanks so much for taking our question. Hi, this is Jasmine on behalf of Ellie.

They've been in.

To a large extent also empathy analyses that within so wheeler apply the same rigour too old programs or a pipeline, whether these or any minority jewelry and oncology.

As we've said in order for us to invest in.

In these two oncology program, we need to be able to see in front of us opportunities to impact.

[noise] broad patient population. So I think our goal criteria for both programs will be driven by opportunities. There are you know both in hematology tumors generally at this level and I think we we we should probably wait for when would disclose.

Nello Manolfi: Thanks so much for taking our question. What's your latest thinking on whether you would take both STAT3 and MDM2 into Phase 2? Or is the thinking that you'll prioritize one over the other, given your focus on immunology? And what would your threshold for success be for each program when thinking about the go and no-go decisions? Thank you. I think I felt like there were two people, but anyway, I think we got the question. I'm sure there were similar questions.

More data later in the year on what exactly the strategy will be what what I will say that for a start three we've shown something that has not been shown before which is this is an active target and we have an active drive we've shown you know small dataset in December at Ashworth show more.

Later in the year and an M. D. M. Two we also have an active drug we've showed really few patients theater in November one show much more later in the year. So I think only one were able together to look at the totality of the data you will be much clearer what the decision making process who's going to look like.

Nello Manolfi: So, a great question. So maybe I will start by saying that, like everything that we've done at Kymera, you know, for the past almost eight years, all our decisions are going to be data driven. So, you know, decisions even that we've made for programs that we discontinued, for example, 4.1.3, even though the molecule was behaving well and was well tolerated, were driven by a plethora of data, obviously clinical, commercial, landscape, and, to a large extent, also NPV analysis that we did. So we'll apply the same rigor to all programs in our pipeline, whether these are in immunology or in oncology.

He thinks that much.

Thank you.

The next question is from the lineup Jack Nature from Bank of America. Please go ahead.

Hi, My Name's <unk>, taking a question can you walk us.

<unk>, Alright indications selection <unk> immunology program, <unk>, <unk>, sorry that take care.

B M I O four.

Just connecting specifically on may be competitive landscape.

What kind of data.

Wait until it that pirate.

Nello Manolfi: As we've said, in order for us to invest in, let's say, these two oncology programs, we need to be able to see in front of us opportunities to impact a broad patient population. So I think our goal criteria for both programs will be driven by opportunities that are, you know, both in heme and solid tumors generally at this level. And I think, you know, we should probably wait until we disclose more data later in the year on what exactly the strategy will be. But what I will say is that for STAT-3, we've shown something that has not been shown before, which is that this is an active target, and we have an active drug. We've shown, you know, a small data set in December, and ASH will show more later in the year.

Crushed in human studies.

Okay. This is.

So I'm gonna take these really high level, just because I want to be consistent with our message, which is being that as we get into the clinic in our head people in tears studies at least for tourists ethics, and and boutique too I think at that point, we would feel more comfortable talking about later development for several reasons one.

We don't have to talk about it now and to Ah Ah Ah Ah you know these these these these the landscape as you said, it's competitive that and I don't believe is defined as necessary to disclose information that are not needed. So it just so that's always a high level what I Wanna sees you know highlight vote for step six.

I don't believe that there are ah well tolerated oral drug even indications in which to pull them up it's been approved.

Nello Manolfi: And in MDM-2, we also have an active drug. We showed really few patients data in November. We'll show much more later in the year. So I think only when we're able together to look at the totality of the data will it be much clearer what the decision-making process is going to look like. Great, thanks so much. The next question is from the line of Geoffrey Meacham and Ben Crawford. Hi, good morning; this is Susan on behalf of Geoff.

They they they they say that what was tolerated stronger activity. So we have a huge potential in a variety of indication that I don't have to name them because they're all well established you.

You know from a D asthma, hopefully soon C O P D.

Chronic ran his ideas and others <unk> there.

Nello Manolfi: Thanks for taking our question. Can you walk us through what the strategy is for indication selection for the immunology program, the STAT-6 and the TIC-2? and the IL-4, and just commenting specifically on maybe the competitive landscape or maybe what kind of data you're going to look at prior to initiating first in human studies. Okay, so I'm going to take this really high level, just because I want to be consistent with our message, which has been that as we get into the clinic in our Healthy Volunteer Studies, at least for Sub-6 and for TIC-2, I think at that point, we will feel more One, you know, we don't have to talk about it now.

There is actually white space in in that area for oral drugs with a good safety profile.

So while obviously all of those indications that are gonna get more and more competitive given large investments that he biopharma he's putting into me analogy, we're actually in a really unique position right now going forward and once we disclose as development plans, you'll see how how actually we would be a.

