Q2 2022 Kymera Therapeutics Inc Earnings Call

Welcome to the Chimera Therapeutics quarterly conference call.

Unknown Executive: Welcome to the Kymera Therapeutics Quarterly Conference Call.

Unknown Executive: Leading the call for management are Nello Mainolfi, founder and CEO, Jared Gollob, Chief Medical Officer, and Bruce Jacobs, Chief Financial Officer.

Kalpit Patel: Please go ahead.

Leading the call from management are narrow.

<unk> founder and CEO , Jared Golomb, Chief Medical Officer, and Bruce Jacob Chief Financial Officer.

Kalpit Patel: Oh, hey.

Unknown Executive: After management's prepared remarks, we will open the call to your questions.

After managements prepared remarks, we will open the call to your questions.

To ask a question you May press Star then one on your telephone keypad.

Unknown Executive: To ask a question, you may press star then one, on your telephone keypad. To withdraw your question, please press star then two.

Draw. Your question. Please press Star then two and.

Unknown Executive: And please note, this event is being recorded.

And please note that see that as being recorded.

Unknown Executive: Before we get started, I would 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.

Before we get started I would 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 and results could differ materially from those expressed or implied by any forward looking statements.

Unknown Executive: Actual events and 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 Kymera's most recent filings with the SEC and any other future filings that the company may make with the SEC.

Various risks uncertainties and other factors, including those set forth in <unk>. Most recent filings with the SEC and any other future filings that the company may make with the SEC.

Unknown Executive: You are cautioned not to place any undue reliance, on these forward-looking statements, and Kymera disclaims any obligation to update such statements.

You are cautioned not to place any undue reliance on these forward looking statements and <unk> disclaims any obligation to update that.

Okay.

I will now hand, the call condello mineral fee founder and CEO .

Nello Mainolfi: I will now hand the call to Nello Mainolfi, founder and CEO.

Kalpit Patel: Good morning.

Unknown Executive: Please go ahead.

Go ahead.

Thank you operator, and thank you everyone for joining us on our second quarter results Conference call.

Nello Mainolfi: Thank you, operator, and thank you, everyone, for joining us on our second quarter results conference call.

Kalpit Patel: Thanks for squeezing me in here.

Nello Mainolfi: We're excited to share with you today the continued progress, we're making towards building Kymera into a best-in-class, fully-integrated, degraded medicines company.

We're excited to share with you today. The continued progress we're making towards building <unk> into a best in class fully integrated be greater.

As we reach our two year anniversary as a public listed publicly listed company. Later this month, we can be really proud of the period brilliant spending growth and achievement at Chimera.

Nello Mainolfi: As we reach our two-year anniversary, as a publicly-listed company later this month, we can be really proud of a period of really outstanding growth and achievement at Kymera.

Nello Mainolfi: I want to start by saying, that the second quarter has been significant for us, particularly in terms of substantial clinical progress we've made by advancing our three lead programs into important stages of their development, specifically with the first patients in our three first-in-class clinical programs, including commencing patient dosing in our Part C of our Phase I trial of KT474.

Kalpit Patel: A question on the stat three program.

Wanted to start by saying that the second quarter has been significant for us, particularly in terms of substantial clinical progress. We've made advancing our three lead programs into important stages of their development, specifically, we dose the first patients in our three first in class clinical program, including commenced commencing.

Kalpit Patel: Another drug developer recently demonstrated clinical activity in late-line liver cancer, with their inhibitor-based approach as a monotherapy.

Kalpit Patel: I guess based on these recent learnings, do we expect you to enrich that solid tumor arm with liver cancer patients, or are there other solid tumors that you're eyeing or prioritizing for this program?

Unknown Executive: Jared, do you want to take that quickly?

Patient dosing in a sea of our phase one trial of <unk> seven 4 billion.

Nello Mainolfi: This achievement ushers in a new phase for the company, as we look forward to demonstrating how targeted protein degradation, and these molecules in particular, can impact disease and patients' lives.

Unknown Executive: Yeah, Kalpen.

The achievement ushers in a new phase for the company as we look forward to demonstrating how targeted protein degradation and these molecules in particular can impact disease and patient lives.

Nello Mainolfi: This is just the start of our journey toward treating patients, in many disease areas, such as adretonitis separativa, atopic dermatitis through degradation of IREC4 with KT474, hematological malignancies and solid tumors with KT333, our selective STAT3 degrader, and mighty 88-newton B-cell lymphomas with our arachnid degrader, KT413, which has the potential to be the first precision medicine for this condition.

This is just the start of our journey towards treating patients in many disease areas such as other than either separate Teva atopic dermatitis through degradation of Eric <unk> with J P 474, Hematological malignancies, and solid tumors with <unk>, our selective stat <unk> and <unk>.

Unknown Executive: I mean, we've been exploring multiple different sort of solid tumor types preclinically, and, you know, we use those data to then drive ultimately whether we decide to enrich for those populations.

And B cell lymphomas, with our Iraq Committee, Greater Keith K T for <unk> III.

Which has the potential to be the first physician medicine could be its condition.

Nello Mainolfi: At Kymera, as evidenced by our initial programs, we have the ambitions and capability to really broadly apply our platform by expanding the drugable proteome to address inadequately drugged or undrugged targets, creating the potential for us to transform the lives of patients, which is really what the company was founded upon and is going towards.

Unknown Executive: So I think that will be based really on our preclinical data.

Okay, Meera as evidenced by our initial programs, we have the ambition and capability to really bulk broadly apply our platform by expanding the drag about proteome to address.

That didn't really drive brand drug targets, creating the potential for us to transform the lives of patients which is really what the company was founded upon and going towards we ended the second quarter in a very solid financial position with approximately $482 million.

Nello Mainolfi: We ended the second quarter, in a very solid financial position with approximately $482 million in cash.

$2 million in cash.

Nello Mainolfi: Three first-in-class DPD assets in clinical studies, one program, KT253, our MDM2 degrader, close to IND filing, and multiple preclinical candidates expected to drive us to our goal of at least one new IND per year, and productive collaborations with our partners, Sanofi and Vertex.

The first in class CPD assets in clinical studies, one program <unk> II <unk> III, our MDM to degree they are close to <unk> filing.

And multiple preclinical candidate expected to drive us to our goal of at least one new IMD per year and productive collaborations with our partners Sanofi and vertex.

We have multiple patient data sets expected by year end, including the part C data for Kt 474.

Nello Mainolfi: We have multiple patient data sets expected by year-end, including the Part C data for KT474, our patient cohort. Our plan is to share this data later this year with the medical, and investor communities, as well as with our partners, Sanofi, to enable their decision, around advancing KT474 into phase two studies.

Our patient cohort our plan is to share. These data later this year with the medical and Investor communities as well as with our partner <unk> to enable their decision around advanced to Katie for seven four into phase II studies.

Nello Mainolfi: Now, Jared will walk you through our recent progress and goals, for 2022 for each of our disclosed programs, before turning the call over to Bruce for then a financial update.

Unknown Executive: And also, you know, again, you know, within solid tumors, you know, our data so far suggests that, you know, combination of our drug with anti-PD-1 agents may be the most effective way to use the drug in solid tumors, whereas in liquid tumors like T and NK cell malignancies and a stat three dependent, we're expecting significant activity with our degrader as a monotherapy.

Now Gerry will walk you through our recent progress and goals for 2022 for each of our disposed programs before turning the call over to Bruce for then a financial update.

Nello Mainolfi: I will then finish with some concluding remarks before, handing the call back to the operator for a Q&A session in which Jared, Bruce, and myself will be available.

I will then finish with some concluding remarks before handing the call back to the operator for a Q&A session with Jared Bruce and myself would be available Jarrod.

Jared Gollob: Jared?

Thanks Noah.

Jared Gollob: Thanks, Nello.

Unknown Executive: But, yeah, the liver data is intriguing, so obviously we'll follow up on that.

