Q4 2022 Kymera Therapeutics Inc Earnings Call

Hello, and welcome to that high Merit Therapeutics Fourthquarter 20 twenty-two earnings conference call.

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I would now like to turn the conference over to Bruce Jacobs Bruce. Please go ahead.

Good morning, everyone and welcome to the primary Therapeutics quarterly conference call I'm, Bruce Jacobs, Chief Financial Officer came here and I'll be joined today by an element of the founder President and CEO and Jared Golf R. Chief Medical Officer. After our prepared remarks will open to call to your question to ask a question. Please press star one on your telephone keypad.

<unk> is that it.

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Where we get started I would like to remind everyone that some of the comments that management may make on this calling could forward looking statements as outlined in the press release actual events the results to differ materially from those expressed or implied by any forward looking statements. As a result of various risks uncertainties and other factors, including those set forth in crime areas. Most recent filings.

C C and any other future buying that the company may made with the SEC you caution not to place any undue reliance on those forward looking statements and kind of marriage disclaimed any obligation to update such statements, except as required by law with that said I'll know hand, the call to now.

Thanks, Bruce and thank you everyone for joining us today I thought I would spend a few minutes. This morning, reflecting briefly on the importance of those the progress we've made in 2022.

And what we believe it means we are ambitious objective to be the best in class fully integrated global magazines company.

2022 was exceptionally important year for okay mirrors evolution with dose healthy volunteers patients with HIV and Andy which is the first time for a degree during immune inflammatory indications patients with lymphomas leukemias and solid tumors with their first three investigation on drugs.

We've seen now across three program strong translation of our preclinical P. K P. D <unk> into the cleaning. This is a substantial accomplishment for a company there is pioneering a new modality in.

In addition, we've seen for the first time clinical benefits. So the head drove by functional it'd be greater any meaningful amateur indications and the first proof of concept clinical differential all the greater versus a small molecule indeed deserve without <unk> baseline data.

In fact, Casey 474 clinical data that we shared late last year from the patient cohort of the phase one study for a degree there exceeded our expectations, we were able to replicate the P. K P. D profile of the head people into your portion of the trial Chesney D patients.

The molecule was generally well tolerated with no serious adverse events, including a resolution of the Qts's Act, we demonstrated an encouraging impact on disease, rather than inflammatory biomarkers in <unk>.

And we were able to produce some early but really encouraging signs of clinical activity in H S. D. Patients that we think represent strong reasons to believe in the clinical potential of effectively dragging the <unk> and in our Degrader molecule and of course lastly, we reported at our partner son of the schedule.

<unk> they will initiate phase two studies in 2023.

Jen would share a little bit more on this call regarding the next steps toward the program, but obviously this was an important milestone for K T 474, a molecule that we believe can I have a unique in broad role in raising the standards of care in a wide variety of inflammatory conditions.

Assuming the molecules profiled remain consistent as we tested in larger studies and.

An additional patient populations, we believe a small molecule with the emerging efficacy and encouraging safety profile.

Could be a best in class Mendocino crossed several diseases and this year. We're excited for our partners sanity to initiate the <unk> studies initially NHS, followed by a D and potentially other indications.

Perhaps somewhat overshadowed by the <unk> four results, we made encouraging progress in our first do clinical stage oncology programs K T 413, the Iraq commute Degreaser NTT 3333 degrees.

Both programs are currently in the dose escalation phase of the phase one clinical studies in December we disclosed pharmacodynamic activity in both blood and tumors and knocked down of their targets without any of those limiting toxicity.

Importantly, we've seen to be there'll be a translation of <unk> from preclinical profiles into this clinical settings further validating our work and highlighting our ability to replicate approach to discovering and developing high value molecules. The.

Promising initial data from this phase one trials physician us to share data later this year that we hope will show a clinical activity, particularly when we reached the expected active dose levels in our targeted patient populations.

Taken together, we believe that these results represented validation of R&D approach and strategy. Since we started the company over six years ago now our founding principles remain unchanged harness the transformative potential of targeted pulling the relation to address areas of significant therapeutic need and improve pay.

<unk> slides.

With this goal in mind, we've made very intentional choices, which we believe represent a differentiated approach to designs in many key areas, including target selection strategies disease area of focus cutting edge platform investment and corporate strategy.

This strategy and approach in conjunction with a clear focus on this is targeting areas of significant patient need that.

That can't meet meaningfully addressed by traditional medicine has led us to targets in markets, where protein degradation is the only or the best way to elucidate the discharge biology or clinical outcome.

I hope that as you reflect in the totality of the day that we presented in December and our progress in building. The company you share our belief that we evaluated the work and investments we've made over the.

The past seven years, almost seven years, resulting in the high quality of the molecular design and platform capabilities and a proven ability to translate our understanding of disease biology, PK Pgn's safety from preclinical models into patients, creating high value program that have the potential to become important to new <unk>.

Before I end the call over to Jareth I should mention that the three programs that just discuss they're just the beginning for camera at the end of last year. We also announced that the SDA ahead clear disd for our our our MDM two degrader K T. Two 503.

MDM too is crucial regulator of the most common tumor suppressor P 53, which remains intact in close to 50% of Kansas.

<unk> will shed more on our plans for K 253. Shortly we also hinted at several other programs in our early stage pipelining, both oncology and immunology indications earlier in the year.

Evidence of the productivity of overdraft discovery engine.

<unk> been fueled in part by innovative computational research tools that have enhance our understanding of disease biology and allows us to develop new ways to harness TPB.

In addition to leadership and the discovery of.

Hedrick Bifunctional Degraders. We are also identifying novel molecular groups that expanded therapeutic applicability of our platform and we hope to share more on this later.

Later in the year as well.

Along with our clinical and scientific progress we work to ensure that we have.

People and resources to build our company's sustainably where.

We recently recently appointed LNG in Euro as Chief legal officer in corporate Secretary, whereas shoe serve as a key member of our leadership team Ellyn joins us from our excellent pharmaceuticals with extensive experience overseeing legal activities that biopharmaceutical companies ranging from discovery phase through commercial.

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This month this month, Rebecca moisture joined us as our senior Vice President of translation a magazine from Montana Therapeutics. She.

She previously held positions of increasing responsibilities in translational medicine translational research and molecular pathology at Novartis, both texts and Millennium. We also recently appointed Juliet Williams came errors new head of research. Juliet was previously are ahead of biology contributed profoundly to our target selection.

<unk> strategy and drank discovery efforts. She has more than 20 years of drug development experience, including leadership roles that Nevada to sanity millennium and curious.

These important roles will have Chimera navigator next stage of development as we work to bring revolutionary be created therapist to patients.

Finally, we ended the year in a very solid financial position with approximately $560 million in cash and.

And expanded runway into the second half of 2025, which will allow us to continue to invest in our clinical programs discovery pipeline and platform and importantly allow us to read out Eric for Phase two proof of concept study an initial proof of concept for this tree oncology clinical programs Jared will now call.

More details are recent progress for each of our disclosed programs before returning the call over to Bruce for financial update I.

I will then finish with some concluding remarks, including covering our key goals for 2023 before handing the call to the operator for a Q&A section in with Jared bruising myself.

It will be available.

<unk>.

Thanks Miller.

I'll provide a brief recap where we stand with our clinical programs and what to expect in 2023.

I'll begin with Iraq for program.

As you all know in October we announced the completion of dosing of the patient cohort portion parts C or a K.

474 phase one clinical trial.

And we shared the full data set in December .

I won't go over all of the data here today, but if you are interested you can find the replay of our December meeting on our website.

The data are also included in our updated corporate presentations.

That said I did want to share our expectations for the progress of the program in 2023.

As you know <unk> will be taking K P 474 interface too.

Just as they were closely involved in the phase one trial that primary Iran.

<unk> jointly discuss the plans for the phase II program.

As we shared in December sanity is committed.

In phase two trials and at least two initial indications.

Getting with Hs and followed by 18.

As for timing it is too early to guide to the expected phase to start date, but <unk> said in the past at least the first phase two is planned to start in 2023.

Turning to our oncology pipeline.

Update everyone on our disclose programs, which include our staff free Iraq commit an empty emptier graders.

Focusing first on our new trial activity.

K T. Two five III, our MTM to the greater received clearance from the FDA in December .

And we have two is the crucial regulator of the most common tumor suppressor 53, which remains intact and close to 50% of cancers.

Hi, Mara is developing a highly potent MDF to the greater that unlike small molecule inhibitors has been shown preclinical to have the ability to overcome the mdm's feedback loop and rapidly induce a bob ptosis, even with brief exposures.

80, 253 has the potential to be effective in a wide range of hematological malignancies, and solid tumors with functioning or wild type hundred 53.

We plan to initiate dosing patients soon and the phase one trial of K 2253.

The phase one study will evaluate the safety Tolerability pharmacokinetics dynamics.

Amex and clinical activity K T 253 in adult patients with relapsed or refractory high-grade myeloid malignancies acute lymphocytic leukemia.

And solid tumors.

The open label dose escalation study is intended to identify the recommended phase two dose it.

It will be comprised of two arms with a selling doses of K two five III and each are the.

The first arm will consist of patients with the farmers and advanced solid tumors and the second arm will consist of patients with high grade myeloid malignancies, and a L. L.

Now turning to our two ongoing oncology trials.

Battery transcriptional regulator that has been linked to numerous cancers and other inflammatory and autoimmune diseases.

Our phase one clinical trial is evaluating 80, 333 as potential and Hematological malignancies in solid tumors.

Specifically the trial is evaluating the safety Tolerability TK PD and clinical activity of K T 333 in adult patients with relapsed indoor refractory lymphomas and solid tumors.

We reported on the first dose level in December showing initial proof of mechanism for staff, three degradation and tbms C and no dose limiting toxicities.

With good translation of PK Apd preclinical models patients.

Based on the peak Apd, we have shown to date with robust target knocked down for 72 hours followed by recovery, we expect to be at efficacious doses by those double three or dose level for.

This year, we expect to show clinical impact of statuary degradation on tumor burden and the target patient populations such as peripheral to sell a former cutaneous diesel lymphoma in LG leukemia.

The trial's second stage will consist of phase one b expansion cohorts to further characterized safety colorability kpd and anti tumor activity of K P 333, and relapsed refractory safrit dependent piece of malignancies as well as in solid tumors.

And finally, our <unk> program K E 413 is a novel hetero by functional the greater that targets degradation of both Iraq, four and the image substrates, a gross and islands, but a single small molecule.

80, 413 was designed to address both the iowan RTR and type one interferon pathways synergistically to broaden activity against <unk> 88 mutant Decelle malignancies.

80, 413 is on a similar timeline is that three and is currently in the dose escalation stage of the phase one trial evaluating the safety Tolerability Kpd and clinical activity of Katie 413 patients with relapsed <unk> refractory diesel non Hodgkin's performance.