Will we believe to be really competitive in terms of timing of of our trials as well as the design of our trials with regards to take two weeks, it's obviously a different landscape.

Nello Manolfi: And two, you know, the landscape, as you said, is competitive, and I don't believe at this point it's necessary to disclose information that is not needed. So just so at the high level, what I want to say is, you know, the high level for Sub-6, I don't believe that there are well-tolerated oral drugs in indications in which pilumab has been approved. As I said, it is a well-tolerated, strong activity, so we have huge potential in a variety of indications. I don't have to name them, because they're all well-established, you know, from AD asthma, hopefully soon COPD, chronic rhinocerosis, and others COE. There is actually white space in that area for oral drugs with a good safety profile. So while obviously all of those indications are going to get more and more competitive given the large investments that biopharma is putting into immunology, we're actually in a really unique position right now going forward, and once we disclose our development plans, you'll see how we would actually be able, we believe, to be really competitive in terms of the timing of our trials as well as the design of our trials. With regard to TIK2, it's obviously

But I would say that there are why there are several take two small molecule any visitors. We've seen also recently data from an odd twenty-three pet died from a protagonist slash J&J.

There is still room to match twenty-three type one interferon biologics, especially in a single or a molecule that is well tolerated an octave and so I think that is the gap that we're gonna feel with our programs. So just patients on the design, but there will come a you know.

As we get into that phase one study.

Okay. Thank you.

The next question.

Comes from.

Thomas Smith from please.

Please go ahead.

Hi, this is well on her Thomas Thanks for taking our questions a couple on the Zen and advanced trials.

If you could give us a sense of how enrollment is progressing thus far at any color on what the patient enthusiasm and willingness to enroll has looked like.

And when enrollment is complete for those trials are you planning to share that information or just wait until the data release, and then I have a follow up.

Nello Manolfi: But I would say that while there are several TIK2 small molecule inhibitors, and we've seen recently data from an R23 peptide from Protagonist-slash-JNJ, there is still room to match R23 type 1 interferon biologics, especially in a single oral molecule that is well-tolerated and active. And so I think that is the gap that we're going to fill with our programs. So just have patience with the design, but it will come as we get into the phase 1 studies. Thank you. Hi, this is Will on behalf of Thomas.

Great. Thanks for the question as you know Sanofi It is running both of those phase two trials you know if you look on Quinn trials Dot Gov. You can see the publicly stated timelines for estimated primary completion for both of those studies, which is in the first half of next year and to our knowledge you know both studies are still on.

<unk> to meet those timelines you know that's pretty much all we can really say right now with regard to how those are staying on track you know my understanding is that there is significant enthusiasm of on on.

Jared Golub: Thanks for taking our questions. A couple on the Zen and ADDvantage trials. If you could give us a sense of how enrollment is progressing thus far and any color on what the patient enthusiasm and willingness to enroll has looked like. And when enrollment is complete for those trials, are you planning to share that information or just wait until the data is released? And then I have a follow-up. Great, thanks for the question.

Various states were being engaged you know that these are both sort of global studies and so I think that's been very encouraging in terms of what we've heard from sanity in terms of site engagement.

And so I think again you know, we're we're still expecting it that both of those studies I would read out on the top of the state of timelines in terms of you know sharing you know data I think that would be something that you know sanity, and K, Maryland to sort of work out in terms of exactly how that will look next year you know in the first half of next year when those readouts are expected to occur.

Jared Golub: As you know, Sanofi is running both of those phase two trials. And, you know, if you look on clintrials.gov, you can see the publicly stated timelines for estimated primary completion for both of those studies, which are in the first half of next year. And to our knowledge, both studies are still on track to meet those timelines. You know, that's pretty much all we can really say right now with regard to how they are staying on track. You know, our understanding is that there is significant enthusiasm on and among the various sites who are being engaged. These are both sort of global studies.

Okay, that's helpful and they're supposed to follow up as well.

Okay.

The next question comes from from.

Jeffries. Please go ahead.

Hi, Good morning, this a year for Kelly, Thanks, very much for taking the questions are able to share the status of a dose escalation and the staff three and also at the M. T. M. Two program and also are able to discuss have you reached the targeted 90% degradation that she's felt.

Could be required for quite classic C.

And also for Ini indications is there a specific threshold like 90 per cent in oncology indication that you think you'll have to cheap and based on your experience with oncology indications. How confident are you that in preclinical degradation data will translate into human data. Thank you.