Jared Gollob: We've made substantial progress, with our clinical programs this quarter, which I am excited to share.

Unknown Executive: We'll do two quick questions, and then we'll wrap.

We've made substantial progress with our clinical programs this quarter, which I am excited to share.

Jared Gollob: I'll start with our IRAC4 program, and our lead candidate, KT474, an orally available potential first-in-class degrader of IRAC4, a key protein involved in inflammation mediated by the activation of toll-like receptors and IL-1 receptors.

Unknown Executive: Yeah, the next question comes from Eric Joseph with J.P. Morgan.

I'll start with our <unk>.

Our core program and our lead candidate <unk> four seven for an orally available potential first in class or greater of Iraq for a key protein involved in inflammation mediated by the activation of toll like receptors and IL one receptor.

Eric Joseph: Please go ahead.

Eric Joseph: Hi, good morning, guys.

Eric Joseph: Just a follow-up on stat three.

Aberrant activation of these pathways as the underlying cause of multiple immune inflammatory conditions.

Jared Gollob: A barren activation of these pathways is the underlying cause, of multiple immune inflammatory conditions.

Jared Gollob: KT474 is being developed for the treatment, of TLR-IL-1R-driven immune inflammatory diseases with high unmet medical need, such as hydradenitis and brachyva, atopic dermatitis, rheumatoid arthritis, lupus, GI inflammation, and potentially others. KT474 is designed to block TLR-IL-1R-mediated inflammation, more broadly compared to monoclonal antibodies targeting single cytokines and to enable pathway inhibition that is superior to IRAC4 kinase inhibitors by abolishing both the kinase and scaffolding functions of IRAC4.

Eric Joseph: Can you talk a little bit about anticipated therapeutic index, any expectations around myelosuppression or neutropenia based on either mechanism or what we're seeing in the preclinical talks package?

<unk> four is being developed for the treatment of CLR INR, driven immune inflammatory diseases with high unmet medical need such as hidradenitis, Suppurativa atopic dermatitis rheumatoid arthritis lupus.

Inflammation and potentially others.

84, 704 is designed to block CLR INR mediated inflammation more broadly compared to monoclonal antibodies targeting single cytokines and to enable pathway inhibition that is superior to Iraq for kinase inhibitors by abolishing both the kinase and scaffolding functions of Iraq for.

We are collaborating with Santa Fe on the development of the greater candidates targeting Iraq war, including Kt sat before outside of the oncology and immuno oncology field.

Jared Gollob: We are collaborating with Sanofi on the development, of degrader candidates targeting IRAC4, including KT474, outside of the oncology and immuno-oncology fields. Late last year, we completed dose escalation, in over 100 healthy volunteers in the single ascending dose and multiple ascending dose portions of the KT474 Phase 1 trial, the first randomized placebo-controlled trial for a hetero-bifunctional degrader. The data demonstrated near-complete IRAC4, degradation in peripheral blood, mononuclear cells, and skin, robust inhibition of multiple ex vivo-stimulated disease-relevant cytokines, and a favorable safety profile.

Late last year, we completed dose escalation in over 100 healthy volunteers and the single ascending dose and multiple ascending dose portions of the KC 47, four phase one trial. The first randomized placebo controlled trial for a robot function will be greater.

The data demonstrated near complete Iraq board degradation in peripheral blood mononuclear cells and skin robust inhibition of multiple ex vivo stimulated disease relevant cytokines and a favorable safety profile.

At the annual meeting in May we disclose that Kt 474, degrades Iraq for and inhibit cytokine production in different immune and skin cell types.

Jared Gollob: At the SID annual meeting in May, we disclosed, that KT474 degrades IRAC4 and inhibits cytokine production in different immune and skin cell types, highlighting the broad impact of KT474 across multiple disease-relevant cell types and supporting the continued development of IRAC4 degraders in patients with HS, AD, and other IONR-TLR-driven autoimmune diseases of the skin, where IRAC4 plays a central role in the pathogenesis of inflammation.

Highlighting the broad impact of <unk> 74 across multiple disease relevant cell types and supporting the continued development of Iraq, where the greater in patients with Hs.

<unk> and other iowan RTL are driven autoimmune diseases of the skin for Iraq Port plays a central role in the pathogenesis of inflammation.

Jared Gollob: You can find that poster along with all our other publications in the scientific resources, section of our website.

Can find that poster along with all our other publications in the scientific resources section of our website.

Jared Gollob: Most recently, as Nello just mentioned, we are excited to share that we commenced dosing, patients in the patient cohort Part C of the Phase I clinical trial. Part C is an open-label study of KT474 that is expected to enroll up to a total of 20, patients with moderate to severe hydradenitis separativa or atopic dermatitis to examine the safety, PK, PD, and exploratory biomarker and clinical activity of this first-in-class degrader therapeutic.

Most recently as <unk> just mentioned we are excited to share that we commenced dosing patients and the patient cohort in part C of the phase one clinical trial.

Part C is an open label study of <unk> four seven and four that is expected to enroll up to a total of 20 patients with moderate to severe hidradenitis suppurativa or atopic dermatitis to examine the safety PK PD and exploratory biomarker and clinical activity of this first in class greater therapeutic.

While we are in the early stages of the patient cohort, we expect enrollment to progress as planned for us to disclose the data before year end.

Jared Gollob: While we are in the early stages of the patient cohort, we expect enrollment to progress as, planned for us to disclose the data before year end. KT474 is being administered daily on an outpatient basis for 28 days, with patients followed, through day 42. Patients will receive a daily dose of 75 milligrams of KT474 with food. This dose is expected to provide a plasma exposure that is approximately equal to that, achieved with the 100 milligram per day dose in the fasted state in healthy volunteers in the MAD portion of the trial, which showed maximal or close to maximal degradation in blood and skin and broad disease-relevant cytokine inhibition ex vivo.

80, 474 as being administered daily on an outpatient basis for 28 days with patients followed through day 42.

Patients will receive a daily dose of 75 milligrams of <unk> 74 with food.

This dose is expected to provide a plasma exposure that is approximately equal to that achieved with the 100 milligram per day dose and the fasted state in healthy volunteers in the <unk> portion of the trial, which showed maximal or close to maximum degradation in blood and skin and broad disease relevant cytokine inhibition ex vivo.

The goal for this study is to confirm that our PD and safety profile in patients is in line with what we have seen in healthy volunteers.

Jared Gollob: The goal for this study is to confirm that our PD and safety profile in patients is in, line with what we have seen in healthy volunteers. The PDM points include the impact of KT474 on IRAC4 levels in PBMC and in active HS and, AD skin lesions, as well as on the expression of pro-inflammatory gene transcripts in skin lesions and on both whole blood ex vivo cytokine induction and plasma biomarkers of inflammation.

The PD endpoints include the impact of <unk> 74 on Iraq, <unk> levels in <unk>, and an active Hs and 80 skin lesions as well as on the expression of pro inflammatory gene transcripts in skin lesions and on both whole blood ex vivo cytokine induction and plasma biomarkers of inflammation.

We are also undertaking an exploratory assessment of early impact on clinical endpoints, including eczema area and severity index or.

Jared Gollob: We are also undertaking an exploratory assessment of early impact on clinical endpoints, including, eczema area and severity index, or EASI for AD, total abscess and inflammatory nodule count for HS, as well as symptom scores and global assessments of disease severity for both AD and HS.

<unk> for <unk>.

Total assets and inflammatory natural account for Hs as well as symptom scores and global assessments of disease severity for both AE and.

Yes.

However, recall that this is an open label study without placebo and a small number of patients and we do not expect to reach steady state Iraq or degradation in skin until the second half of the four week dosing period.

Jared Gollob: However, recall that this is an open-label study without placebo in a small number of, patients, and we do not expect to reach steady-state IRAC4 degradation in skin until the second half of the four-week dosing period.