We reported in December that the first two dose levels have been completed showing initial approval mechanism with Iraq for a growth and ilo's degradation and Pbms C and tumor and those safety signals with good translation of TK PD from preclinical models patients.

We are continuing enrollment and expect to be at applications doses by dose level, three or dose double four.

And as with K D. 333 later this year, we expect to show clinical effects of Iraq, and the degradation tumor burden and Mighty 88.

Missions.

The trials second stage will consist of faith in the expansion cohorts and <unk> to further characterize the safety Tolerability PK ped anti tumor activity of Katie for Winfrey, and relapse refractory Mighty 88, and 88, while type WCF.

We look forward to sharing more progress on these programs throughout the year.

I will now hand, the call to Bruce who will share some brief comments on our financial results for the fourth quarter.

Jared I will quickly cover the financials before turning to call back to <unk> for concluding remarks for the quarter, we recognized $16 $1 million of revenue. This total refracts reflects revenue recognized pursuant to our sanity and vertex collaboration.

At the end of the quarter are deferred revenue total on the balance sheet was approximately $63 million that reflects partnership revenue, we expect to recognize over the next several years, excluding the receipt of any potential future milestones.

With respect to operating expenses R&D for the quarter was $43.1 million of which $4.5 million represented non-cash stock based compensation digested cash R&D span of $38.6 million, excluding sock based comp is essentially unchanged from the comparable amount in the September quarter are G&A spending for the quarter was 11.6 million.

In which four $4 million represented non-cash stock based compensation, the adjusted cash G&A span of $7.2 million, excluding stock based compensation reflects a 13% increase from a comparable amount in the September quarter. Finally on cash we exited the fourth quarter with the cash equivalents balance of approximately $560 million.

As we shared earlier in the year, we believe that our cash runway extends into the second half of 2025, a projection that now includes milestones related to the phase two start I'll now turn the call back tomorrow.

Thanks, Bruce with our accomplishments last year, it's clear that came errors made considerable progress in its evolution and begun to demonstrate the incredible potential of these modality.

Company to make a meaningful difference in patients lives were.

We're excited to have the opportunity this year to assess the impact there were four program may have for patients with cancer and immunological conditions and to further demonstrate the potential advantages over technology and platform have over traditional medicines will feed that we're just getting started and energized by the opportunity we.

Have in front of us.

I said earlier 2023 will be a busy year, we have a lot that we expect to achieve much of which was discussed earlier in the call, but just to quickly state are key.

2023 goals, we will collaborate with <unk> to initiate the first <unk> study. We're also working to publish the results of the phase one trial.

In a top tier journal, we intend to evaluate the effects of our Iraqi meat instead three programs on tumor burden in patients in our phase one studies, we plan to initiate the key to five <unk> Trialling solid then hematological tumors in order to demonstrate pupil mechanism in patients and with respect to our pipeline our objective.

Two delivered at least two new <unk> from the preclinical pipeline and also continued to our expansions of our novel Molecular grew franchise at this point I would like to thank became era team as well as our partners and the patients participating in clinical trials and for sharing this journey with us.

Finally, thank you all for your for participating in our call and I look forward to your questions I will now hand, the microphone to the operator, so that we can take your questions.

Thank you.

At this point, we will open the cost of questions. As a reminder to ask a question. Please press one on your telephone keypad. If at any time, you would like to Ah Jonathan the queue. Please press star tale based.

We will now take a moment to review Ikea.

Today's the first question comes from Eric Joseph That's J P. Morgan. Please go ahead.

Oh, Thanks, good morning, and thanks for taking my questions. Just a couple of questions on the M. D. You have two program if we could I guess first what is.

Can you lay offs, what perfect mechanism looks like with Casey 253 later this year and does it.

Look slowly and liquid simmers episodes in solid tumors and then secondly.

With respect to the anticipated a profile with the drug.

Do you anticipate any differences I guess relative to.

Competitor M. Two inhibitors, particularly on the aspect of miles depression any potential this sort of reduced rates of great free neutropenia with this Comcast. Thank you.

Thanks, Eric So I'll I'll start and then.

<unk> come in more on the proof of Mexican news, but maybe I'll take the second question first just because actually points to the core thesis for our investment in the <unk> program, which is creating or.

Allowing us to create a larger therapeutic index that will allow us to finally interrogate these macanese beamed to clean the fully.

And as you heard this setting the past the rationality.

Really based on concert genetics, if you look at data that has been published over the years and that has fueled all the drug development programs. In this pathway, we know that P 50, threes Wi type.

In more than 50% of cancers in those type of cancers, both live within solid tumors. If you believed MDM too if you're genetically belief MDM too we genetic tools that we have the prequel uniquely you see a high dependency of these tumors.

These tumors on the spot where all the presence or absence of MDM too and that basically genetic removal of MDM. Two leads to rapid response in those tumors that have P 53 wildlife.

And if you look on one of those plants that have been generated it's probably one of the most impressive sensitivity.

Plus that we've seen in concert.

Now I think the field has made the assumption and that has been true for many programs.

College, you have in the past 20 years since we started to understand the human genome in the relationship with the human Proteome, we made the assumption that any bidding MDM two will lead to that kind of response and what we've learned is actually that's not true. We've learned that if you inhibit MDM two P 53 interaction.

You are able to actually stabilize b 53, but not fully and mostly because the inhibition of that interaction leads to the upregulation of MDM too so as you're inhibiting the interaction you see more MDM two digits produced and the small morula has a hard time finding that.

So you end up having to those longer and that creates a very narrow window. If at all between your antitumor effect in your impact on bone bone marrow derived sales, which are one of the most sensitive cell types to MDM two options, we have been able to do with degrading.

Two is to remove the protein quickly and we've seen the first two to four hours. It rapid commitments were both doses and that lead concert says there are sensitive to these mcnamee to die quickly while healthy sales.

While they might have an initial impact have time to recover between the first and the second dose.

And so that creates in tumors that are highly sensitive I would want to be sure that is clear.

Therapeutic index, then no small molecule as seen before in our hands.

So what we're talking about and I think Jared comment on it before and this is work that we're still doing obviously I think it's not fair to assume that at all.

53, wildfire tumors will have these why they're therapeutic index I think thats scientifically not true based on our experimentation, but we have found subsets of tumor types within the <unk> larger.

There are highly sensitive and the ones that are highly sensitive.

These increased therapeutic index. So alright positive is going into the clinic is that we will have a drug that is well tolerated.

While it's being effective.

In the patient populations that are sensitive sweet the only indications that we have shared so far we've seen these high sensitivity.

Our AML, including the patients that are refractory to.

The existing line therapy. So that's an exciting area for us to explore lymphomas and some solid tumors that we will be disclosing later in the year or as we go into the expansion cohort.

So maybe I'll, let Jared common moron.

The proof of mechanism is going to look like and whether I think your question was also whether it's going to be different between leave within solid tumors.

Okay, maybe if I could just quickly comment I'll also on [noise].

The question around mindless oppression.

Fact that we have this unique mechanism of action that never laid out.

Just a dose infrequently given given the drug is an Ivy infusion. Once every three weeks and that is a frequent dosing. We think is going to give us. This.

Unique therapeutic index that will allow us to mitigate milo suppression by allowing plenty of time for normal cells in tomorrow to recover in between doses.

Coming back to proof of mechanism our aim for showing through the mechanism at least this year is to focus on impacting the empty M. Two P 53 pathway and peripheral blood mononuclear cells, which we can do essentially and all of the patients on the study we've done this with our prior programs for 13333 looking at <unk>.

On the targeted Pbms C and we're available in tumor as well now here I think in the empty of tuesday's when the trial. The initial focus will be Pbms C. And then I think when there is tumor available for biopsy or once we're in RMB, where we're treating high grade myeloid malignancies, including Anl. We may have more opportunities there to also show impact on the path.

Uhm in malignant cells, including leukemia.

The next question comes from <unk> with you B S. Please go ahead.

Hi, This is kathleen on the line for Alley, Thank sandwich tried taking <unk>.

So you can match thing you're working correctly.

A couple of questions are and.

My perspective.

Could I, please and can you spell that first thing I'll try get 15.

<unk> and then second.

Basically this is there something you think could be feasible over the next few years <unk>, okay. So for Ya.

Okay.

Thank you further question.

Great question, because it allows us to talk about I think one of the key differentiator for this company, which has always been to go after heart problems. So as you've heard that.

Your team is paid a lot of attention to what we said in the past and boost on this particular topic. We've said that we are using molecular glues to go after problems that drove by functional it'd be greeters cannot solve.

Maybe just a step back without a drove by functional degrees of solving for solving for Android or poorly drug targets, where you have an ability to bind to that particular disease, causing proteins and we've shown that you can go after transcription factors, Scott Bolden protein et cetera. So.

There's plenty of targets out there that obviously hetero by functional degraders can solve meaningful clinical problems.

But there are also many validated targets.

Caller gene immunology and rare disease in cardiovascular and CNN.

Where you don't have an opportunity to find discrete binders to those proteins, mostly because those are let's see ah disorder proteins or difficult to Lincoln proteins, and so you either choose not to go after them or you choose to build capabilities to go after them and we chose.

Again, the hardest part which is.

Developing technologies to go after them and so we take in need three legged agnostic approach.

So yes, the answer to your second question is yes, there will be molecular glues that Don new cellphone.

And in fact, I think there are already examples out there.

They are in the literature pointing to those possibilities.

We take as I've always said in the past the transmission on magazine approach. We think about what are the clinical problems. We're trying to solve for and what are the molecular mechanism that will enable us to do that and so now I have to give again.

Kudos to our team by Juliet and others in our platform.

Team that have uncovered.

Actually an overview.

You as of proteins that we can go after using a completely new <unk> <unk>.

<unk> that we can engage with with.

<unk> and we deal with some molecular designs that we've made.

And it turns out that these proteins that we've already identified that are multiple key on drugs begun the bulk protein many of whom are in immunology and some some are in oncology.

And I think it's unlikely that we will be disclosing the molecular mechanism because we feel this could be.

The beginning of a completely new era of molecular glue I would kind of look back at when he made and setup onwards discover then how many targets that then subsequently been drug by that interaction I.

Suspect that we've uncovered here could lead to that type of discoveries and so.

We're just at the beginning we're very excited.

Where first program there is already already lead optimization.

Driving towards the development candidate and.

It will continue to talk about this as the program moves into development will talk about with targeted is probably unlikely that will reduce closing the molecular mechanism or even the three legged.

The next question comes from Brad <unk> with Stifel. Please go ahead.

Good morning, and thanks for the updates to questions from me first no I guess the recent announcement for the the parts of the global head of R&D, etc, John Reed and the company's searching for a new successor I'd just like to hear your optimism that Katie 474 has enough as advocates or champions so to speak at Santa fee So that.