Jared Golub: And so I think that's been very encouraging in terms of what we've heard from Sanofi in terms of site engagement. And so I think, again, we're still expecting that both of those studies will read out on the publicly stated timelines. In terms of sharing data, I think that will be something that Sanofi and Kymera will need to sort of work out in terms of exactly how that will look next year, in the first half of next year when those readouts are expected. Okay, that's helpful, and that is a follow-up as well. Thank you. This question comes from... Hi, good morning. This is Yuen for Kelly.

I think three questions I, even lost track of them, but so let's start with the oncology program. So we we generally do not provide.

Faith in this quarterly called on how recruitment is going we provide updates when we disclose data, obviously and we tried to target medical meetings.

Nello Manolfi: Thanks very much for taking the questions. Are you able to share the status of dose escalation in the STAT-3 and also the MDM-2 program? And also, are you able to disclose whether you have reached the targeted 90% degradation that could be required for clinical efficacy? And also, for INI indications, is there a specific threshold, like the 90% in oncology indications, that you think you will have to achieve? And, based on your experience with oncology indications, how confident are you that preclinical degradation data will translate into human data? Thank you. I think there are three questions. I even lost track of them.

So you should just look out for the you know meetings later in the year, where a full update on each of those two programs will be provided now you know we love to share.

But because as you know there is abstract admission and then we need to hear from the conferences you know, we're not able to do now confidence, we'd say exactly where but just know that there is a planning. Please and we believe these these will be both presented a high impact medical meetings.

Within 2024, if you look at what we've disclosed so far obviously, we have reached a four star tree. The target is big relation and really here. We continue those escalation because we're getting through we're targeting to reach an M. T D, a which as we've seen pre clinically.

Nello Manolfi: So let's start with the oncology program. We generally do not provide updates in these quarterly calls on how recruitment is going. We provide updates when we disclose data, obviously, and we try to target medical meetings. So you should just look out for meetings later in the year where a full update on each of those two programs will be provided. Now, you know, we love to share our plans, but because, as you know, there is abstract omission and we need to hear from conferences, we're not able to now confidently say exactly where, but just know that there is a plan in place, and we believe this will be presented at high-impact medical meetings within 2024. If you look at what we've disclosed so far, obviously, we have reached, for stat three, the targeted And really here, we continue those escalations because we're getting through, we're targeting to reach an MTD, which, as we've seen preclinically, seems to be, you know, above our targeted degradation. And that's really a testament to the design of the molecule, the design of the study, that translation has happened in a very predictable and positive manner.

It seems to be you know a ball that targeted big relation and that's really a testament to the design of the molecules the design of the study.

The translation it had been in a in a very predictable and positive manner. Four M. P. M. Two weeks earlier I I I think it's hard for us to comment based on you know three or four patients worth of data that we shared in November. So just stay tuned for our next update where it'd be clearer, where we are with regards to targeting.

Hagemann.

You know I think if you look at all of our programs. If you look at our our M. D data God actually on a corporate back today, you will see that each one of our programs whether in college or immunology, we have reached targeted bigger a nation indirectly need with a good safety profile with our export we've reached complete big relation in blog.

We'd we'd start three we've reached the more than 90% around 90% or more depending on patients in both the blood and tumors. We even 413, we reach that target a degradation. So we know really well how's the designer molecule interest made the those profiles.

Nello Manolfi: For MDM-2, as we said earlier, I think it's hard for us to comment based on, you know, three, four patients' worth of data that we shared in November. So just stay tuned for our next update, where it will be clearer where we are with regard to target engagement. You know, I think if you look at all our programs, if you look at our R&D data, or actually on our corporate deck today, you will see that each one of our programs, whether in college or immunology, we have reached targeted degradation in the clinic with a good safety profile. With Rx4, we've reached complete degradation in blood. With STAT3, we've reached more than 90%, around 90% or more, depending on patients in both blood and tumors. With even 413, we reached that targeted degradation. So we know really well how to design our molecule and translate those profiles in the clinic. So we expect that for STAT6 and TIK2, that should happen just the same way. That is one thing that we're not concerned about here at Kymera.

In the clinic. So we expect that for set six and think too that should have been just the same way like that is one thing that we're not concerned about here I came here with regards to what is the profiling immunology the profiling immunologist, what you've seen in our frequently nicos data you've seen that if you are degrees for example start fix any.

The way it between 80 and 90% you can match.

The pillow mob activity indoors preclinical for example, asthma modules or even a D models. So it doesn't look like you need complete target removal, but we will as we've done in the past target completing that start fix their relation and I know that we can obviously do Ah those exploration.

In the cleaning Ah similarly, with it too so.

So you know once once we generate data and we can talk more about what he's are late stage design, but the the phase one design will look a lot like the the our export program.