Jared Gollob: The objective of Part C, therefore, is to confirm PK, PD, and safety with the additional, information on early signs of clinical activity.

The objective of part C. Therefore is to confirm PK PD and safety with the additional information on early signs of clinical activity.

With regard to safety and Tolerability, which so far has been quite favorable with no serious adverse events with only few mild to moderate adverse events. We will continue to monitor the safety profile, including whether the modest non adverse qt prolongation that we observed with multi dosing in healthy volunteers that plateaued after seven days.

Jared Gollob: With regard to safety and tolerability, which so far has been quite favorable with no serious, adverse events and with only few mild to moderate adverse events, we will continue to monitor the safety profile, including whether the modest non-adverse QTC prolongation that we observed with multidosing and healthy volunteers that plateaued after seven days continues to show evidence that it is self-limited, but in this case, out to 28 days.

Continues to show evidence that it is self limited, but in this case out to 28 days.

We look forward to sharing the data from the patient cohort before year end.

Jared Gollob: We look forward to sharing the data from the patient cohort before year-end.

Jared Gollob: With respect to Sanofi and their decision to advance KT474 into Phase 2, we plan to, share these patient data with them as soon as they are available and expect a decision on their plans within the timeframe set forth in our collaboration.

With respect to <unk> and their decision to advance <unk> 474 into phase two we plan to share these patient data with them as soon as they are available and expect a decision on their plans within the timeframe set forth in our collaboration.

Moving on to our oncology programs. We are pleased to report that the three disclosed oncology programs Scot free Iraq, and <unk> are all progressing well.

Jared Gollob: Moving on to our oncology programs, we are pleased to report that the three disclosed, oncology programs, STAT3, Arachnid, and MDF2, are all progressing well.

Eric Joseph: And then from a PD perspective, particularly in solid tumors, can you just clarify if you're taking serial biopsies, will you be able to look at not only target degradation in the periphery, but also distribution or activity and impact in tumor samples as well?

Jared Gollob: First, I will discuss our STAT3 program. A target long considered undruggable, STAT3 is a transcriptional regulator that has been, linked to numerous cancers and other inflammatory and autoimmune diseases.

Eric Joseph: Thanks.

First I will discuss our stat three program.

Our target long considered undruggable fat free is a transcriptional regulator and has been linked to numerous cancers and other inflammatory and autoimmune diseases.

Unknown Executive: So, you know, we have options for biopsies in the dose escalation.

Unknown Executive: This is not mandated, given that this is an early dose escalation.

Jared Gollob: Our focus here is on developing selective STAT3 degraders for the treatment of hematological, malignancies and solid tumors, as well as autoimmune and fibrotic diseases.

Our focus here is on developing selective staff integrators for the treatment of Hematological malignancies, and solid tumors as well as autoimmune and fibrotic diseases.

We believe our SaaS integrators has the potential to provide a transformative solution to address multiple statutory dependant apologies.

Jared Gollob: We believe our STAT3 degraders have the potential to provide a transformative solution to address, multiple STAT3 dependent pathologies. KT333 is a potent and selective hetero-bifunctional small molecule protein degrader of the STAT3, protein in development for the treatment of liquid and solid tumors. Patient enrollment and dosing are ongoing in our phase one trial, which is evaluating, the safety, tolerability, PKPD, and clinical activity of KT333 in adult patients with relapsed and or refractory lymphomas and solid tumors.

Unknown Executive: So we're relying on really patients to help us there.

83, <unk> three is a potent and selective heterodyne functional small molecule protein integrator of the stat three proteins in development for the treatment of liquid and solid tumors.

Unknown Executive: And we, so we can't commit that we'll have the data, but we're trying to collect the tumor data.

Patient enrollment and dosing are ongoing in our phase one trial, which is evaluating the safety Tolerability PK PD and clinical activity of <unk> three in adult patients with relapsed <unk> refractory lymphomas and solid tumors.

Unknown Executive: And as you know, we are very keen on, as I've said, on translations, on also the correlation between PK and PT in blood and, and in tumor is important.

Unknown Executive: So we'll try and get there, hopefully.

The first stage of the study is exploring escalating doses of <unk> three.

Jared Gollob: The first stage of the study is exploring escalating doses of KT333. It is important to highlight that in order to expedite dose escalation, we have been, recruiting broadly in phase 1a across solid and liquid tumors in order to reach pharmacologically active doses as soon as possible, before then focusing on patient populations where we expect to see clinical activity, either as a monotherapy or in combination with other agents.

Unknown Executive: I think the first question was on safety.

It is important to highlight that in order to expedite dose escalation, we have been recruiting broadly in phase one a across solid and liquid tumors in order to reach a pharmacologically active doses as soon as possible before then focusing on patient populations, where we expect to see clinical activity either as a monotherapy or in combination with other agents.

Unknown Executive: I mean, at pharmacologically active doses, these compounds are quite well tolerated preclinically.

Unknown Executive: So we expect to see a similar profile in the clinic, but we will continue to monitor things and obviously report if there are things to be concerned about.

Unknown Executive: Sounds like last, last question.

Jared Gollob: The second stage will consist of four phase 1b expansion cohorts to further characterize, safety, tolerability, PKPD, and anti-tumor activity of KT333 in relapsed and or refractory peripheral T-cell lymphoma, cutaneous T-cell lymphoma, large granular lymphocytic leukemia, and solid tumors.

The second stage will consist of four phase <unk> expansion cohorts to further characterize safety Tolerability PK PD and anti tumor activity of <unk> hundred three three in relapsed <unk> refractory peripheral T cell lymphoma, cutaneous T cell lymphoma, large granular lymphocytic leukemia and solid tumors.

Jared Gollob: Dose escalation is expected to proceed throughout 2022, and we look forward to sharing preliminary, safety and proof of mechanism data before year end, with the goal, based on the broad population of liquid and solid tumors in phase 1a, of showing that we can attain levels of target degradation associated with anti-tumor activity in these relevant animal models at doses that are safe and well-tolerated.

Unknown Executive: Yes.

This escalation is expected to proceed throughout 2022, and we look forward to sharing preliminary safety and proof of mechanism data before year end with the goal based on the broad population of liquid and solid tumors and phase one way of showing that we can obtain levels of target degradation associated with anti tumor activity that is relevant animal models at doses that are safe.

Mike Kratky: The next question is from Mike Kratky with SBP.

Mike Kratky: Please go ahead.

Mike Kratky: SBB.

And well tolerated.

Recall that we are also exploring statute degradation and immune inflammatory indications using other stats for integrators.

Jared Gollob: Recall that we are also exploring STAT3 degradation in immune inflammatory indications using other, STAT3 degraders. To that end, at the UR Congress in June, we presented data showing that KTX115, a tool, STAT3 degrader, selectively and potently degraded STAT3 in human peripheral blood mononuclear cells and whole blood, abrogated STAT3 phosphorylation and MCP-CCL2 released by human monocytes more potently than JAK inhibition, and inhibited CD4 positive Th17 development and related cytokine production in vitro, and prevented collagen-induced arthritis in mice.

Mike Kratky: Yeah.

Mike Kratky: Hi, everyone.

And at the <unk> Congress in June we presented data showing that <unk> 105 tools pathway to greater selectively and potently integrated stats rates and human peripheral blood mononuclear cells and whole blood.

Corrugated statutory loss correlation in MCP <unk> released by human monetize more importantly, the JAK inhibition.

And inhibited CD four positive th 17 development and related cytokine production in vitro and prevented collagen induced arthritis in mice.

Jared Gollob: You can find those posters in the scientific resources section of our website.

Mike Kratky: Really appreciate you fitting me in here.

You can find those posters and the scientific resources section of our website.

Moving now to our argument program <unk> is a novel Araroba function integrated that targets degradation of both Iraq and the <unk> substrate grossing iOS with a single small molecule.