The program there continued to be prioritized, even with any future shakeup of portfolio strategies and initiatives from a new R&D head.

And then for Jared on K T 413.

Can you remind us the type of DLP sale patients that are being recruited in terms of likely prior therapies are these patients post <unk> carty by specifics et cetera.

And if so what is your confidence in the ability to recapitulate. The preclinical model results in such a heavily appreciated population, particularly with a mighty idiot mutation. Thank you.

Great bread there was the perfect questions for our colleague that benefits, so I will try and answer it.

Obviously understanding that I cannot speak for for for for them. First you gave me the opportunity to thank John that has been an amazing partner along the way from the.

The beginning which was when we started to talk about a partnership.

K T 474, all the way through his last day I will say that we've.

We've had the fortune to connect with several leaders in the company without naming names at the executive level that have continued along the way.

To be excited to be.

Helpful to be supportive of the partnership and understanding and appreciating the value of 474. So again speaking pro camera I have no doubt that the the molecule is in the right hands and there is the excitement commitment and appreciation of what this molecule can do for.

To be honest millions of patients out there and I expect that there will be no change of priorities are commitment going forward.

Regarding the second question again, I'll leave it to Gerald to answer.

Yeah. Thanks Brat on the 413 study.

Recruiting vsel malignancies, including DLP, CL, and including patients we might be 88 mutations.

<unk> noted.

Many of the patients will have had prior therapies and we anticipate that many of these patients will have had and especially if they had the L. D. C. L. Perhaps pyre carty, if they were eligible maybe prior policy or by specifics.

Or even <unk>, but I think what's important to note is our unique mechanism of action. The fact that with forward three were drugging IraQ4 and we're also dragging the iron for pathway with the image activity.

It makes us a unique mechanism of action and so we don't expect there to be cross-resistance to these other therapeutics and lifestyle if therapies are liked by specifics.

So I think we're confident that with the right patient population, especially those with a mighty 88 mutation sort of regardless of prior therapy is or how many prior therapies, we still expect that the mechanism of action here should yield.

Significant as a tool responses with 413.

The next question comes from <unk>, That's Morgan Stanley . Please go ahead.

Hi, good morning, Thanks for taking our questions. So we have two one on 474 and then one on.

You sat three program.

So going back to your relationship with Saffy.

Wondering if you could provide some more color on what are some of the considerations that you were thinking through with sad. If you when you explore indications beyond H as in 84 faced development for this molecule and then forced at three.

Just curious to get an update on where efforts stand with.

I'll be waiting a stat, three to greater and autoimmune and far broader conditions and when we could expect to.

Here, an update on that effort.

But thanks Vikram so first.

First question is.

What we've done so if you actually look historically, how we developed the molecule and this program.

There is a slide that actually we haven't changed in a couple of years, and our deck, which which are clinical opportunities that could be.

Realized by targeting the <unk>.

Usually.

Sure. These kinds of th <unk> th 17, driven diseases like Hs like a ray like lupus IBD and others and then.

On the th two type species.

Like the asthma.

COPD and others.

And we said that with Validations macanese in some of those diseases, representing kind of this too.

Slightly kind of differentiated ways to thinking about immunology, then you can think about expanding.

And so I believe that the high level.

Both Saturday and came here looking at the opportunity.

That way now practically.

We have prioritized as you know H as in a D and we've been fortunate I have to say that even with small patient numbers in a in a in a in a study design land and even study design generally that was not set up to look for clinical activity we've been fortunate.

To have seen really early validation of this mechanism in both a chat again <unk> the th two typed inflammation.

You know obviously, we look for further validation and a placebo controlled randomized phase to study and we go into these we do this study with high degree of confidence and expectations based on the data we've seen so far so I I do conversations that obviously are happening and will continue to happen to us.

The next type of indications that we will go after what I will say that I can't again speak further collaboration in terms of particular indication what I will say from our perspective.

From my perspective, there is such a high unmet need and many of those indications where there are really no small molecules.

With the activity and safety profile that we can merge with Eric four degree there obviously are stocked with a D. I don't think there is one going to H S. I don't think there is one that I go to IBD large unmet need I don't believe there is a good molecule now that can can really help patients.

Going through that horrible.

Experience I look at our Rey, which is commercially quite crowded, but again I don't I think there is an opportunity for a for a web tolerated active drug, but I look at <unk>, which is an unsolved disease and then I look on the other side on the th two type inflammation again really no.

Small molecules in those indications that I mentioned earlier like like asthma or COPD.

Providers and others. So I think we have a large opportunity I think we have to be rational with how we select few opportunities and we have to be data driven.

I suspect we will be updating you all has we make those determinations and clearly initial proof of concept and the randomized study in phase two will be the drivers of that of the of those.

Further selection downstream of this initiative to diseases, but I think we have a unique opportunity here in the landscape to have millions of patients as I said earlier.

Let's not forget and I don't want to spend the whole.

20 minutes on this but let's not forget that the unique value proposition of <unk> that this is a systemic inflammatory molecules with broad anti inflammatory effect with local employment with local anti inflammatory.

Also affect.

The molecule has demonstrated systemic anti-inflammatory efficacy as measured by the ulcer biomarkers.

Across a wide variety of downstream cytokines in chemo behind is also shown as you know a preferred.

Distribution and tissues, especially as you seem skin.

As well as as we know and <unk> activation.

Anti inflammatory effect. So has this was really unique combination of both molecular properties as well as the pathway engagement properties that makes it very unique molecule in the landscape. So.

We're excited to continue to develop the molecule to explore further how many other diseases. We can we can potentially develop it and.

The other question.

Yes, so is that three.

I said.

Relatively recently that there is an area that we are continuing to do work.

We plan to being able to update further later in the year I can maybe share more than what we said recently.

The next question comes from Michael Smith.

<unk>. Please go ahead.

Good morning. This is Paul I'm from Michael and Thanks for taking my question. We just have to on the MGM two program I guess first on the dosing strategy.

Is there a potential in this study to evaluate alternatives dosing interval, that's essentially optimize the clinical profiling 253 between fallen versus liquid tumors and talk with images and take Apd in those settings are you fairly comfortable with the basically the same across all super tight.

And then secondly, obviously, you're just starting logged therapy does escalation, but how are you currently thinking about the strategy for 253 and combinations. It seems like they're coming out of ash that are competitive.

Combination might be on the table for and now I just wanted to be with US here. Thank you.

Thanks is a great question, maybe judge you want to take them.

Sure Yeah, maybe starting with the with the dosing schedule.

As you stated upfront we are going in without once every three week IV infusion uhm, which we think.

The potential to be highly active based on our preclinical.

Models, but also has the ability to mitigate miles depression we.

You have flexibility based on our preclinical talk studies to dose.

Less frequently even every two weeks if we thought that was necessary. Your question is an interesting one could.

Could we ever additional situation, where you might have one scheduled for liquid tumors and one for solid tumors, that's always a possibility.

And I think we do have that flexibility our plan right now is our expectation rather is that everything dosing there'll be activate both liquid and solid tumors, but but at least we do have that flexibility to those less frequently if we think it's necessary from a stomach with AMIC standpoint, and if we think that it would be tolerated from a safety standpoint.

In terms of combinations you know that's obviously a very good question as well you mentioned the need a class you know we've been doing some I think very interesting preclinical work I'm looking at our drug.

<unk> resistant insensitive AML models, and we can see activity of our empty up to the greater as a motto therapy, even in the cracks resistant models, which is very encouraging for the possibility of are seeing activity with our drug in patients with previously seen for eight o'clock Tonight, you know more and more patients are getting Benito clacks either in the upper.

<unk> setting or in the relapse refractory setting, but I think we've also seen some very encouraging data with our drug combined with benita <unk>, either <unk> resisted or venetoclax sensitive AML. So I think we will have the opportunity to look at that combination I think that will be probably one of the combination that we do prioritize what's we're through with monotherapy.

Ah dose escalation have a good sense for the safety profile and then start to look at combinations that we can use for development in the future, but I think I think I want to be clear that I think we do feel that the activity received preclinically is such that we believe that there's a substantial opportunity for <unk> to greater as a mono therapy and both liquid tumors answer all to read but I think these.

Combination approaches always give us even additional develop a opportunity that we want to take advantage of.

The next question comes from <unk> from.

<unk>. Please go ahead.

Hi, Thanks for taking my question, maybe just pulling up a MDM to some of the same questions.

What is the target degradation profile, you're <unk>, you're aiming for in terms of per cent reduction but.

Yeah, given all your saying about kind of therapeutic window, just at least as important as the duration of that degradation.

Yes, Martha thanks for the Great question. So what we've seen pre clinically is that the degradation.

Bob 80% 80, 90% for really a short period of time, even two to four hours.

Easy enough to lead to these really profound apathetic responds.

And that's why I actually would design the type of drug with this type of dosing paradigm, where we'd those at Ivy.

We are able to reach these really high quick.

Quick.

<unk> initially that leads to quick downregulation, and then clearance of the drug relatively quickly so that we can optimize on.

Big relation of the target in tissues that are highly sensitive.

So that we can capture maximal antitumor effect and then we can kind of peak the time for has to recover before we those again actually monitoring.

The the MDM to dig relation in pathway engagement.

A large piece of work that the team here has done even actually the complexity of the pathway and also how to measure MDM two levels, which are initially already relatively low so.

So it's it's actually also some really innovative signs that we've done here at K mirror to monitor and to understand those are getting engagement in terms of MDM to dig relation, but also downstream biomarker readout, which for us that are just as critical scene.

Seeing.

Biomarker, either increase or decrease downstream is what really drives that kind of antitumor effect. So I think part of that puku Mexican using data that charge was mentioning.

That will share hopefully this year at least the obviously that's the goal and plan will will obviously have.

That type of information that targeting engagement time of targeting engagement and and also safety there we'll go with that.

The next question is from Mike Kratky with S. VB Securities. Please go ahead.

Hi, everyone. Thanks for taking our questions for K T 413 can you talk a little bit about the potential next steps from a clinical development standpoint, and how you can aim to proceed with potential accelerated regular path forward here.

And it just beyond that and how should investors think about the potential sequencing of indications you're going to be perceiving.

Okay.

Thanks, Mike.

You want to take that one yeah.

Yeah sure. Thanks for that question I mean, clearly for us before one three <unk>.

<unk> 88 mutated piece of malignancies are front and center in terms of development and there I think we see three at least three potential opportunities DLP C. L. A course, where that mutation is seen in about 25% to 30% of patients which represents a substantial opportunity we're talking about.

Prevalent somebody better in the thousands.