Nello Manolfi: With regard to what the profile in immunology is, the profile in immunology is what you've seen in our preclinical data. You've seen that if you degrade, for example, STAT6 anywhere between 80 and 90%, you can match. Dupilumab activity in preclinical models, for example, asthma models or even AD models. So it doesn't look like you need complete target removal, but we will, as we've done in the past, target complete statistics degradation and then know that we can obviously do those explorations in the clinic, similarly with TIK2. So,

What do you mean like.

Thank you very much.

Thank you.

The next question comes from Adam Vulgar.

Cycle. Please go ahead.

Hey, Thank you for taking my call today My mom for a Derek So maybe just a few quick questions for months on oncology hotline can you Marcus further what data you expect to share from T. T. Two by three will you be reading out data for both arms a E and then perhaps giving your deeper.

Can focus <unk>.

Would you be looking to partner either 333 or 253 in the future. Thank you.

Alright, So just maybe you think the first one I just wanted to take the second one first.

Nello Manolfi: So, you know, once we generate data, we can talk more about what our late-stage design is. But the Phase I design will look a lot like the IREC-IV program for Immunology. Thank you very much.

So.

You know I think we need to think about.

For us that decision to invest in programs is driven by if philosophy of.

You'll portabilities and reset and an investment.

Jared Golub: The next question comes from Adam. Hey, thank you for taking my call today. I'm on for Derek, so maybe just a few quick questions from us on the oncology pipeline. Can you walk us through further what data you expect to share from KT253? Will you be reading out data from both arms, A and B?

And each patient impact.

It turns out that based on our analysis. If you look at our current immunology pie fine. We believe that you know these are all extremely valuable program.

At the outset.

I think four hour oncology pipeline, we believe that if the program translate in the way that we hoped based on preclinical data those could be also really valuable programs MVM too if we can unlock it.

Nello Manolfi: And then perhaps, given your deepening focus and efforts on I&I, will you be looking to partner with either 333 or 253 in the future? Thank you. Alright, so Gerard, maybe you take the first one; I just want to take the second one first.

That biology that is gonna be another really large program for a century, if we're able to also on lobby of the Saudi tumor opportunity I think that would be the case too. So I think that partnering discussion comes with the conversation around what type of.

Nello Manolfi: So, um... You know, I think we need to think about. For us, our decision to invest in programs is driven by a philosophy of opportunities, return on investment, and patient impact. It turns out that, based on our analysis, if you look at our current immunology pipeline, we believe that, you know, these are all extremely valuable programs at the outset. I think for our oncology pipeline, we believe that if the program translates in the way that we hope based on preclinical data, those could also be really valuable programs. MDM2, if we can unlock it, that biology, that is going to be another really large program for SET-3. If we're able to also unlock the solid tumor opportunity, I think that will be the case too.

Expertise, we Wanna build in terms of late stage clinical and commercial even though we're still in early company I think a sample and hopefully we won't be asked anymore. You know you can only do one versus the other because we're trying to build a a large commercial stage company and as you've seen all of the.

[noise] successful one can navigate multiple disease areas, but we also are not naive.

So we understand that at this stage in terms of late stage capabilities.

Probably makes much more sense to invest in one area and we've said already clearly that we're committed heavily and immunology.

And so I think we we don't college you. The question is what are the key value driver that came out of it wants to drive this program through and then if we feel that these programs are bad position.

Nello Manolfi: So I think the partnering discussion comes with the conversation around what type of expertise we want to build in terms of late stage clinical and commercial, given that we're still an early stage company. I think at some point, hopefully, we won't be asked anymore, "You know, you can only do one versus the other because we're trying to build a large commercial stage company, and as you've seen, all the successful ones can navigate multiple disease areas." But we are also not naive.

Collaboration for maximum value creation, we can do that but we also Rivera reserve the right to being able to advance this program or one of these programs on our own if we believe that the body proposition faith, the philosophy of the company right now.

Maybe you can comment on the type of data on 253 sure. So our our plan for this year is to complete dose escalation you know across both in studies to 333 and two by three.

Jared Golub: And so we understand that at this stage, in terms of late-stage capabilities, it probably makes much more sense to invest in one area. We've already said clearly that we're committed heavily to immunology. And so I think with oncology, the question is, what are the key value drivers that Kymera wants to drive this program through? And then if we feel that these programs are best positioned in a collaboration for maximum value creation, we can do that. But we also reserve the right to be able to advance this program or one of these programs on our own if we believe that the value proposition fits the philosophy of the company right now. Jared, maybe you can comment on the type of data on 253. Sure.

When they trials into establishing M. P D and then to present those data at a medical meeting later in the year that would include of course update on enrollment types of patients that were including and for 253 as you mentioned, yes, we're enrolling in both the solid tumor lymphoma Army is when I was in the high grade my wouldn't like with the email or B for the show.