Jared Gollob: Moving now to our arachnid program, KT413 is a novel heterobifunctional degrader that, targets degradation of both IRAK4 and the imid substrates, the querosinolase, with a single small molecule.

Mike Kratky: In terms of the previously, disclosed QT finding, is there any plan to run a thorough QT-QTC study and then have a follow-up on efficacy?

Jared Gollob: KT413 was designed to address both the IONR, TLR, and the type 1 interferon pathways synergistically, to broaden activity against MIT88 mutant B cell malignancies.

<unk> hundred three was designed to address both the <unk> and type one interferon pathway synergistically.

<unk> activity against <unk> 88, B cell malignancies.

Jared Gollob: KT413 is on a similar timeframe as STAT3, with patient enrollment and dosing ongoing, in our phase 1 trial, evaluating the safety, tolerability, and PKPD of KT413 in patients with relapsed and or refractory B cell non-Hodgkin's lymphomas. The first stage is exploring escalating doses of single agent KT-413.

Any forward three is on a similar timeframe as stacked rates with patient enrollment and dosing of ongoing in our phase one trial evaluating the safety Tolerability and PK PD and <unk> for <unk> three in patients with relapsed <unk> refractory b cell non Hodgkin's lymphomas.

The first stage is exploring escalating doses of single agent <unk> four with three.

Using a similar strategy as I just described for the KC 333 phase one we are expediting dose escalation in phase one by enrolling a broad population of T cell lymphoma patients before then focusing on patients with whom we expect to see the most substantial clinical activity.

Jared Gollob: Using a similar strategy as I just described for the KT-333 phase 1, we are expediting, dose escalation in phase 1a by enrolling a broad population of B-cell lymphoma patients before then focusing on patients in whom we expect to see the most substantial clinical activity.

Jared Gollob: Specifically, the second stage will consist of two phase 1b expansion cohorts in DLBCL, to further characterize the safety, tolerability, PKPD, and anti-tumor activity of KT-413 and relapse refractory MyD88 mutant and MyD88 wild type DLBCL.

Typically the second phase will consist of two phase one expansion cohorts in <unk> to further characterize the safety Tolerability PK PD and anti tumor activity of <unk> in relapsed refractory <unk> 88, and <unk> 88, Wild type DLP ECL.

Jared Gollob: Dose escalation is expected to proceed throughout 2022, and we look forward to sharing preliminary, safety and proof of mechanism data before year end with the goal, based on the broad population of B-cell lymphoma patients in phase 1a, of showing we can attain levels of target degradation associated with anti-tumor activity and disease-relevant animal models at doses that are safe and well-tolerated.

Dose escalation is expected to proceed throughout 2022, and we look forward to sharing preliminary safety and proof of mechanism data before year end with the goal based on the broad population of B cell lymphoma patients in phase one a im showing we can obtain levels of target degradation associated with anti tumor activity and disease relevant animal models at doses that are safe.

And well tolerated.

I wanted to touch briefly on MDM to a program we announced for the first time at our R&D day late last year as we have shared we are very excited about the potential of this program.

Jared Gollob: I want to touch briefly on MDM2, a program we announced for the first time at our R&D, day late last year. As we have shared, we are very excited about the potential of this program. MDM2 is the crucial regulator of the most common tumor suppressor, P53, which remains, intact or wild type in more than 50% of cancers.

Mike Kratky: Can you just clarify whether you'll be reporting the mean reductions in EZ at day 28?

Mike Kratky: And if you may be reporting any other metrics such as EZ 50 or 75 or 90 in those atopic dermatitis patients?

Mike Kratky: Thank you.

<unk> is the crucial regulator of the most common tumor suppressor, <unk>, 53, which remains intact or wild type and more than 50% of cancers.

Our highly potent MDM due to greater <unk> III. Unlike small molecule inhibitors is able to suppress the MDM to feedback loop and thereby rapidly induce apoptosis.

Jared Gollob: Our highly potent MDM2 degrader, KT253, unlike small molecule inhibitors, is able to suppress, the MDM2 feedback loop and thereby rapidly induce apoptosis in susceptible P53 wild type tumors with brief exposure.

<unk> P 53, wild type tumors can brief exposure.

We believe <unk> has the potential to be effective in a wide range of hematologic malignancies, and solid tumors with functioning P 53.

Jared Gollob: We believe KT253 has the potential to be effective in a wide range of hematological malignancies, and solid tumors with functioning P53. Specifically, our use of biomarkers for an acute apoptotic response to MDM2 degradation, has enabled the identification of several indications where we expect to see robust activity and a favorable safety profile with intermittent IV dosing, such as AML, lymphomas, and multiple different solid tumor types, including but not limited to oovule melanoma, mesothelioma, colorectal, and breast cancer.

Specifically, our use of Biomarkers for an acute episodic response to MGMT degradation has enabled the identification of several indications, where we expect to see robust activity and a favorable safety profile with intermittent IV dosing such.

Such as AML lymphomas, and multiple different solid tumor types, including but not limited to uveal melanoma, mesothelioma, colorectal and breast cancer.

Jared Gollob: These all represent potential development opportunities for KT253 with patient selection, to be further guided by ongoing work focused on mutation and or gene expression profiles.

These all represent potential development opportunities for <unk> to five three with patient selection to be further guided by ongoing work focused on mutation <unk> gene expression profiles.

Jared Gollob: As planned, KT253 is currently in IND-enabling activity support, an IND filing in the second, half of 2022.

As planned <unk> 253 is currently in IND, enabling activities to support <unk> filing in the second half of 2022.

Before nello wraps up the call with some closing remarks, I will hand, the call to Chris Jacobs, Our Chief Financial Officer, who will share. Some brief comments on our financial results for the first quarter Bruce. Thanks, Jared I'll keep my comments brief for the quarter, we recognized $11 $5 million of revenue. This total reflects revenue recognized pursuant to our San.

Jared Gollob: Before Nelo wraps up the call with some closing remarks, I will hand the call to Bruce Jacobs, our chief financial officer, who will share some brief comments on our financial results for the first quarter.

Unknown Executive: Joe, why don't you take that one?

Bruce Jacobs: Bruce?

Unknown Executive: Yeah.

Bruce Jacobs: Thanks, Jared.

Unknown Executive: In terms of the, the endpoints themselves, you, know, we'll be analyzing, you know, those endpoints in a number of different ways.

Bruce Jacobs: I'll keep my comments brief. For the quarter, we recognized $11.5 million of revenue. This total reflects revenue recognized pursuant to our Sanofi and Vertex collaborations. And at the end of the quarter, our deferred revenue total on the balance sheet was approximately, $84 million. That reflects partnership revenue we expect to recognize over the next several years, excluding the receipt of any potential future milestones.

Unknown Executive: We haven't finalized exactly how we'll be looking at those endpoints such as the EZ and AD.

Unknown Executive: So really we'll provide more color on that, you know, once the data emerge.

Unknown Executive: The first, question was?

Nepean vertex collaboration.

Unknown Executive: The thorough QT study.

And at the end of the quarter, our deferred revenue total on the balance sheet was approximately 84 million that reflects partnership revenue, we expect to recognize over the next several years, excluding the receipt of any potential future milestones on operating expenses R&D for the quarter was $41 $3 million of that $4 8 million represented noncash stock based.

Unknown Executive: Oh, thorough QT.

Unknown Executive: Yeah.

Unknown Executive: You know, the fact that, you know, within our phase one, we've had extensive ECG monitoring in the healthy volunteer portions, including culture monitoring, and we detected this, you know, subclinical modest QT finding, I think that sort of precludes the need for any thorough QT study in the future.

Bruce Jacobs: On operating expenses, R&D for the quarter was $41.3 million. Of that, $4.8 million represented non-cash stock-based compensation.

Compensation, the adjusted cash R&D spend of $36 5 million, which excludes the stock based compensation.