We think also Walton strums backup copy Lamia is another very interesting opportunities since about 90 95 per cent of those patients have this mutation in as or higher met need both in the relapse refractory setting after butacaine inhibitors, but even upfront to find novel therapies that can achieve complete responses rather than just partial responses and then finally.

Primary seeing this with former where this mutation is seen in about 80 per cent of patients also a very very high end that need for that population, albeit a smaller population than D. L. P. C L.

I think what do you think about this drug you have to think about the unique positioning here, especially with India B C. L. W.

<unk> Yeah, there really is no therapeutic add that is aimed at a genetically defined subset of DLP CL and as one knows in this.

This disease.

The.

Genetic cause of the disease now is really more important than the histology and add more and more of the trend is really defining.

Genetic populations based on their.

Their outcome their survival to frontline or chopper other frontline therapies and really trying to hone in on genetic subtypes. What the prognosis is of the subtypes of them finding new drugs that can take advantage of vulnerabilities in patients with those different genetic abnormalities and I think forward sweep it has the potential to be the first drug for <unk>.

Mutated lymphoma.

Disputation prefer is actually a worst survival outcome. After fault line art shop. So there really is a higher that need for these patients and having a drug that really for the first time would be going after genetically defined subset of <unk>, we think positions that uniquely not just therapeutically, but also from a regulatory standpoint, we know there are precedents from FDA four grand.

Thing accelerated approval for drugs that are active, especially in genetically to find subsets within oncology and so we do think that there is a real accelerated approval opportunity here and relapse refractory Mighty 88, mutated there'll be C L with.

With a potential rapid development path following phase one b that could even just consist of an open label phase two study that could lead to accelerated approval. So that is a possibility. We think <unk>. So that I think is really the first near term opportunity for developing this drug it might be 88 mutated malignancies would that being said, we think there could be off.

So rapid accelerated approval opportunities in second line Walton strums, if we have transformative activity in patients who have progressed. After prior <unk> inhibitor is that could also.

Lead to a rapid development and certainly in primary scene, that's lymphoma, where there's a very high that need a very few drugs at all being developed in that space I think they're too we see another potential rapid development opportunity.

The next question comes from Derek Taylor with Wells Fargo. Please go ahead.

Hi, <unk>. Thanks for taking my question. So quick ones from US first on the step. Please program what kind of data update kind of expect it here in a second question from that typically perspective, giving direct developing close by functional the equator and tissue specific like I said is there any plan to look at extra settled there.

Protein.

Great. Thanks, Great question, So maybe I'll start with the second one.

We always look at.

What is the.

What is the unmet needs and the problem that we're trying to solve and I personally feel that.

80% of the protean, roughly hopefully I don't have the number wrong is intracellular we have really great tools today.

Two drug extracellular proteins.

So the real opportunity for extracellular proteins.

Have.

If you are able to compete with.

Biologics by developing molecules that you can be.

Kind of as a.

As frequently dozing as the antibodies do.

Four or more or if you have an oral be greater or extracellular proteins. So I think there are clearly opportunities. There at this stage of the company I don't think that an area where there is the the.

The highest opportunity and risk reward scenario at this stage, but you know as we continue to grow the company that might be opportunities offered to go into the space. We actually looked at that a couple of years ago and decided not to go into that particular space.

With regards to your first question on set three as we said.

And the press release and also in the remarks that we made earlier.

The goal this year is to dose patients that.

Exposures and degradation profiles that we expect to be therapeutically relevant and we also hope and expect and are driving towards recruiting patients. Those those is where we expect to see clinical activity meanings user tumor types that we've seen briefly premium clinics.

<unk> to be sensitive to set three degradation and so what we expected to hopefully share. This year is are we seeing.

Antitumor respond in patients that are.

Again.

Radically sensitive to start three the irritation at the right, though isn't it the right.

Again length of those even so it will be what we call that initial concept it will be three degradation indirect patients illegit, an anti tumor response.

As a reminder, please limit yourself to one question in the interest of time.

The next question comes from <unk>, let's be Riley. Please go ahead.

Good morning. This is Andy on for <unk>. Thank you for taking questions. Some from us on K T 413, first I understand that you're looking for meaningful clinical activity and dose levels three and four have you observed any evidence of anti cancer activity so far.

Stable disease.

And then second Uhm, you noted needing to maintain target knocked down for 72 hours and were seen robust target knockdown and plasma up the target proteins, <unk> and <unk>, but they're rebounding two or above the baseline level and get at the end of the dosing interval do you anticipate tweaking the dosage.

Frequency, perhaps from every three weeks to every two weeks to ensure adequate depletion of target proteins at all times and it sustained depletion actually need it based on your preclinical model for meaningful antechamber activity.

Alright, I think these three questions, but okay, let's do the first one was.

I forgot already consumer activated.

Yeah. So obviously, we what we said we expect to shared data.

Meeting or in an event in which we decided to share data and we decided not to give it kind of updates.

In along the way so I guess I'm not going to answer that question on the second one which is second and third good question. So first I want to remind everybody that slides on our website that actually be big relation profile that we believe.

At least we know Preclinically and we believe with breastplate clinically into antitumor effect and good safety is the one where we degrade these proteins for about 72 hours and then we need to see food rebound of of those proteins before we those again, so actually the fact that bye week three we see.

Full recovery of these proteins not only.

Is good but is necessary at least based on preclinical data to avoid seeing neutropenia. Another another safety events that come with image, we do have flexibility to change.

Those in paradigm is if we need to but right now we re.

Asking the biological question of ease the degradation profile that we've seen preclinically to be the most active in mind, you idiot amusing tumors out of all the other agents that we've tested does that translate in similar levels of antitumor activities in the clinic and I think only after we.

Kind of answered the question, we can start talking about.

Is there an opportunity to tweak the dosing one way or the other.

The next question is Sam Z issue with Battenburg. Please go ahead.

Good morning. Thank.

Taking a question I have a quick one.

<unk>.

Corporate <unk> disclosed some of the strawberry programs won't be around I I'll fly out 13 pathway.

I thought that's interesting can I talk about the.

The potential.

Essentially advantage for using protein degradation approach person is a biologic approach and talk about the <unk>.

Associates in does.

Is it.

Yeah, So I think that's.

That's a great question, we only have a couple of minutes I could spend a couple of hours on this but just very quickly.

Which is the company with working in pathways with these high validation, where we believe protein degradation cannot lock the biology better fully or.

Sure.

With a better.

Technology, and so I think it's.

I'm not going to reveal anything new that.

An antibody four therefore, those put that particular pathway, he's probably going to be the largest drug.

In the market in the next few years and it's been approved in a D and in other believes for other indication and we.

We believe that there is.

Both an opportunity to develop an oral drug in that possibly and actually we believe there is an opportunity to develop the better drive in the past with meaning and drive with a better efficacy profile.

And so you know I don't have to do the math on the opportunities, but obviously, if you look at the <unk> and the penetration and how much money.

Drug makes a year you can imagine it announced small molecule that conserve their patient population.

Better way what are the opportunities there. So that's really what we're trying to solve for help patients be treated with the best drug.

We believe is we're working on.

The next question comes from Taylor exotic off with Raymond James. Please go ahead.

Yeah. Thank you for the question. So just four K T. Four cell for just trying to understand the strategy for the studies a little better I think H S study starting first so do you think there will be an overlap and tie.

Those two studies just wanted to make sure that there's no gatekeeping factor as an H S. H S study like safety or efficacy data, Tennessee may want to see before.

Starting to 80 study.

That's a great question I mean, I'll answer short this we're kind of out of time from our understanding there will be a.

Hi, likelihood that there would be an overlap between the studies I don't believe there are.

There are.

Expectations that will inform necessarily when and how the second that it will start but again. This is we will talk more about the specifics as the study's initiate and that's those are questions that <unk> will have a better answer for it.

The next question comes from chest Meacham with Bank of America. Please go ahead.

Alright, Thanks for taking the question. This is Joe on for Jeff Uhm, So we've talked a bit about the club's collaboration with Sanofi. So far I was wondering how are you thinking about additional partnerships and collaborations in the near term because you called them out in your press releases strategic objective for the year can you provide like a little bit of color around like what types of partnerships you may be pursuing.

Yeah. It is it's a great question. So again try to be brief there is 222 ways to think about strategic partnerships one is.

Our technologies even asset.

Early tools that will enable primera to grow better faster and then are there instead companies that we can partner some of our programs or our technology to create more value together versus independently developed bingo <unk>.

Civilized drugs and I will say that those both areas areas that we always think about and.

I don't have any specifics to update right now, but obviously accompany like him are with the expertise that we build there is way more that we could do than what we're doing and then the question is how did you get that that.

You saw that right and I think at this point I don't have any specific update on it.

The last question today comes from Kelly She with Jeffries. Please go ahead.

Okay, Oh, congrats <unk> on for Kelly, Thanks for taking our questions. So I have a question on.

Four can you provide more color on how you will work with.

Going forward do you anticipate continuing to engage with them over the course of face to.

Jason and maybe expanding the collaboration.

<unk> <unk> immunology program, that's coming up thank you.

So I mean, we had the fortune to have a really good partner would sign up the along the way I will continue to say that because it's true and we've worked very closely with them. When we were rounding our program the program and we already are working very close.

He is now they're operationally and financially responsible for the program I will also remind everybody we have an opting macanese before phase III. So we're fully vested in the success of the programs not only we have comedians in plays so obviously follow progress, but we actually have.

Weekly or biweekly interactions with them to make sure that we both give our best for the success of this drug. So I have no doubt that that will continue to be the case on I think that was the second question about other collaborations maybe I can't really comment on that for now the rest of our pie.

Blind that we've talked about is is our own and that's for now what we're doing and continuing to to generate value with web fine on does you see to continue to do that.

To advance these programs and create values and that's our goal at this point.

This concludes the question and answer session I would like to turn the conference back of it and now that for any kind of thing that Max.

Yeah first I would like to thank everybody for listening to our call for the engaging Q&A you all at great questions. We hopefully we need our best to answer them in the most comprehensive way possible.

We're excited about what we've done but we've always said.

Five to do better year by year. So we hope and expect that 2023 would be even more exciting than 2022, according to everybody who follow us and reach out to us. If you have further questions and we always wait for amazing data to speak for us. So.

We're excited to see how all these programs unfold and had patients in a wide variety of indications. So thanks again for the time apologies for being a bit late and have a good rest of the day.

The conference has now concluded. Thank you for attending today's presentation you may now disconnect.

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Hello, and welcome to the Cai marrow Therapeutics fourth quarter 2022 earnings conference call. All participants will be in listen only mode should you need assistance. Please signal a conference specialist by pressing that Starkey followed by zero.

After todays presentation, there will be an opportunity to ask questions to ask a question you May Press Star then one on your telephone keypad to.

To withdraw from the question queue. Please press Star then two please note. This event is being recorded.