What types of patients every enroll what's the safety profile look like and what is P. D and what kind of a clinical efficacy or be seen to start to give us insights into where we Wanna go in terms of the next stage of development for both of these programs as I mentioned earlier you know in the presentation upfront you know for 253. We've also been doing a lot of work on preclinical work excellent or good work really.

Understand you know patient selection you know both for the remainder of days when they but also for the next steps in development and so I think we're also looking for an opportunity because she had a medical meeting to present those data sometime this year as well to get further insights into how we think about patient selection rather liquid into a solid tumors are willing to pay for it.

Jared Golub: So our plan for this year is to complete dose escalation across both studies, the 333 and 253, phase 1A trials into established and MTD, and then to present those data at a medical meeting later in the year. That would include, of course, an update on enrollment, and the types of patients that we're including. And for 253, as you mentioned, yes, we're enrolling in both the solid tumor lymphoma arm A, as well as in the high-grade myeloid malignancy, AML, arm B.

Great. Thank you.

The next question comes from from some Tiki carvings. Please go ahead.

Hi, Thanks for taking my questions.

Maybe no.

With Iraq for when when we get the data next year in San if you will make their own decision of going forward or not but you guys will also have well if they choose to to move forward you guys will have an opt in decision to say how are you kind of approaching the the opt in what do you want to see that you know you would commit came marriage.

Jared Golub: So to show what types of patients we have enrolled, what the safety profile looks like, and what PD is, and what kind of clinical efficacy we are seeing, to start to give us insights into where we want to go in terms of the next stage of development for both of these programs. As I mentioned earlier, you know, in the presentation up front, we've also been doing a lot of work on preclinical work and clinical work to really understand patient selection, you know, both for the remainder of phase 1a but also for the next steps in development. And so I think we're also looking for an opportunity, potentially at a medical meeting, to present those data sometime this year as well, to give further insights into how we think about patient selection for either liquid or solid tumors.

Resources.

Early on.

And how important is kind of phase one data from stat, six and took two and seem kind of exposure do you want to to make an etiquette prior at port.

Oh, Yeah. That's a great question and you know probably requires a very nuanced answer so I'll try and do my back to the short time, we had so first I thought I should say it earlier, we are you know extremely bullish on Iraq for our value proposition, it's only grown with more.

Data besides the potential to be one of the largest drug and inflammatory diseases. We had early positive data, but I think we are all here recognizing that we just don't know how active this drug use and people Iran. E. At web powered randomized study, which is what we're doing with sun it'd be actually we're doing towards.

Jared Golub: Great, thank you, from, Thanks for taking my questions. Maybe, Nilo, with IRAC-4, when we get the data next year and, you know, Sanofi will make their own decision about going forward or not, but you guys will also have, well, if Sanofi chooses to move forward, you guys will have an opt-in decision. So, how are you kind of approaching the opt-in? What do you want to see that, you know, you would commit Kymera's resources to early on?

Then the value proposition for this drug in our view is as I said earlier, you'd say inactive Laurel drive with a good safety profile.

Eating in eaten indications that to be honest go well beyond H as in a D. I think these are these are obviously intriguing exciting early indications, but by no means our view is that disease, where the drug should go only.

Nello Manolfi: And how important is the kind of phase one data from STAT-6 and TIC-2 and seeing kind of the exposures you want to make that decision for IRAC-4? That's a great question and probably requires a very nuanced answer, so I'll try to do my best in the short time we have. So first, as I just said earlier, we are extremely bullish on IRAC4. Our value proposition has only grown with more data.

I think if the drug fulfilled that profile.

And we believe that the company's position to to to to to support the growth of the company. The way we see today for us would be a no brainer to too often when the time is right again, if these the drug fulfill that profiles.

Nello Manolfi: This has the potential to be one of the biggest drugs in inflammatory diseases. We have early positive data, but I think we are all here recognizing that we just don't know how active this drug is until we run a web-powered, randomized study, which is what we're doing with Sanofi. Actually, we're doing two of them.

And the reasons are very not only.

The value that can be created downstream, but the way that our collaboration is built we've done all sorts of analyses and all the analogies that we've done financially, even though it might be a bit more expensive early on in the opting phase while we're doing cozy bethmann the value creation. The backhand is so vast.

Nello Manolfi: The value proposition for this drug, in our view, is, as I said earlier, it's an active oral drug with a good safety profile in indications that, to be honest, go well beyond HS and AD. I think these are obviously intriguing, exciting early indications, but by no means is our view that this is where the drug should go only. I think if the drug fulfills that profile, and we believe that the company's position to support the growth of the company the way we see it today, for us, it would be a no-brainer to opt in when the time is right, again, if the drug fulfills that profile. And the reasons are varied, not only the value that can be created downstream.