Bruce Jacobs: The adjusted cash R&D spend of $36.5 million, which excludes the stock-based compensation, reflects a 14% increase from the comparable amount in the March quarter.

Flex a 14% increase from the comparable amount in the March quarter on the G&A side, our spending was $11 million of which $4 9 million was noncash stock based comp there. The adjusted cash G&A spend was $6 1 million that reflects 8% decrease from the comparable amount in the March quarter, and then finally, we exited the second quarter with a cash.

Bruce Jacobs: On the G&A side, our spending was $11 million, of which $4.9 million was non-cash stock-based, comp. There, the adjusted cash G&A spend was $6.1 million. That reflects an 8% decrease from the comparable amount in the March quarter.

Bruce Jacobs: And then finally, we exited the second quarter with a cash and equivalence balance of approximately, $482 million. That provides a runway based on our current anticipated spending levels into 2025. And recall that it's our policy not to include in our cash runway any payments for milestones, that we have not yet received.

And equivalents balance of approximately $482 million that provides a runway based on our current anticipated spending levels into 2025 and recall that it is our policy not to include in our cash runway any payments for milestone that we have not yet received with that I will turn it back to narrow for some concluding remarks. Thanks, Bruce So in conclusion, we are.

Nello Mainolfi: With that, I'll turn it back to Noah for some concluding remarks.

Nello Mainolfi: Thanks, Bruce and Jared.

Unknown Executive: We essentially, know sort of what we're dealing with and we'll be able to sort of do routine sort of ECG monitoring to sort of follow that finding.

We're clearly very excited about all that we've accomplished this year it came era as well as by all that.

In front of US we're in a strong position with an exciting first in class pipeline is progressing through the cleaning.

Nello Mainolfi: A best-in-class platform and discovery engine about which you will continue to hear as we, disclose more programs and data, productive partnerships with Virtex and Sanofi that allow us to extend across multiple disease areas, and a very strong casposition that you just heard from Bruce that enables us to continue to invest in high-value programs and generate several important data sets in the next few years.

Unknown Executive: Great.

Our best in class platform and discovery engine about which you will continue to hear as we disclose more programs and data.

Unknown Executive: Thanks, Jared.

Through partnerships with various fixed incentive fee that allow us to extend across multiple disease areas and a very strong cash position that you just heard from Bruce that enables us to continue to invest in high value programs and generate several important data sets in the next few years.

Nello Mainolfi: We're poised to deliver key clinical insights in the second half of this year and continue, to demonstrate the potential of our approach to targeted protein degradation to improve the lives of patients.

Unknown Executive: Maybe to wrap up, we're out of time.

We're poised to deliver key clinical insights in the second half of this year and continued to demonstrate the potential of our approach.

Unknown Executive: So no more questions.

Two targeted protein degradation to improve the lives of patients.

Unknown Executive: I know we're past our time, so I'll be very brief.

Nello Mainolfi: In the second half of the year, in fact, as you've already heard, we look forward to generating, for the first time key patient data, NHSNAD, from our KT474-IRF4 degrader program, as well as key proof-of-mechanism data in the two oncology clinical programs, KT413-IRF3 degrader and KT333-IRF3 degrader.

In the second half of the year's impact as you've already heard we look forward to generating for the first time key patients data in Hs and EDI from our TT posed to them for IRA four degree their program.

As well as key proof of mechanism data into two oncology clinical programs.

For <unk>, we mentioned earlier, our key goals for these dataset, but to just summarize briefly TCE for seven four we're looking to confirm that healthy volunteer PD and safety profile in this patient cohort.

Nello Mainolfi: We mentioned earlier our key goals for this data set, but to just summarize briefly, for, KT474, we're looking to confirm that healthy volunteer PD and safety profile in this patient cohort, which we believe could be a game-changing profile in the world of small molecule oral anti-inflammatory drugs.

Which we believe could be a game changing profiling the world's small molecule oral anti inflammatory drugs.

Nello Mainolfi: In oncology, we want to demonstrate that these molecules are behaving as predicted based, on our preclinical studies, and the translation of degradation and safety is happening in a predictable way.

In oncology, we wanted to demonstrate that these molecules are behaving as predicted based on our preclinical studies and the translation of degradation in safety is happening in a predictable way. If we can do this well, which we have competencies than we we can set clear expectations.

Nello Mainolfi: If we can do this well, which we have confidence in, then we can set clear expectations of, clinical activity starting from 2023 and beyond, once we will be focusing on our responders' population.

Nicole activities, starting from 2023 and beyond once we would be focusing on a responder population.

Nello Mainolfi: We're also very excited about the prospect of adding our fourth clinical program later, in the year with our MDM2 degrader, KT253, which we believe will have significant clinical potential.

We're also very excited about the prospect of adding a fourth clinical program later in the year.

With our MDM to degree that Q2, <unk> III, which we believe will have significant clinical potential.

We have also several earlier programs with clear degree the rationale and large commercial opportunities that we're advancing towards the clinic and we will be disclosing as we approach clinical investigation.

Nello Mainolfi: We have also several earlier programs with clear degrader rationale and large commercial, opportunities that we're advancing towards the clinic, and we'll be disclosing as we approach clinical investigation.

Nello Mainolfi: With the tremendous progress that we've made in mind, I want to thank the Chimera team, our collaborators, our partners, and at last, but not least, all the healthy volunteers and patients, which allow us to advance development of our potentially transformative therapies.

We did the tremendous progress that we've made in mind I want to thank <unk> collaborators partners and a lot.

Monopolies older healthy volunteers and patients, which allow us to advance development of a potentially transformative therapy.

Nello Mainolfi: Finally, I would like to thank all of you who have taken time this morning for our call.

Unknown Executive: I just wanted to thank everybody for joining in on our call and for all the really good, questions.

I would like to thank all of you with taking time. This morning for our call I look forward to a great Q&A discussion and for that I will hand, the microphone back to the operator, so that we can take your questions. Thank you again.

Nello Mainolfi: I look forward to a great Q&A discussion, and for that, I will hand the microphone back, to the operator so that we can take your questions.

Unknown Executive: We are excited, you know, beyond our expectation to be here in 2022 dosing patients with HSAD, lymphoma, solid tumors, leukemias, with programs that were all de novo first-in-class programs developed at Chimera within our team.

Unknown Executive: Thank you again.

Unknown Executive: We will now begin the question and answer session.

Unknown Executive: So this is an amazing accomplishment.

Unknown Executive: Obviously, we haven't accomplished anything until we impact the lives of patients.

We will now begin the question and answer session to ask a question you May Press Star then one on your telephone keypad. If you are using a speakerphone. Please pick up your handset before pressing the keys.

Unknown Executive: So we're focused on how to do that in the most responsible, data-driven, and thoughtful, way, and to continue to engage with you to make sure that there is continued communication with the external community so that we can advance these, hopefully, game-changing therapies and all the new generation programs that we haven't disclosed yet, and make Chimera this fully integrated commercial stage company in the next few years.

Unknown Executive: To ask a question, you may press star, then one on your telephone keypad.

Unknown Executive: So thanks again and have a good day.

Unknown Executive: The conference is now concluded.

Unknown Executive: Thank you for attending today's presentation.

Unknown Executive: If you are using a speakerphone, please pick up your handset before pressing the keys.

Unknown Executive: To withdraw your question, please press star, then two.

Your question. Please press Star then two.

And we also ask that you please limit.

Unknown Executive: We also ask that you please limit questions to one question and one follow-up.

One question and one follow up.

Unknown Executive: We will pause momentarily now to assemble our roster.

Unknown Executive: You may now disconnect.

We will pause momentarily to assemble our roster.

Our first question comes from Brad <unk> with Stifel.

Unknown Executive: The first question comes from Brad Canino with Stipple.

Unknown Executive: Title Microsoft Office Word Document MSWordDoc Word.

Unknown Executive: Document.8, [music]

Please go ahead.