I would now like to turn the conference over to Bruce Jacobs Bruce. Please go ahead.

Good morning, everyone and welcome to the Cai Merit Therapeutics quarterly conference call I'm, Bruce Jacobs, Chief Financial Officer at Chimera, and I'll be joined today by now a woman I'll be founder President and CEO and Jerry <unk>, Our Chief Medical Officer. After our prepared remarks, we'll open the call to your questions to ask a question. Please press star one on your telephone keypad.

If at any time, you would like to withdraw from the queue. Please press star two.

Before we get started I'd like to remind everyone that some of the comments that management may make on this call include forward looking statements as outlined in the press release actual events or results could differ materially from those expressed or implied by any forward looking statements. As a result of various risks uncertainties and other factors, including those set forth in <unk>, most recent filings with SEC.

And any other future filings that the company may make with the SEC you are cautioned not to place any undue reliance on those forward looking statements and disclaim any obligation to update such statements, except as required by law, but that said I'll now hand, the call to now.

Bruce and thank you everyone for joining us today I thought I would spend a few minutes. This morning, reflecting briefly on the importance of all of the progress we've made in 2022 and what we believe it means for our ambitious objective to build a best in class fully integrated global medicines company two.

2022 was exceptionally important year for cameras evolution with dose healthy volunteers and patients with HSA D, which is the first time for integrator in immune inflammatory indications in patients with lymphomas leukemia, and solid tumors with their first III investigational drugs.

We have seen now across three programs strong translation of our preclinical PK PD and safety into the cleaning. This is a substantial accomplishment for a company that is pioneering a new modality.

In addition, we have seen for the first time clinical benefits of the hydro by function will be greater in immune inflammatory indications and the first proof of concept clinical differential or the greater versus a small molecule inhibitor with our key post to them for phase one data.

In fact, 80 474 clinical data that we shared late last year from the patient cohort of the phase one study for a degree either exceeded our expectations, we were able to replicate the PK PD profile of the healthy volunteer portion of the trial in <unk> patients.

The molecule was generally well tolerated with no serious adverse events, including a resolution of the Qt effect, we demonstrated an encouraging impact on disease, rather than inflammatory biomarkers in blood and skin.

And we were able to produce some early but really encouraging signs of clinical activity in Hs in eight patients that we think represent strong reasons to believe in the clinical potential of effectively dragging the aric full pathway and in our degree their molecule and of course lastly, we reported that our partner side of the schedule.

Our enthusiasm and we'll initiate phase II studies in 2023.

Jed will share a little bit more on this call regarding the next steps for the program, but obviously this was an important milestone for <unk> 47 for a molecule that we believe can have a unique and broad role in raising the standard of care in a wide variety of inflammatory conditions.

Assuming the molecules profile remained consistent as we tested in larger studies.

And additional patient populations, we believe it's small molecule with the emerging it's an encouraging safety profile.

Could be a best in class medicine across several disease and this year. We're excited for our partner strategy to initiate Kt posted enforced studies initially NHS, followed by AAD and potentially other indications.

While perhaps somewhat overshadowed by the <unk> posted record results, we made encouraging progress in our first two clinical stage oncology programs <unk> 413, the Iraq commit degrader NTT <unk> III.

Three degree there.

Both programs are currently in the dose escalation phase of the phase one clinical studies in December we disclosed pharmacodynamic activity in both blood and tumors and knockdown of their targets without any dose limiting toxicity.

Importantly, we've seen fidelity of translation of PK, PD and safety from preclinical profile into these clinical settings further validating our work and highlighting our ability to replicate our approach to discovering and developing high value molecules.

Promising initial data from these phase one trials position us to share data later this year that we hope will show a clinical activity, particularly when we reached the expected active dose levels.

<unk> patient populations.

Together, we believe that these results represent a validation of our R&D approach and strategy. Since we started the company over six years ago now our funding principles remain unchanged harness the transformative potential of targeted protein degradation to address areas of significant therapeutic need and improve patient.

On slides.

With this goal in mind, we made very intentional choices, which we believe represents a differentiated approach to design in many key areas, including target selection strategies.

This area of focus cutting edge platform investment and corporate strategy.

These strategy and approach in conjunction with a clear focus on disease targeting areas of significant patient need it can't meet meaningfully addressed by traditional medicine has led us to targets in markets, where protein degradation is the only or the best way to elucidate the desired biology or clinical outcome.

Sure.

I hope that as you reflect on the totality of the data we presented in December and our progress in building. The company you share our belief that we have validated the work and investments we've made over the past seven years, almost seven years, resulting in the high quality molecular design and platform capabilities.

And our proven ability to translate our understanding of disease biology, PK PD and safety from preclinical models into patients, creating high value program that has the potential to become important new medicines.

Before I hand, the call over to Jared I should mentioned that the three programs that just discussed they are just the beginning for camera at the end of last year. We also announced that the FDA had cleared the IND for our MDM to degree there Katy <unk> III MDM.

<unk> two is a crucial regulator or the most common tumor suppressor P 53, which remains intact in close to 50% of cancers.

Ed will share more on our plans for <unk> two phase III. Shortly we also hinted at several other programs in our early stage pipeline in both oncology and immunology indications earlier in the year further evidence of the productivity of our drug discovery engine.

Advances have been fueled in part by innovative computational research tools that have enhanced our understanding of disease biology, and allowed us to develop new ways to harness PPD.

In addition to leadership in the discovery of <unk>.

By functional Degraders. We are also identifying novel molecular glues that expand the therapeutic applicability of our platform and we hope to share more on this later in the year as well.

Along with our clinical and scientific progress we work to ensure that we have the people and resources to build our company sustainably.

We recently recently appointed LNG.

Chief Legal officer, and corporate Secretary, where she will serve as a key member of our leadership team and joins us from a lexicon pharmaceuticals with extensive experience overseeing legal activities biopharmaceutical companies ranging from discovery phase through commercialization. This month this month Rebecca Moshe.

<unk> joined us as our senior Vice President of translational medicine from <unk> Therapeutics. She previously held positions of increasing responsibilities in translational medicine translational research and molecular pathology at Novartis vertex in Atlanta.

We also recently appointed Julie Williams at <unk>, New head of research Juliet was previously our head of biology and contributed profoundly to our target selection strategy and drug discovery efforts. She has more than 20 years of drug development experience, including leadership roles at Novartis sanity millennium and curious.

These important roles will have camera navigate their next stage of development as we work to bring revolutionary be greater therapies to patients.

We ended the year in a very solid financial position with approximately $560 million in cash and expanded runway into the second half of 2025, which will allow us to continue to invest in our clinical programs discovery pipeline and platform and importantly allow us to readout for phase III.

For the study and initial proof of concept for this three oncology clinical programs Joe will now cover in more details our recent progress for each of our disclosed programs before returning the call over to Bruce for a financial update.

I will then finish with some concluding remarks, including covering their key goals for 2023 before handing the call to the operator for a Q&A session with Jared Bruce and myself.

It will be available.

Sure.

Thanks Miller.

I'll provide a brief recap of where we stand with our clinical programs and what to expect in 2023.

I'll begin with our Iraq War program.

As you all know in October we announced the completion of dosing of the patient cohort portion part C of the KC 47, four phase one clinical trial and.

And we shared the full data set in December .

I won't go over all of the data here today, but if you are interested you can find the replay of our December meeting on our website.

The data are also included in our updated corporate presentation.

That said I did want to share our expectations for the progress of the program in 2023.

As you know <unk> will be taking KC 47, four into phase II.

Just as they were closely involved in the phase one trial that primary Iran.

<unk> jointly discuss the plans for the phase III program.

As we shared in December Santa Fe is committed.

Two phase II trials and at least two initial indications.

Beginning with Hs and followed by <unk>.

As for timing it is too early to guide to the expected phase two start dates, but <unk> said in the past at least the first phase II is planned to start in 2023.

Turning to our oncology pipeline.

Want to update everyone on our disclosed programs, which include our stat three Iraq amid an MDM to integrators.

Focusing first on our new trial activity.

253 are MDM to the greater received IND clearance from the FDA in December .

<unk> is the crucial regulator of the most common tumor suppressor, <unk> 53, which remains intact and close to 50% of cancers.

<unk> is developing a highly potent MDM due to greater that unlike small molecule inhibitors has been shown pre clinically to have the ability to overcome the <unk> feedback loop and rapidly induce <unk>, even with brief exposures.

80, 253 has the potential to be effective in a wide range of hematological malignancies, and solid tumors with functioning or wild type <unk> 53.

We plan to initiate dosing patients soon and the phase one trial of <unk> III.

The phase one study will evaluate the safety Tolerability pharmacokinetics.

And amex and clinical activity of <unk> three in adult patients with relapsed or refractory high grade myeloid malignancies, acute lymphocytic leukemia lymphoma and solid tumors.

The open label dose escalation study is intended to identify the recommended phase two dose.

It will be comprised of two arms with ascending doses of <unk> III and HR.

The first arm will consist of patients with lymphomas in advanced solid tumors and the second arm will consist of patients with high grade myeloid malignancies and <unk>.

Now turning to our two ongoing oncology trials.

That rate is a transcriptional regulator that has been linked to numerous cancers and other inflammatory and autoimmune diseases.

Our phase one clinical trial is evaluating <unk> potential in Hematological malignancies and solid tumors.

Specifically the trial is evaluating the safety Tolerability PK PD and clinical activity of <unk> hundred 33 in adult patients with relapsed <unk> refractory lymphomas and solid tumors.

We reported on the first dose level in December showing initial proof of mechanism for <unk> III degradation in <unk> and no dose limiting toxicities with good translation of PK PD from preclinical models to patients.

Based on the PK PD, we have shown to date with robust target knockdown for 72 hours followed by recovery, we expect to be at efficacious doses by dose level, three or dose level four.

This year, we expect to show clinical impact of statutory degradation on tumor burden in the target patient populations, such as peripheral T cell lymphoma, cutaneous T cell lymphoma, and LG <unk> leukemia.

The trial's second stage will consist of phase <unk> expansion cohorts to further characterize the safety Tolerability PK PD and anti tumor activity of <unk> hundred 33, and relapsed <unk> refractory <unk> dependent T cell malignancies, as well as in solid tumors.

And finally, our <unk> program <unk> hundred three is a novel enrolled by functional the greater that targets degradation of both Iraq for and the image substrates grossing iOS with a single small molecule.

84, <unk> was designed to address both the <unk> and the type one interferon pathways synergistically to broaden activity against <unk> 88, B cell malignancies.

A depot and three is on a similar timeline is that three and is currently in the dose escalation stage of the phase one trial evaluating the safety Tolerability PK PD and clinical activity of <unk> hundred three in patients with relapsed <unk> refractory b cell non Hodgkin's lymphomas.