That the that that that that decision would be so easy.

Yes, if we have successful programs with phase one, which we believe we will put Sussex and think too I mean, I I suppose that Ah cost of copies of it will be different that we can continue to sustain.

The growth of this company to support the pipeline.

So hopefully that answered the question, but that's that's how reviewing it at this point.

Okay, that's very helpful.

Thank you.

Nello Manolfi: But the way that our collaboration is built, we've done all sorts of analysis, and all the analysis that we've done financially, even though it might be a bit more expensive early on in the opt-in phase while we're doing co-development, the value creation at the back end is so vast that the decision would be so easy. Yes, if we have successful programs with phase one, which we believe we will, for statistics and TIC2, I mean, I suppose that our cost of capital will be different, and we can continue to sustain the growth of this company to support the pipeline. So hopefully, that answers the question, but that's how we're viewing it at this point. Okay, thanks. Very helpful. This question comes from... Morning, this is Brad.

The next question comes from back in you know some stifle. Please go ahead.

Marty this is Brad.

Perhaps an expansion in the prior questions really for M. D M. Two and the date of this year it'd be great to get just more of a scope of the disclosure that you expect to present in terms of patients to these types and would you flag any key data elements to watch and then just maybe to be clear on the decision making process. At this disclosure will you be in a position to outline.

Broader development thesis thank you.

So maybe it's just a high level and then I'd like to try to come in on on some more.

Specifics if it if we're willing to lose her but.

I think there is the totality of of our data about disclosure plans, which hopefully was clearing off from from a press release from our comments from Jareth earlier. So what is the totality of the day that the Italians today that is you know a large.

Nello Manolfi: Perhaps an expansion of the prior questions really for MDM2 and the data this year. It'd be great to get just more of a scope of the disclosure that you expect to present in terms of patients, disease types, and would you flag any key data elements to watch? And then, just maybe, to be clear on the decision-making process at this disclosure, will you be in a position to outline the broader development thesis? Thank you. So maybe just eye level, and then I'll let Jared comment on some more. I don't know the specifics if we're willing to do so.

You know hopefully close to complete data set from the dosage Scully shouldn't even both solid lymphomas and leukemias.

Married with a D.

The patient specification.

Worse, they were doing that should enable us to build a development program extremely differentiated from others in the space.

Thank you to those things come together.

Jared Golub: I think the totality of our data, of our disclosure plans, which hopefully was clear enough from our press release and from our comments from Jared earlier. So, what is the totality of the data? The totality of the data is, you know, a large, hopefully a close to complete data set from the dose escalation in both solid lymphomas and leukemias, married with the patient certification work that we're doing that should enable us to build a development program extremely differentiated from others in the space. I think if those things come together, and we believe we should be able to bring those things together in 2024, and if all of those are suggesting that we both have activity and also we have a, let's call it a smart way to develop this drug, I think that decision of continuing investment will be a no-brainer.

And we believe we should be able for those things become together in 2024.

And if.

All of those are suggesting that we both have activity and also we had E. Let's go to the smart way to develop this drug I think that decision of continuing investment will be a no brainer. Obviously then depending on you know nuances there the decisions can be.

But I think that's highly about the expectation I think this year you know what I hear obviously, a lot of excitement around the immunology programs and we share those those would be 2025 datasets. Many datasets impactful dataset, but I also want to make sure. We're also paying attention to.

224 day of their releases around these programs because we believe there is an opportunity here to change how we think about these target.

Jared Golub: Obviously, then, depending on, you know, nuances there, the decisions could be different, but I think that high level of expectation. I think this year, while I hear obviously a lot of excitement around immunology programs, and we share those, but those would be 2025 data sets, many data sets, impactful data sets, but I also want to make sure we're also paying attention to 24 data releases around these programs because we believe there is an opportunity here Jaron, what about patients? I don't know what we can say at this point.

Yeah, what what about patience I don't know what we have today, yeah I I mean, I think maybe just briefly elaborate you know I mean, obviously with this program you know we we do plan on providing a pretty comprehensive update you know later in the year.

As I mentioned earlier I hope it will be through dose escalation you know in both arms you know the solid tumor.

Mm arm and the he malignancy arm really provide a comprehensive update on safety P. D and efficacy you know keeping in mind again that one of the important premises here is that this is going to be very differentiated from M. T. M. Two small molecule inhibitors. We wanted to show that we have a therapeutic index that is superior to M. D. M. Two small market inhibitors. So that takes into account both superior safety.