Brad Canino: Good morning.

Good morning on K, two 474 can you share any additional findings from your preclinical investigations of the potential mechanism behind the Qt effect in and why it becomes saturated.

Observed in the phase one maybe previously discussed the Cardiomyocyte assay around the <unk> call, but is there anything else to add that you've done.

Brad Canino: On KT474, can you share any additional findings from your preclinical investigations of the potential mechanism behind the QTC effect and why it becomes saturated as you've observed in Phase 1?

And then on <unk>.

Some of your peers have had recent difficulty finding a therapeutic window for these given the on target Ikea is yet one neutropenia can you talk about your confidence in achieving the required Iraq for degradation within a feasible window and then maybe discuss the likelihood of observing any anecdotal clinical activity in <unk> 88 mutated <unk>.

Patients that might be enrolled within that all comer group. Thank you.

Brad Canino: I think you previously discussed the cardiomyocyte assay around the 1Q call, but is there anything else to add that you've done?

Thanks, Brad.

Brad Canino: And then on KT413, the Arachamid, some of your peers have had recent difficulty finding a therapeutic window for these given the on-target IKZF1 neutropenia.

Those were two questions, but we'll let it go at this time.

So just to address that.

At some level and then I'll, let Jared also jump in so maybe I'll start with the second one.

So what is our approach with the Iraq commit degree there as we've said early on.

The hypothesis there is to have a synergistic cell autonomous anticancer effect, meaning that the biology of <unk>.

Direct for degradation and the biology.

B groh of denials degradation intersect in my view using lymphoma to provide a very substantial.

Synergistic anti tumor effect in both in vitro and in vivo.

The way that we've managed the combination in a single molecule has been to really understand fully the key 90, some degradation the impact on the <unk> side and then the <unk>.

<unk>.

Management of the well known E made pharmacology, which as we all know.

Well characterized both the one on ones that I think we have two major differences from what has been done in the past one is that from IRA export degradation, we expect to see no contribution to unwanted pharmacology, meaning we know it adequately degradation as well tolerated so.

Brad Canino: Can you talk about your confidence in achieving the required IRAC4 degradation within a feasible window?

Brad Canino: And then maybe discuss the likelihood of observing any anecdotal clinical activity in MIT88 mutated patients that might be enrolled within that all-comer group.

Brad Canino: Thank you.

The only let's say.

Pharmacology that we need to monitor it from the.

The EBIT part and as we know our drugs actually behave quite differently from any other drug that have been tested with this mechanism. We those are drive once every three weeks and we have a PK PD profile that allow us to have profound degradation for the first two to three days and then we see a recovery.

<unk> targets as well as the recovery of some blood.

Cell types, which we know can be impacted by EBIT biology, and so the combination of kind of PK PD and are those in our ability to do gene frequently given that we're able to drive really strong doses in early days and then we don't need to continue to do is allow us to have.

Unknown Executive: Thanks, Brad.

Unknown Executive: So, technically, those were two questions, but we'll let it go this time.

Unknown Executive: So, just to address at some level, and then I'll let Jared also jump in.

Unknown Executive: So, maybe I'll start with the second one.

A safety profile that is.

We think very manageable I mean, we've started these extensively in nonhuman primate.

Unknown Executive: So, what is our approach with the Arachamid degrader?

And we expect that profile to translate well into cleaning I will only also add one more thing, which we said in meetings.

Portability to share broadly.

We are I guess the company that focuses on translation of PK PD, which is the core of the technology Youre looking at protein levels.

So thats really what were translating into cleaning and so when we've selected our starting dose in all of our trials.

We have been.

Targeting.

The PK PD profile or a degradation profile that we believe will allow us to both understand the translation and Derisk. The translation. So in all of our oncology trials, especially learning from KCG posted before we've been able to translate.

Digitization profile that we believe was quite conservative and de risk. So that we will learn in human.

The kinetics.

And in a productive manner.

On the 47, four and then I'll pass it to Jarrett comment on both.

I don't know that we have any particular update what we've said.

In the past very clearly is that.

These qt finding.

First of all not adverse so obviously, we're talking about a known adverse event, which we brought it up so we're happy to discuss it.

That's the context.

One dose responsive any self limiting in we believe exaggerated based on the fact that we have.

A mild.

CBD for the hurt channel that seems to be saturated by how the molecule distributes.

Tissues.

And I think the fact that this this.

This finding is non dose responsive and non concentration response is the most important aspect that de risks the profile of the molecule going forward because really what we are avoiding is the exclusion of qt that goes into areas, where the risk of a reason to retire.

In all cases, we've seen so far but Jerry maybe you want to contextualize the mechanism based on the latest.

In terms of the mechanism from the in vitro work with the Ibs C. Cardiomyocyte I think what's been encouraging to us is that what we've seen in vitro really does mirror, what we've seen in vivo in healthy volunteers and that the effect, we see on current and these cardiomyocyte due to this.

Mild effect on herd is delayed which is consistent with the delayed effect that we see in vivo also importantly, it really does appear to be youll compound specific not due to any on target effect I think extending it was shown that the effect were seeing on herd is not due to degradation of Iraq, four we'd be able to show that by user.

Another Iraq border greater in this in vitro system at the great direct work quite well it has no impact whatsoever on her.

Unknown Executive: As we said early on, the hypothesis there is to have a synergistic cell-autonomous anticancer effect, meaning that the biology of IRAC4 degradation and the biology of E. coli degradation intersect in MIT88 mutant lymphoma to provide a very substantial synergistic antitumor effect, both in vitro and in vivo.

Coming back to your question on whether we're going to be able to see any activity at <unk> 88 mutant lymphoma.

Unknown Executive: The way that we've managed the combination in a single molecule has been to really understand fully the kinetics of degradation, the impact on the right cell type, and then the potential management of the well-known image pharmacology, which, as we all know, is well-characterized, both the wanted and unwanted.

Unknown Executive: I think we have two major differences from what's been done in the past.

During dose escalation.

As I mentioned, we are enrolling a broad population of T cell lymphoma in phase one as it really helps to expedite moving through dose escalation. Our goal we know from our preclinical studies that 60% to 80% knockdown of Iraq for and the image substrates and growth in islands is what is required for anti tumor activity in it.

<unk> lymphoma.

So while we are rolling a broad population of B cell lymphoma in phase one once we get up to doses that are giving us that 60% to 80% knockdown, we probably will start to make an effort to bring on more <unk> patients than maybe even a few might be 88 in patients with possible as we get through towards the end of phase one.

We may have some anti tumor activity in my view.

Populations, but really are our primary goal is to really focus on anti tumor activity in phase one b, where we then specifically enroll <unk> wild type <unk> and that will really happen next year. So our goal for what we plan to report out later this year is really focused on as <unk> was saying before that we can.

Obtaining the desired sort of knockdown of.

These three targets that is associated with anti tumor activity pre clinically and we can do it at doses that are safe and well tolerated.

Yes, and then really de risking the molecule right as I said in the remarks earlier, it's about making sure that the molecule has the profile. There is in line with what we seem to be really active pre clinically if we can show that basically the degradation and safety than we've derisked the molecule than the bylaw.

Unknown Executive: One is that from IRAC4 degradation, we expect to see no contribution to unwanted pharmacology, meaning we know that IRAC4 degradation is well-tolerated.

Unknown Executive: So, the only, let's say, pharmacology that we need to monitor is from the image part.

Electrical and clinical question will be on us once we focus more of my view using patients which will be.

As soon as we can most likely in 2023 and beyond.

Thanks, Brad.

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

Hey, guys. Thanks for taking my questions I had.

Couple on K T 474 as well.

On the Q T.

Thanks.

Assuming that.

This non adverse.

In our level of Qt prolongation.

Is being confirmed in the patient study.

I guess, what is your expectation how that might potentially affect.

The longer term clinical potential of the drug.