We reported in December that the first two dose levels have been completed showing initial proof of mechanism with Iraq for a growth and <unk> degradation in pbms and tumor and no safety signals with good translation of PK PD from preclinical models to patients.

We are continuing enrollment and expect to be at efficacious doses by dose level, three or dose level four.

And as with <unk> hundred 33 later this year, we expect to show clinical effect of Iraq degradation on tumor burden and <unk> 88.

<unk>.

The trial's second stage will consist of phase <unk> expansion cohorts and <unk> to further characterize the safety Tolerability PK PD and anti tumor activity of <unk> four with rate in relapsed refractory <unk> 88, and <unk> 88 Wild type <unk>.

We look forward to sharing more progress on these programs throughout the year.

I'll now hand, the call to Bruce who will share some brief comments on our financial results for the fourth quarter.

Jared I will quickly cover the financials before turning the call back to <unk> for concluding remarks for the quarter, we recognized $16 $1 million of revenue. This total refracts reflects revenue recognized pursuant to our Santa <unk> and vertex collaboration at the end of the quarter, our deferred revenue total on the balance sheet was approximately $63 million.

It reflects partnership revenue, we expect to recognize over the next several years, excluding the receipt of any potential future milestones.

With respect to operating expenses R&D for the quarter was $43 1 million of which $4 5 million represented noncash stock based compensation adjusted cash R&D spend of $38 6 million excluding stock based comp is essentially unchanged from the comparable amount in the September quarter, our G&A spending for the quarter was $11 6 million.

Of which $4 $4 million represented noncash stock based compensation the adjusted cash G&A spend at $7 2 million, excluding stock based compensation reflects a 13% increase from the comparable amount in the September quarter. Finally on cash we exited the fourth quarter with a cash and equivalents balance of approximately $560 million.

As we shared earlier in the year, we believe that our cash runway extends into the second half of 2025, a projection that now includes milestones related to the phase III start I'll now turn the call back to narrow.

Thanks, Bruce with our accomplishments last year. It is clear that <unk> made considerable progress in its evolution and began to demonstrate the incredible potential of this modality and our company to make a meaningful difference in patients' lives. We are excited to have the opportunity this year to assess the impact.

They were full program may have for patients with cancer and immunological conditions and to further demonstrate the potential advantages of our technology and platform have over traditional medicines, we'll feed that we're just getting started and are energized by the opportunity we have in front of us.

As I said earlier 2023 will be a busy year, we have a lot that we expect to achieve much of which was discussed earlier in the call, but just to quickly state. Our key 2023 goals, we will collaborate with Sanofi to initiate the first gatekeepers to importantly study. We're also working to publish the results of the phase one.

Trial.

In a top tier journal, we intend to evaluate the effects of our IRAK commit instead three programs on tumor burden in patients in our phase one studies, we plan to initiate the <unk> phase one trial in solid and Hematological tumors in order to demonstrate proof of mechanism in patients and with respect to our pipeline.

<unk> is to deliver at least two new Dcs AMD from the preclinical pipeline and also continue to.

The expansions of our novel molecular Glu franchise at this point I'd like to thank the <unk> team as well as our partners and the patients participating in our clinical trials and for sharing this journey with US finally, thank you all for your for participating in our call and I look forward to your questions I will now hand, the microphone to the opera.

Later, so that we can take your questions.

Thank you at this point, we will open the call for questions. As a reminder to ask a question. Please press star one on your telephone keypad. If at any time, you would like to withdraw from the queue. Please press star two.

Now take a moment to review our Q.

Today's first question comes from Eric Joseph with Jpmorgan. Please go ahead.

Oh, Thanks, good morning, and thanks for taking the questions.

Just a couple of questions on the <unk> program.

Program, if we could.

I guess first what is.

Maybe can you layout, what proof of mechanism looks like with <unk> to $5. Three later this year.

And does it.

Look similarly in liquid tumors as it does in solid tumors and then secondly.

With respect to the anticipated AE profile with the drug.

Do you anticipate any differences I guess relative to.

Competitor MDA two inhibitors.

Currently on the aspect of modest compression any potential to sort of reduce rates of grade three neutropenia with this compound. Thank you.

Thanks, Eric I'll start and then I'll, let Jerry comment.

Come in more on the proof of mechanism, but maybe I'll take the second question first just because actually points to the core thesis for our investment in the <unk> program, which is creating.

Allowing us to create a larger therapeutic index that will allow us to finally interrogate these mechanism being the clinique fully.

And as you heard this said in the past the rationale.

Really based on kinds of genetics. If you look at data that's been published over the years and that is fueled older drug development program. In this pathway, we know that <unk> wild type.

In more than 50% of cancers in those type of cancers in both liquid and solid tumors. If you delete MDM too if you'd genetically believe MDM to genetic tools that we have pre clinically you see a high dependency of these tumors of these tumors.

The spot we are in the presence or absence of MDM too and that basically generic removal of MGM two leads to rapid level.

Response in those tumors that have <unk> three wildlife.

And if you look on one of those clients that have been generated its probably one of the most impressive.

Sensitivity.

<unk> that we've seen in concert.

Now I think the field is made the assumption and that has been true for many programs.

In oncology or in the past 20 years.

We started to understand the human genome and the relationship with the human Proteome, we made the assumption that inhibiting <unk> will lead to that kind of respond to what we've learned is actually thats not true we've learned that if you're an EBIT MDM to P 53 interaction.

You are able to actually stabilize b 53, but not fully and mostly because the inhibition of that interaction needs too.

<unk>.

Regulation of MDM to so as you are inhibiting the interaction you see more MDM to the get produced and the small molecule has a hard time finding that.

And so you end up having to dose longer and that creates a very narrow window. If at all between your anti tumor effect in your impact on bone bone marrow derived cells, which are one of the most sensitive cell types to MDM to absence.

We have been able to do with degrading MDM too is to remove the protein quickly and we've seen the first two to four hours at rapid commitments level doses and that lead cancer says there are sensitive to these mechanisms to die quickly while healthy sales.

While they might have an initial impact had time to recover between the first and the second dose.

And so that creates in tumors that are highly sensitive I want to be sure that's clear.

A therapeutic index, then no small molecule as seen before in our hands.

So what we're talking about.

I think generally comment on it before and this is work that we're still doing.

Obviously, I think it's not fair to assume that at all.

<unk> Wild type tumors will have these wider therapeutic index I think scientifically not true based on our experimentation, but we have found subsets of tumor types within the <unk> wild type larger set there are highly sensitive even the ones that are highly sensitive have these increase.

Therapeutic index, so our hypothesis going into the clinic is that we will have a drug that is well tolerated.

While it is being affected.

In the patient populations that are sensitive to it the all indications that we have shared so far we've seen these high sensitivity.

<unk>, including the patients that are refractory to.

The existing line therapy, so thats, an exciting area for us to explore lymphomas and some solid tumors that we will be disclosing.

Later in the year or as we go into the expansion cohort.

So maybe I'll, let Jared comment more on what the proof of mechanism is going to look like and whether I think your question was also whether it's going to be different between lead within solid tumors.

Maybe if I can just quickly comment also on the question around model suppression.

The fact that we have this unique mechanism of action that never laid out allows.

Allows us to dose infrequently given given the drug is an IV infusion. Once every three weeks and that infrequent dosing. We think is going to give us. This.

Unique therapeutic index that will allow us to mitigate milo suppression by allowing plenty of time for normal cells in the marrow to recover in between doses.

Coming back to proof of mechanism or aim for showing proof of mechanism at least this year is to focus on.

Impacting the MDM $2 53 pathway in peripheral blood mononuclear cells, which we can do essentially.

All of the patients on the study we've done this with our prior programs for 1333 looking at impact on the targeted <unk> and were available in tumor as well here I think in the MTF to phase one trial. The initial focus will be <unk> and then I think when there is tumor available for biopsy or once were in.

<unk>, where we're treating high grade myeloid malignancies, including AML, we may have more opportunities there to also show impact on the pathway.

In malignant cells, including leukemia.

The next question comes from Ellie Merle with UBS. Please go ahead.

Hi, This is Jasmine online for Ali Thanks, very much for taking.

A question so you've been mentioning youre working with.

We just had a couple of questions Eric.

Thanks, so much.

Perspective.

The ability of the market.

And to be selected for single target protein as you think about target selection and then second.

Airbnb squeezed is this something you think could be feasible over the next few years or is this more.

Okay.

Thanks.

Thank you for the question.

Great question, because it allows us to talk about I think one of the key differentiator for this company, which has always been to go after heart problems.

So as you've heard that.

Your team.

Made a lot of attention to what we said in the past in this on this particular topic.

We've said that we are using molecular glues to go after problems that hydro by functional degraders cannot solve.

So maybe just to step back what are either a bifunctional degree, they're solving for and solving for on drug or poorly drug targets, where you have an ability to bind to that particular disease, causing proteins and we've shown that you can go after transcription factors scaffolding protein et cetera. So.

Again, there is plenty of targets out there that obviously feed hydro by functional degraders can solve meaningful clinical problems.

But there are also many validated targets.

Oncology, and immunology, and rare disease, and cardiovascular and CNN.

Where you don't have an opportunity to find discrete binders to those proteins, mostly because those are let's see disordered proteins or difficult to leak in proteins and so you either choose not to go after them or you choose to build capabilities to go after them and we chose.

Again, the hardest part which is.

Developing technologies to go after them and so we take a need three legged agnostic approach.

So yes, the answer to your second question, yes, there will be molecular glues that Don new therapy alone.

And in fact, I think there are already examples out there in the literature pointing to those possibilities.

We take as I've always said in the past the transmission of medicine approach, we think about what are the clinical problems. We're trying to solve for and what are the molecular mechanism that will enable us to do that and so I have to give again.

Kudos to our team led by Juliet.

Others in their platform.

Team that have uncovered.

Virtually all new.

Series of proteins that we can go after using a completely new background.

That we can engage with.

<unk> and <unk>.

We had some molecular designs that we've made.

And it turns out that.

These proteins that we've already identified that are multiple are key on drug and begun the bulk protein many of whom are in immunology and some some are in oncology and.

I think it's unlikely that we would be disclosing the molecular mechanism because we feel this could be.

Beginning of a completely new area of molecular Glu I would kind of look back at <unk>.

And he made in Thera bond, where discover then how many targets have been subsequently been dropped by that interaction.

Fact that what we've uncovered here could lead to that type of.

Discoveries and so.

We're just at the beginning we're very excited.

First program there is already ready lead optimization.

<unk> driving towards the development candidate.

We will continue to talk about this.

As the program moves into development, we'll talk about with targeted is probably unlikely that we'll be disclosing the molecular mechanism or even the three legged.

The next question comes from Brad Ken Nino with Stifel. Please go ahead.