As well as potentially superior efficacy, that's what I think our aim is to be able to show. The data set that will hopefully establish you know that we are well differentiated from emdeon too small milk inhibitors and show what the real potential is for this drug and both solid tumors and then liquid tumors into Mary that's sort of presentation potentially with a separate presentation.

Jared Golub: Yeah, I think maybe just to briefly elaborate, you know, obviously for this program, we do plan on providing a pretty comprehensive update later in the year. As I mentioned earlier, our hope is to be through dose escalation in both arms, you know, the solid tumor lymphoma arm and the hemolygamy arm to really provide a comprehensive update on safety, PD, and efficacy. You know, keeping in mind, again, that one of the important premises here is that this is going to be very differentiated from MDM2 small molecule inhibitors. We want to show that we have a therapeutic index that is superior to MDM2 small molecule inhibitors that takes into account both superior safety, as well as potentially superior efficacy.

On our patient selection strategy, which is also going to be a very important part of what we do moving forward after phase one.

Thank you.

The next question comes spot.

Securities. Please go ahead.

Yeah, Hey, good morning, and thanks for taking my question one for the for the Stat snakes and take two program.

You've shown data from their proteome study to confirm being so activity and maybe rule out the off target effects can you share how many proteins were identified in those studies, then and what the coverage right laws and that was probably on studies. Thank you.

Jared Golub: And so I think our aim is to be able to show a data set that will hopefully establish that we are well differentiated from MDM2 small molecule inhibitors and show what the real potential is for this drug in both solid tumors and liquid tumors. And to marry that sort of presentation potentially with a separate presentation on our patient selection strategy, which is also going to be a very important part of what we do moving forward. That's fine. Yeah, hey, good morning, and thanks for taking the question. One for the for the STAT6 and TIK2 programs.

So we'd run.

So we're not gonna share.

Any more data today on that program and we're going to be to be honest quite sensitive about what else. We're gonna share just based on we want to maintain a competitive advantage year, but that doesn't mean I'm not going to answer your questions. So we have high proteome coverage in these studies, we usually you can detect north.

There'll be 11000 proteins in every.

Proteonomic study and what we do it came era, we actually look across several said types. So what we've shown I believe we're P. B M Ts.

Nello Manolfi: You've shown data from the proteome study to confirm the selectivity and maybe rule out the off-target effects. Can you share how many proteins were identified in those studies and what the coverage rate was in those proteome studies? Thank you. So we run, so we're not going to share any more data today on that program, and we're going to be, to be honest, quite sensitive about what else we're going to share just based on the fact that we want to maintain our competitive advantage here. But that doesn't mean I'm not going to answer your question.

Because we believe are you know one of the more relevant for the B C. C. As we're going after but in order for us to actually be covered the whole proteome, which is you know 18 to 20000 proteins roughly hopefully hygiene.

You can get a round number here. So we actually go across many setbacks. So that we actually called 100 per cent of the proteome and the picture that you've seen in our lives. This consistent we only really degrades the seats and I would say we are really really bind does that seats.

Nello Manolfi: So we have high proteome coverage in these studies. We usually can detect north of 11,000 proteins in every proteomic study. And what we do at Kymera, we actually look across several cell types. So what we've shown here, I believe, were PBMCs because we believe them to be one of the more relevant for the diseases we're going after, but in order for us to actually cover the whole proteome, which, as you know, it's in the 20,000 proteins, roughly, hopefully I didn't..., didn't get a round number here. So we actually go through many setbacks so that we actually cover 100% of the proteome. And the picture that you've seen in our slides is consistent. We only really degrade STAT6.

And that's true also for the team to program.

For the airport.

Okay, great. Thank you.

Alright, I can keep going yeah, thanks got bidding.

Thank you.

Okay I'm from Andy check.

But it was pretty such please go ahead.

Hi, This is Anna.

I guess.

Two.

Just how much.

Yeah.

Something like that.

I didn't notice weakness differentiations of yours.

The weekend, sorry, I didn't hear very well, so I mean, as we said before there.

There are several layers of differentiation Ah Ah. So there is first did that small molecule inhibitors. These or other steric any visitors there actually block also this guy and he's function and some of the Sky falls function.

Nello Manolfi: And I would say we only really bind to STAT6. And that's true also for the TIC-2 program, and for the Eric book, and for this presentation. Sorry, I can keep going. Yeah, thanks. The other question comes from... and Emma Anderson, for taking our questions. I guess. I want to work here.

But not the fool Scott folding function and so the actual phenotype of small molecule, even though those Derek theater.

He's closer to kinda is any better than to the loss of function profile.

We have a sliding aren't that that shows you with the pluses and and the shows where is the kind of his dad versus lots of function of his wife died and only a degree there marries matches sorry, the loss of function profile, which basically means we block out twenty-three as well.