Is there an expectation for example of that.

That would preclude certain patients down the road from potentially using that drive or certain combinations that might be affected by that.

And the other question I had is just on a part C on the exploratory clinical endpoints.

Understanding that it is non.

Placebo controlled and as you said steady state knockdown. It is only a range in the second half of this or four week period, but I guess is there a certain level of efficacy that <unk>.

Based on these outcomes in <unk> that one would expect they are hoping to see based on that PK PD off the top of the drug. Thanks, so much.

Okay.

Thanks.

Maybe just to address a couple of questions here.

From Michael So the first one and then I'll pass it to Jerry maybe more for the second one but so we've done as you can imagine.

Sensitive work on trying to.

Contextualized contextualize.

These non adverse events <unk>.

For for moving forward this drive towards clinical and commercial success and so our view is this.

If the finding remain within the range that we observe we have observed so far.

We expect that there would be no impact on clinical regulatory and commercial success.

Success of this drug and I'll explain a bit where we're coming from.

For a 10 to 20 milliseconds, especially in the absence of concentration dependency and large excursion than what we're talking about is something that slightly modified let's see the baseline of subjects that never really reaches.

Area of.

Really high risk of arrhythmia, so from from our early.

The exploration.

We are expert as well as be the interaction with FDA, we expect that we.

We can advance this molecule in a broad variety of disease indications.

Regardless of.

Kind of background and then.

Jerry will comment on which specific small number of patients may not be.

Suited for for this for this particular drug.

With this profile, but so then going back to regulatory so what we've seen based on FDA databases as well as work that we've done ourselves.

Is that for 10 to 20 milliseconds Qt changes usually what we've seen is maybe the most impactful kind of label.

Impact we've seen.

Morning, and precautions statement.

I say, it's usually these drug can extend EQT would be aware in case you take on the other drugs that can extend beauty and in terms of commercial.

Success I mean, we've seen these and also talking to.

Two.

Scribing doctors in this space is that with these type of.

Our profile there is no expectations of having to have monitoring associated with prescription of the drug and in the absence of monitoring then I think the uptick should be should be just as.

Any other drug that might not have this particular, finding and maybe John you can comment on this subset of patients that we might be.

Not selecting renewable development plan, yes, I mean, I think we feel as though this should affect very few patients in the targeted indications patients who have <unk>.

A prolong qt at baseline and there are rare patients, we had sort of hereditary syndromes.

Qt prolongation or patients who are on other drugs that they cannot come off of that are clearly shown to prolong the qt interval those would be the sort of patients that would not be able to go onto a study it might be excluded from use of the drug.

If approved and commercially available, but we expect that to be a very small.

A fraction of the total patients who would be eligible for this treatment.

Then going back to the part C. Again, maybe we'll double team here as well just as the high level I just want to reiterate.

The goal of the study as we've been saying for now two years will go obviously the focus has been more recently given that the studies.

In progress.

But we've always said that the desire here. The goal was to demonstrate that transitioning this technology from healthy volunteers to patients and I just wanted to remind everyone everybody, we actually haven't said that.

But I've said it in social media. This is the first drug that has gone in patients outside of oncology are coming from our hydro bye bye.

Unknown Executive: And as we know, our drugs actually behave quite differently from any other drug that has been tested with this mechanism.

Unknown Executive: And so, the combination of kind of PKPD and our ability to dose infrequently, given that we're able to drive really strong apoptosis in the early days, and then we don't need to continue to dose, allow us to have a safety profile that is, we think, very manageable.

By functional and be greater mechanism. So.

So the actually the reason for running the patient studies exactly for that reason, we wanted to see that going from healthy volunteers to patients.

Where again there is a plethora of zelle thought that contribute to the pharmacology. We wanted to make sure that degradation profile was maintained. So this was the initial design reason for designing the study and I'll remind everybody. The initial study design with 14 days now we've learned.

Unknown Executive: And we've studied this extensively in non-human primates, and we expect that profile to translate well in the clinic.

Unknown Executive: I will only also add one more thing, which we said in meetings, maybe this is an opportunity to share broadly.

From the healthy volunteer study new things until we adopted this study to the new things that we've learned so we moved from 14 days to 28 days and the reason for moving from 14 days to 28 days has been because.

Unknown Executive: We are, I guess, a company that focuses on translation of PKPD, which is the core of the technology.

Unknown Executive: You're looking at protein levels, and so that's really what we're translating in the clinic.

For two reasons, one we've seen that skin degradation in two weeks if not has not reached steady state and so we wanted to make sure we reach steady state. So the when we select phase two dose we do with that information in hand, the second one we uncovered this qt finding in the healthy volunteer study.

Unknown Executive: And so, when we've selected our starting doses, in all of our trials, we have been targeting a PKPD profile or a degradation profile that we believe will allow us to both understand the translation and de-risk the translation.

Unknown Executive: So, in all of our oncology trials, especially learning from KT474, we've been able to translate in a degradation profile that we believe was quite conservative and de-risked, so that we would learn in human the kinetics in a safe and in a productive manner.

Unknown Executive: This QT finding is, first of all, non-adverse.

Unknown Executive: So, obviously, we're talking about a non-adverse event, which, you know, we brought it up, so we're happy to discuss it.

We saw that between day, seven and day foreseen, we had reached steady state of plateau of these mechanism we wanted to confirm by extending the study.

Tumor week, so that we would de risk running.

The 16 week Phase II study.

So this is really the backdrop. So the goal is confirming PPE and confirming safety now given that we've extended to 20 days and given other data with other molecules. We're in 28 days. There has been some early signs of clinical efficacy we have either these exploratory clinical endpoints.

Unknown Executive: But that's the context.

Unknown Executive: It's non-dose responsive, and it's self-limiting, and we believe it's saturated based on the fact that we have a mild affinity for the herd channel that seems to be saturated by how the molecule distributes in tissues.

Unknown Executive: And I think the fact that this finding is non-dose responsive and non-concentration responsive is the most important aspect that de-risks the profile of the molecule going forward.

Unknown Executive: Because, really, what we are avoiding is the excursion of QT that goes into areas where the risk of arrhythmia is higher, which in no cases we've seen so far.

<unk>.

Again, our focus is on the PD and safety and we'll be happy to collect and share any data on efficacy, but as Jared said earlier given that we expect to reach maximum pharmacology one in the back.

Unknown Executive: So, Jared, maybe you want to contextualize a bit the mechanism based on the latest?

Jared Gollob: Yeah, in terms of the mechanism from the in vitro work with the iPSC cardiomyocytes, I think what's been encouraging to us is that what we've seen in vitro really does mirror what we've seen in vivo in healthy volunteers in that, you know, the effect we see on current, in these cardiomyocytes due to this mild effect on herd is delayed, which is consistent with the delayed effect that we see in vivo.

Jared Gollob: Also, importantly, it really does appear to be, you know, compound specific, not due to any on target effect.

Jared Gollob: I think we've definitively shown that the effect we're seeing on herd is not due to degradation of IRAC4.

Jared Gollob: We've been able to show that by using, you know, another IRAC4 degrader in this in vitro system that degrades IRAC4 quite well, but has no impact whatsoever on herd.

The back two weeks of the study.

Jared Gollob: You know, coming back, Brad, to your question on whether we're going to be able to see any activity in MI-D88 mutant lymphoma during dose escalation, you know, as I mentioned, you know, we are enrolling a broad population of B cell lymphoma in Phase 1a, to really help to expedite moving through dose escalation.

Jared Gollob: Our goal, you know, we know from our preclinical studies that 60 to 80% knockdown of IRAC4 in the immunosubstrate zikrosinol is what is required for anti-tumor activity in MI-D88 mutant lymphoma.

Jared Gollob: So while we are rolling a broad population of B cell lymphoma in Phase 1a, once we get up to doses that are giving us that 60 to 80% knockdown, we probably will start to make an effort to bring on more DLBCL patients and maybe even a few MI-D88 mutant patients.