Good morning, Thanks for the update two questions from me first no I guess the recent announcement for the departure of the global head of R&D at Saturday, John Reed and the companies searching for a new successor I'd just like to hear your optimism that KC 47, four has enough as advocates or champion so to speak at Santa fee So that.

The program will continue to be prioritized, even with any future shakeup of portfolio strategies and initiatives from our new R&D head.

And then for Jared <unk> three.

Can you remind us the type of <unk> patients that are being recruited in terms of likely prior therapies.

Patients post <unk> car T biospecifics et cetera.

And if so what is your confidence in the ability to recapitulate. The preclinical model results in such a heavily pretreated population, particularly with the <unk> mutation. Thank you.

Great Brian that was a perfect question for our colleagues.

So I will try and answer it.

Obviously understanding that I cannot speak.

For them first you gave me the opportunity to thank John that it's been an amazing partner along the way from the beginning which was when we started to talk about our partnership on <unk> for all the way through his last day I will say that.

We've had the fortune to connect with several leaders in the company without naming names at the executive level that have continued along the way.

To be excited to be.

Helpful to be supportive of the partnership in understanding and appreciating the value of 474. So again speaking for <unk> I have no doubt.

Debt.

The molecule is in the right hand, then there is the <unk>.

<unk> commitment and appreciation of what this molecule can do for to be honest millions of patients out there.

And I expect that there will be no change of priorities or commitments going forward.

Regarding the second question again, I'll leave it to Jerry to answer.

Yes, Thanks, Brad.

On the <unk> III study.

We are recruiting b cell malignancies, including <unk> and including patients we might be 88 mutations as you noted.

Many of the patients will have had prior therapies, but we anticipate that many of these patients will have had and especially if they had the UCL, perhaps prior car T. If they were eligible maybe prior pahlavi or bi specifics.

Or even Tesla, but I think what's important to note is our unique mechanism of action. The fact that with 403, where drugging Iraq for and we're also dragging the IRS four pathway with the immediate activity.

It makes us a unique mechanism of action and so we don't expect there to be cross resistance to these other therapeutics like cellular therapies or like bi specifics.

So I think we're confident that with the right patient population, especially those with the <unk> eight mutation sort of regardless of.

Prior therapies or how many prior therapies, we still expect that the mechanism of action here should yield.

Significant anti tumor responses with <unk> III.

The next question comes from Vikram <unk> with Morgan Stanley . Please go ahead.

Hi, good morning, Thanks for taking our questions. So we have two one on <unk> four and then one on your.

Your stat three program.

So going back to your relationship with Santa Fe.

Wondering if you could provide some more color on what are some of the considerations that you're thinking through what's sad when you explore indications beyond HSA for phase II development for this molecule and then for Stat III.

Just curious to get an update on where efforts stand with <unk>.

Evaluating our statutory to greater in autoimmune and fibrotic conditions on when we could expect to.

Here's an update on that effort.

Thanks, Vikram. So first question is.

So what we've done there. So if you actually look historically, how we develop the molecule and this program. There is a slide that actually we haven't changed in a couple of years in our deck, which of which our clinical opportunities.

That could be.

Realized by targeting the <unk> pathway.

Usually.

Sure these kind of ph, one ph 17, driven diseases like Hs.

Like our array like lupus IBD and others and then we.

On the th two types.

Like the asthma.

COPD and others.

And we've said that with validation of <unk> mechanism in some of those diseases, representing kind of this two slide.

Slightly kind of differentiated ways to thinking about immunology, then you can think about expanding further.

And so I believe that the high level.

Both <unk> and <unk> are looking at the opportunity in that way now.

Practically.

We have prioritized as you know <unk> and <unk> and we've been fortunate I have to say.

That even with small patient numbers and in Asia.

In a study design land and even study design generally that was not set up to look for clinical activity we've been fortunate.

Two have seen really early validation of this mechanism to be both a check again ph one ph <unk> th two type inflammation.

Obviously, we look for further validation in a placebo controlled randomized phase II study and we go into these we do the study with high degree of confidence and expectation based on the data we've seen so far.

No.

The conversations that obviously are happening and will continue to happen.

What are the next type of indications that we will go after what I will say that I cant again speak further collaboration in terms of particular indication what I won't say from our perspective and even from my perspective.

Perspective, there is such a high unmet need in many of those indications where there are really no small molecules.

With a TBD and safety profiles that we can match with their IRA or degree, they're obviously I'll start with a D. I don't think there is one going to Hs I don't think there is one.

Two IBD large unmet need I don't believe there is a good molecule now that can can really help patients go through horrible.

Experience.

I look at our array, which is commercially quite crowded but again.

I think there is an opportunity for a for a well tolerated active drug.

Lucas, which is an unsolved disease.

And then I look on the other side on the th two type inflammation again.

Really no good small molecules in those indications that I mentioned earlier like like asthma COPD.

Providers and others so.

I think we have a large opportunity I think we have to be rational with how we select the opportunities and we have to be data driven.

Suspect we will be updating you all on as we make those determinations and clearly initial proof of concept in a randomized study in phase two will be the drivers of that of the cell dose.

Further selection downstream of this initial two diseases, but I think we have a unique opportunity here in the landscape to help millions of patients as I said earlier.

Let's not forget that I don't want to spend the whole.

20 minutes on this but let's not forget that the.

<unk> unique value proposition of <unk> first of <unk> is that this is a systemic anti inflammatory molecule with broad anti inflammatory effect with local employment with local anti inflammatory.

Also effect.

The molecule has demonstrated systemic anti inflammatory efficacy as measured by also biomarkers across a wide variety of downstream cytokines and hemoglobin is also shown as you know it preferred.

Distribution in tissues, especially as you see skin as well as as we know and anti <unk> activation.

Anti inflammatory effects. So has this really unique combination of both molecular properties as well as the pathway engagement properties that makes it very unique molecule in the landscape. So we're excited to continue to develop the molecule to explore further how many others.

As we can we can potentially develop it in.

The other question.

Yes, yes, so as I said.

Relatively recently that is an area that we are continuing to do work.

We plan to being able to update further later in the year I can maybe share more than what we've said recently.

The next question comes from Michael Schmidt with Guggenheim. Please go ahead.

Hey, Good morning. This is Paul on for Michael Thanks for taking our question. We just have two on the MGM two program I guess first on the dosing strategy.

Is there a potential in the studies to evaluate alternative dosing intervals that could potentially optimize the clinical profile of two five to three between solid versus liquid tumors.

And PK PD in those settings are you fairly comfortable with the relief across all tumor types and then secondly, obviously youre just starting to monotherapy dose escalation, but how are you currently thinking about the strategy for <unk> two 5 billion in combination it seems like coming out of ash amended.

A bit of hot combination might be on the table for AML, who just wanted to get your thoughts there. Thank you.

Okay.

Thanks, Great question, maybe Jared do you want to take them.

Sure Yeah, maybe starting with the with the dosing schedule.

As we stated upfront we're going in with a once every three week IV infusion.

Which we think.

Has the potential to be highly active based on our preclinical.

Models, but also has the ability to mitigate mildest depression, we do have flexibility based on our preclinical tox studies to dose.

Frequently even every two weeks and we thought that was necessary.

<unk> is an interesting one could we ever additional situation, where you might have one schedule for liquid tumors and one for solid tumors, that's always a possibility.

And I think we do have that flexibility our plan, though right now it's our expectation rather is that every three week dosing will be more active in both liquid and solid tumors, but at least we do have that flexibility to dose less frequently if we think its necessary from a pharmacodynamic standpoint, and if we think that it would be tolerated from a safety standpoint.

In terms of combinations. That's obviously a very good question as well you mentioned that <unk>, we've been doing some I think very interesting preclinical work and looking at our drug.

Both <unk> resistant insensitive AML models, and we can see activity of our MTF to the greater as a mono therapy, even in <unk> resistant models, which is very encouraging for the possibility of seeing activity with our drug.

AML patients who are previously seen with <unk> and as you know more and more patients are getting <unk> either in the upfront setting or in the relapsed refractory setting.

We've also seen some very encouraging data with our drug combined with benita <unk>, either <unk> resistant <unk> sensitive AML. So I think we will have the opportunity to look at that combination I think that will be probably one of the combinations that we do prioritize what's.

Were through with monotherapy dose escalation and have a good sense for the safety profile and then start to look at combinations that we can use for development in the future, but I think I think I wanted to be clear that I think we do feel that the activity. We see pre clinically is such that we believe that there is a substantial opportunity for <unk> to greater as a monotherapy in both liquid.

<unk> and solid tumors, but I think these combination approaches always give us even additional development opportunity that we want to take advantage of.

The next question comes from mere from with Cowen. Please go ahead.

Hi, Thanks for taking my question.

Maybe just following up on the MDM to some of the testing questions.

What is the kind of target degradation profile youre aiming for in terms of <unk>.

Percent reduction but.

Given all you are saying about kind of a therapeutic window.

At least as important as the duration of that degradation.

Yes, Mark Thanks for the Great question. So what we've seen pre clinically is that the degradation.

<unk>.

<unk>, 8090% for really a short period of time, even two to four hours.

Is enough to lead to this really profound antiapoptotic respond.

And Thats why actually we design.

Type of drug with this type of dosing paradigm, where we dose it Ivy.

<unk>.

Where we are able to reach these really high.

Quick Heisey marks initially that leads to quick downregulation, and then clearance of the drive relatively quickly so that we can optimize on.

Gradation of the target in tissues that are highly sensitive so that we can capture maximal anti tumor effect and then we can kind of peak the time for healthy SaaS to recover before we those again.

That should be monitoring.

The MDM to degradation pathway engagement.

A large piece of work that the team here has done even obviously the complexity of the pathway and also.

How to measure MDM to levels, which are initially already relatively low.

So it's actually also some really innovative signs that we've done here at <unk> to monitor and to understand those are getting engagement in terms of MGM two degradation, but also downstream biomarker readout, which for US are just as critical by seeing.

The right biomarker, either increase or decrease downstream is what really drives that kind of anti tumor effect. So I think part of that proof of mechanism data that judge was mentioning.

That will sure hopefully this year, obviously, that's the goal and plan, we'll will obviously have.

That type of information that target engagement time of target engagement.

And also safety that will go with that.

The next question is from Mike Kratky with SBB Securities. Please go ahead.

Hi, everyone. Thanks for taking my questions for <unk> can you talk a little bit about the potential next steps from a clinical development standpoint, and how you could able to pursue a potential accelerated regulatory path forward here.

And just beyond that I mean, how should investors think about the potential sequencing of indications youre going to 8%.

Thanks, Mike the Jared do you want to take that one.

Yes sure yes. Thanks for that question I mean, clearly for us with 403.