Nello Manolfi: Inhibitors on the market and just how much headroom there is for them, for information, and Frank Schmidt. Ah, the weakness. Sorry, I didn't hear you well. As we said before, there are several layers of differentiation. So there is first that small molecule inhibitors, these are allosteric inhibitors that actually block the kinase function and some of the scaffold function but not the full scaffolding function. And so the actual phenotype of small molecule, even allosteric inhibitors, is closer to the kinase inhibitor profile than to the loss of function profile. We have a slide in our deck that shows you the classes and shows where the kindest dead are versus loss of function versus wild type.

One interfere in his spare time.

So the compiler is approved the drug that was approved right now.

Which is a an almost derek and he'd be there that actually is not as selective.

It actually impacts also Jeff one and so also impacts Io Tan, which is a big detriment four G. I N vacation. It's also not very selective so they had to play around with the doses in order to eat the target Ah at a reasonable target engagement other molecules in the clinic.

Nello Manolfi: And only a degrader matches the loss of function profile, which basically means we block L23, L12, type 1 interferon and spare IL-10. So the compound that is approved, the drug that is approved right now, which is an allosteric inhibitor that actually is not as selective, it actually impacts JAK1, and so it also impacts IL-10, which is a big detriment for the GI indication. It's also not very selective, so they have to play around with the doses in order to hit the target at a reasonable engagement.

More I would say, maybe a higher selectivity profile, but they're not able to block what was described folding function and match the loss of function profile and we believe that by blocking the pathway fully we should be able again as we've shown we start six we've shown with Eric for once you you are you fine.

The mode of food pathway blockade, you should be able to match the upstream biologics so diaz twenty-three biologics.

Nello Manolfi: Other molecules in the clinic have, I would say, maybe a higher selectivity profile, but they're not able to block all of the scaffolding functions and match the loss of function profile. And we believe that by blocking the pathway fully, we should be able, again, as we've shown with STAT6, and we've shown with REC4, once you find the mode of full pathway blockade, you should be able to match the upstream So the R23 biologics, the type 1 interferon biologics in a single oral molecule. So how is that going to translate in the clinic? You know, we don't have a number, right? So if you look at biologics in psoriasis, they reach, you know, close to 90% of Pi D75, for example. Small molecules don't get there. They get into the 60s and 70s, maybe, yet still pushing into the mid-70s.

[noise] type one interferon biologics in a single or a molecule. So what does that what is that going to translate into cleaning.

You know, we don't have a number right. So if you look at biologic seemed Verizon is they reach you know close to 90%.

Ah Ah Ah five G 75 for example, small molecules don't get there they got into the sixties seventies maybe.

Yeah pushing into the mid seventies.

So maybe that is a god that we can feel but I think that the actual extent of.

Oh gosh, they were gonna be feeling with a degree there we have a goal of biologics, but we actually don't know it might be even superior or maybe be I'd be even.

Even slightly inferior I think that is it clean evil experiment that we have to run.

Oh, we're saying here is that biologically we have a differentiated profile and we have confidence that that will clinically resolved in a meaningful the certainty of the drug.

Nello Manolfi: So maybe there is a gap that we can fill. But I think that the actual extent of the GAP that we're going to be filling with our degrader is a goal of biologics, but we actually don't know. It might be even superior, or it might be slightly inferior.

Okay.

Thank you.

This country Whatsapp question and answer session.

I would like to turn the conference back where where it's not just him.

For any closing remarks.

Mmm cantilena on behalf of that kind of maroquin, we'd like to thank everyone for joining us. This morning, and look forward to keeping you updated on our progress in the meantime, please don't hesitate to reach out if there are any additional questions. Following today's call. Thank you.

Nello Manolfi: I think that is a clinical experiment that we have to run. All we're saying here is that, biologically, we have a differentiated profile, and we have confidence that that will clinically result in a meaningfully differentiated drug and the New York Times. Thank you. Thank you. Thank you, and on behalf of the Kymera team, we'd like to thank everyone for joining us this morning and look forward to keeping you updated on our progress. In the meantime, please don't hesitate to reach out if there are any additional questions following today's webinar. Thank you. Goodbye. Southern Illinois University-Singapore,......... Learn more at allsafes.com www.microsoft.com.au, Reed Newman, Rhoda Clark, David Elder, Jeremy Loftus, Rex Anderson, Jeff Hoglan, Richard Berton Justice, Michael Moran, Wayne Brown, Matt Johnson, Max Handler Effects Camera

Thank you.

The conference.

Judy.

Thank you for attending today's presentation.

[noise] disconnect Goodbye.

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