<unk> 88, butane at B cell malignancies are front and center in terms of development and there I think we see three at least three potential opportunities <unk> of course.

That mutation is seen in about 25% to 30% of patients which represents a substantial opportunity we're talking about.

Prevalence numbers that are in the thousands.

We think also walton's drums.

<unk> in EMEA is another very interesting opportunity since about 90% to 95% of those patients have this mutation and has a high unmet need both in the relapsed refractory setting after PTK inhibitors, but even upfront to find novel therapies that can achieve complete responses rather than just partial responses and then finally primary CNS lymphoma, where this mutation.

<unk> has seen in about 80% of patients also are very very high unmet need for that population, albeit a smaller population than <unk>.

I think when you think about this drug you have to think about the unique positioning here, especially with <unk>.

<unk> is it really has no therapeutic that is aimed at a genetically defined subset of <unk> and Thats why nose.

In this disease.

The.

The genetics of the disease now is really more important than the histology and add more and more of the trend is really defining.

Genetic populations based on there.

The outcome to survival to frontline R chop or other frontline therapies and really trying to hone in on genetic subtypes, what's the prognosis of the subtypes of and finding new drugs that can take advantage of vulnerabilities in patients with those different genetic abnormalities and I think forward three has the potential to be the first drug.

<unk> <unk> mutated lymphoma, disputation confers actually a worst survival outcome. After frontline R. Chop. So there really is a high unmet need for these patients and having a drug that really for the first time would be going after a genetically defined subset of <unk>, we think positions us uniquely not just therapeutically, but also from a regulatory standpoint.

No there are precedents from FDA for granted accelerated approval for drugs that are active, especially in genetically defined subsets within oncology and so we do think that there is a real accelerated approval opportunity here in relapsed refractory <unk> 88, mutated <unk> Bcl with.

The potential rapid development path following phase one b that could even just consists of an open label phase II study that can lead to accelerated approval. So that is a possibility. We think for <unk>. So that I think is really the first near term opportunity for developing this drug at <unk> eight mutated malignancies, but with that being said, we think there could be also.

Rapid accelerated approval opportunities in second line Walden from if we have.

Transformative activity in patients who have progressed after prior PTK inhibitors that could also.

Lead to a rapid development path certainly in primary CNS lymphoma, where there's a very high unmet need and very few drugs that are being developed in that space. I think there are two we see another potential rapid development opportunity.

The next question comes from Derek <unk> with Wells Fargo. Please go ahead.

Hi, This is Sarah on for Derik. Thanks for taking my question two quick ones from US first on the stats we program what kind of data update can we expect this year and the second question from activity perspective, giving toward developing growth followed by functional the greater and tissue specific like is there any plan to look at <unk>.

<unk>.

Great. Thanks, great questions. So maybe I'll start with the second one.

We would look at.

What is the what is the unmet need and the problem that we're trying to solve.

I personally feel that.

80%.

The proteome roughly hopefully I don't have the number wrong is intracellular.

We have really great tools.

Today to drive extra cellular protein.

So the real opportunity for extracellular proteins you have.

If you are able to compete with.

Biologics by.

Developing molecules that you can be kind of as is.

As infrequently dosing as the antibodies do.

Or or or.

More or if you have an oral be greater or extra cellular protein. So I think there are clearly opportunities. There at this stage of the company I don't think Thats an area, where there is the.

The highest opportunity and risk reward.

<unk> at this stage, but as we continue to grow the company that might be.

Attunity is also to go into this space, we actually looked at that a couple of years ago and decided not to go into that particular space with regards to your first question on set three as we've said in the press release and also in the remarks that we made earlier.

The goal this year is to dose patients at.

At exposures in degradation profiles that we expect to be therapeutically relevant and we also hope and expect and are driving towards recruiting patients at those doses, where we expect to see clinical activity, meaning these are tumor types that we've seen frequently premium cleaning.

<unk> to be sensitive to set three degradation.

So what we expected to hopefully share.

This year is are we seeing.

Anti tumor response in patients that are.

Again.

Theoretically sensitive to set three degradation.

Right. So then at the right.

Again length of dosing and so it will be what we call. It initial proof of concept it will be.

Three degradation in the reputation elicit an anti tumor response.

As a reminder, please limit yourself to one question and the interest of time. The next question comes from <unk> Patel with B Riley. Please go ahead.

Good morning. This is Andy on for <unk>. Thank you for taking questions.

From us on <unk> first I understand that you are looking for meaningful clinical activity in both level three and four but have you observed any evidence of anti tumor activity so far.

It's just stable disease.

And then second you noted needing to maintain target knockdown for 72 hours and we're seeing robust target knockdown in plasma up the target proteins at growth and ILS, but they are rebounding to or above the baseline level near the end of the dosing interval do you anticipate tweaking the dosing.

Frequency, perhaps from every three weeks every two weeks to ensure adequate depletion of target proteins at all times and is sustained depletion actually need it based on your preclinical model for meaningful anti tumor activity.

Great I think these were three questions, but okay that's too.

The first one was.

I forgot already consumer activation.

Yes, so obviously, we what we said we expect to share data.

Scientific meeting or in an event in which we decided to share data and we decided not to give that kind of update.

In along the way so I guess I'm not going to answer that question on the second one which is the second and third.

Good question. So first I want to remind everybody that there are slides on our website that actually be degradation profile that we believe.

At least we know pre clinically we believe will translate clinically into anti tumor effect and good safety is the one where we degrade these proteins for about 72 hours and then we need to see full rebound of of those proteins before we those again, so actually the fact that by week three week.

The full recovery of these proteins not only.

Good, but it's necessary at least based on preclinical data to avoid <unk>.

<unk> neutropenia, and other and other safety events that come with image, we do have flexibility to change it.

Dosing paradigm is if we need to.

But right now we're really asking the biological question.

He is the degradation profile that we've seen pre clinically to be the most active in my view using tumors out of all the other agents that we've tested does that translate in similar levels of antitumor activity in the clinic I think only after we kind of answered. This question, we can start talking about.

Is there an opportunity to tweak the dosing one way or the other.

The next question is from Z issue with Baird. Please go ahead.

Good morning, Thanks for taking the question I have a quick one.

Our updated.

Corporate deck, you disclosed some of the discovery programs won't be around IL, four IL 13 pathway.

That's interesting can you talk about the sort of the.

The potential.

Essential advantage for using <unk>.

Our protein degradation approach versus a biologic approach and also talk about the unmet medical need.

And in.

In the us.

Diseases.

Yes.

Z Thats a great question, we only have a couple of minutes I could spend a couple of hours on this but just very quickly.

<unk>.

We've always we built the company with working in pathways, where there is high validation, where we believe protein degradation cannot lock the biology better fully or.

For sure with a better.

Technology, and so I think.

Im not going to reveal anything new that.

And antibody further for those for that particular pathway is probably going to be the largest drug.

In the market in the next few years.

And it has been approved.

And in other I believe for other indications.

And.

<unk>.

We believe that there is.

Both an opportunity to develop an oral drug in that pathway and obviously, we believe there is an opportunity to develop a better drug in desktop where meaning a drug with a better efficacy profile.

And so I don't have to do the math on the opportunities, but obviously if you look at the peaks in the D and the penetration.

How much money.

Drug makes a year you can imagine an oral small molecule that can serve that patient population in a better way.

What are the opportunities there. So that's really what we're trying to solve for had patients be treated with a backdrop.

Which we believe is what we're working on.

The next question comes from Timur <unk> with Raymond James. Please go ahead.

Yes. Thank you for the question. So just for <unk> just trying to understand.

Our strategy for the study is a little better I think Hs study starting first so do you think there will be an overlap in time.

Those two studies I just wanted to make sure that there is no gatekeeping factors in Hs Hs study like safety or efficacy data tell us they want to see before.

Starting to ADP study.

That's a great question.

Answer short because we're kind of ahead of time from our understanding there will be.

There's a high likelihood that there will be an overlap between the studies I don't believe there are.

There are expectations that will inform necessarily when and how the type of study will start but again this is.

We will talk more specifics as the studies initiate and that's those are questions that.

<unk> will have a better answer for it.

The next question comes from Geoff Meacham with Bank of America. Please go ahead.

Alright, Thanks for taking the question. This is Joe on for Jeff.

So we've talked a bit about the club for collaboration with Sanofi. So far I was wondering how are you thinking about additional partnerships and collaborations in the near term because you called them out in your press release as a strategic objective for the year can you provide a little bit of color on like what types of partnerships you may be pursuing.

Yes. It is.

Great question. So again try to be brief there is two to two ways to think about strategic partnerships, one is where our technology even assets.

Our early tools that will enable <unk> to grow better faster.

And then are there instead companies that we can partner some of our programs or our technology to create more value together.

This is independently developed bingo commercialized drugs and I will say that those both areas the areas that we always think about and.

I don't have any specifics to update right now, but obviously a company like <unk> with the expertise that we built there is way more than we could do than what we're doing and then the question is how do you get that debt.

How do you solve that right and I think at this point I don't have a specific update on it.

The last question today comes from Kelly <unk> with Jefferies. Please go ahead.

Okay, well congrats strong tenant onshore Kelly, thanks for taking our questions.

I have a question on <unk>.

Thanks.

Or can you provide more color on how you will work with.

Going forward do you anticipate continuing to engage with them over the course of phase two initiation in maybe expanding the collaboration.

Other will be our immunology program, that's coming up thank you.

So I mean, we had the fortune to have a really good partner with some of the along the way.

We will continue to say that because it's true.

We've worked very closely with them when we were rounding our program the program and we already are working very closely is now they are operationally and financially responsible for the program I will also remind everybody we have an opt in manganese before phase III so were fully vested in the.

Success of the programs not only we have committees in plays to obviously follow progress, but we actually have almost.

We clear biweekly interactions with them.

To make sure that we both give our best for the success of these drugs. So I have no doubt that that will continue to be the case I think there was a second question about other collaborations maybe I can't really comment on that for now the rest of our pipeline that we've talked about this is.

Our own in that for now what we're doing and continuing to to generate value would work fine on that you see to continue to.

The advanced these programs and create values and that's our goal at this point.

This concludes the question and answer session I would like to turn the conference back over to Melo for any closing remarks.

Yes, first I would like to thank everybody for listening to our call for the engaging Q&A.

You all had great questions hopefully, we did our best to answer them in the most comprehensive way possible.

Excited about what we've done but we've always said.

Five to do better year by year. So we hope and expect that 2023 would be even more exciting than 2022 and encourage everybody who follow us.

Reached out to us if you have further questions and we always wait for amazing data to speak for us. So.

We're excited to see how all of these programs unfold and had patients in a wide variety of indications. So thanks again for the time I apologies for being a bit late and.

Have a good rest of the day.

The conference has now concluded. Thank you for attending today's presentation you may now disconnect.