Be unfair that expectations from that point of view, but again, we remain committed to sharing that data and we will share with all of you.

Jared Gollob: So it's possible as we get through toward the end of Phase 1a, we may have some anti-tumor activity in MI-D88 mutant populations.

Jared Gollob: But really, our primary goal is to really focus on anti-tumor activity in Phase 1b, where we then specifically enroll MI-D88 mutant and wild-type DLBCL, and that will really happen next year.

Jared Gollob: So our goal for what we plan to report out later this year is really focused on, as Nella was saying before, that we can obtain the desired sort of knockdown of these three targets that is associated with anti-tumor activity preclinically, and we can do it at doses that are safe and well-tolerated. Yeah, and really de-risking the molecule, right?

Jared Gollob: As I said in the remarks earlier, it's, about making sure that the molecule has the profile that is in line with what we've seen to be really active pre-clinically.

Jared Gollob: If we can show that, basically, the degradation and safety, then we've de-risked the molecule.

Jared Gollob: Then the biological and clinical question will be asked once we focus more on MID-88 mutant patients, which will be as soon as we can, most likely in 2023 and beyond.

The next question is from Chris Sheppard Tony with.

<unk>. Please go ahead.

Jared Gollob: Thanks, Brad.

Hey, Chris we can't hear you if you're on mute.

Michael Schmidt: The next question is from Michael Schmidt with Guggenheim.

Can you hear me now.

Yes.

Yes, Okay I apologize for that.

Michael Schmidt: Please go ahead.

Part C study for <unk> hundred 74 on dosing and patient selection you made the modification to the 75 milligrams in the fed state can you just.

Make sure that we all understand the basis for that selection of the change and then secondly, with the two types of patients.

Hs and <unk>.

Will.

Should be a differential in terms of the kinds of exploratory responses that you might see.

From this part C group based upon your understanding of the kinetics of degradation as well as kind of the kinetics of the pathophysiology of the different diseases States I realize that we're only going out to 28 days, but if there's any basis for thinking that there might be a difference between those two patient types that would be held.

Up to now and would you share that and break out that data based upon those patient types.

Thanks, Chris maybe Joe do you want to take this one yeah, hi, Chris So maybe starting with your first question why the 75 milligram dose just to clarify which is that our aim all along has been to bring in what we call the.

Michael Schmidt: Hey, guys.

Michael Schmidt: Thanks for taking my questions.

Sort of minimally efficacious dose into part C, meaning the smallest dose that gives us maximum pharmacology that we think would be associated with down the down the road with clinical activity from the part B, we determined that the 100 milligram dose, which was administered in a fasting state with giving us maximum knockdown in the blood near maximum.

Michael Schmidt: I had a couple on KT474 as well.

Michael Schmidt: On the QT, signal, assuming that this non-adverse level of QT prolongation is being confirmed in a patient study, I guess, what is your expectation how that might potentially affect the longer term clinical potential of the drug?

Michael Schmidt: Is there any expectation, for example, that would preclude certain patients down the road from potentially using the drug or certain combinations that might be affected by that?

Lockdown in the skin and also significantly impacting <unk> side kind of injection. So we really saw that as a minimally effective dose.

Michael Schmidt: The other question I had is just on Part C, on the exploratory clinical endpoints.

Now in the healthy volunteer study. These subjects were all treated on inpatient basis in part C. In patients. This is all going to be done on an outpatient basis 28 dosing. So it is not practical it's really to dose subjects in the fasting state. If we wanted to make sure we can dose them in the fed state we did observe a very modern.

Michael Schmidt: Obviously, understanding that it is non-placebo controlled and, as you said, the steady state knockdown is only reached in the second half of this year, four-week period.

Food effect.

That led to a modest increase in plasma exposure in the presence of food. So we did an additional.

Food effect cohort to determine what is the dose in the fed state and would give us the same plasma exposure at a 100 milligrams in the fasting state and we found out from that cohort that that dose is 75 milligrams and that's the dose that we're bringing into part C.

With regard to your question around.

Michael Schmidt: But I guess, is there a certain level of efficacy that, based on these outcomes in ADNHS, that one would expect or hoping to see based on that PKPD of the drug?

Michael Schmidt: Thanks so much.

Unknown Executive: Thanks.

Purchase versus Hs and the ability to detect a clinical signal.

We note that in studies using active agents were subject to treated for a long period of time 12 to 16 weeks you can see signs of clinical response as early as 28 days in either <unk> or <unk>. So.

So we don't expect if we were to see any clinical signal for there to be any advantage of ADP or Hs, which is why we're planning on accruing approximate equal number of <unk> in Hs patients to part C.

Restricting the enrollment of patients with moderate to severe disease.

Unknown Executive: Maybe just to address a couple of questions here from Michael.

Maybe I just want to add a couple of things.

Just to clarify so we expect 75 makes those who have the same activity in terms of PD 100 mix those in the <unk> cohort. That's the go it's pure math actually has nothing to do with us.

Unknown Executive: The first one, and then I'll pass it to Jared, maybe more for the second one.

Unknown Executive: We've done, as you can imagine, extensive work on trying to contextualize these non-adverse, event QT findings for moving forward this drug towards clinical and commercial success.

Unknown Executive: Our view is this, if the findings remain within the range that we have observed so far, then, we expect that there will be no impact on clinical, regulatory, or commercial success of this drug. I'll explain a bit where we're coming from.

<unk> of the exposure 75 is the same as the exposure 100, whether you'd further dawn <unk>.

Depending on the two doses the other part is obviously on the second part.

The physiology is very different.

<unk>.

Eric for degradation impact on budgets etiology of those two diseases might be different so we actually don't know the.

The question is that's why the 28 day study has to be focused on does the molecule do what it's supposed to do this is degrade and is well tolerated because we want to leave the real answer to your question in a 12 to 16 weeks study.

To be fair.

The other key point here is that one reason why we are not sort of pacing our focus so much on the clinical endpoint for on the PD endpoints is what's most important in either <unk> or <unk> is that we are able to observe with Iraq for knockdown in the scanner, which we want to achieve at least 85% or greater knockdown, we can see an impact.

The expression of pro inflammatory gene transcripts and those gene transcripts that are elevated at baseline that could be different in <unk> versus <unk>, but the key is that we want to see downregulation of those transcripts in conjunction with downregulation of Iraq, where protein expression, if we see that in <unk> as well as in Hs, regardless of what we see in <unk>.

A clinical endpoint that four weeks that will give us confidence moving forward that we should be able to impact the natural history of the disease for either of those diseases with studies of longer duration that we would be able to test in phase III.

The next question is from Richard <unk> with Credit Suisse. Please go ahead.

Hi, guys good morning.

Can you talk more about the type of patients that you are recruiting for the phase one study regarding the use of priority.

Any information on this type of patients that you're recruiting will be great.

Unknown Executive: For a 10 to 20 millisecond, especially in the absence of concentration dependency and, large excursion, then what we're talking about is something that slightly modifies, let's say, the baseline of subjects that never really reaches an area of really high risk of arrhythmia.

And also a follow up question that would be.

Unknown Executive: From our early exploration, both with our experts as well as with interaction with FDA, we expect that we can advance this molecule in a broad variety of disease indications regardless of the background.

You mentioned earlier that the 10% to 20 minutes.

Monetary thresholds.

<unk> threshold for TTC prolongation debt.

Monitoring from the FDA. Thank you.

Unknown Executive: Then Jared will comment on which specific small number of patients might not be suited for this particular drug with this profile.

I think in terms of your first question in terms of the patient population for part C. And these will be Hs in 80 patients with moderate to severe disease.

There could be treatment naive patients or they could be patients who have had prior treatments, including prior biologic therapy patients.

Our on biologic therapy is there really any therapies at the time that they are screened for the study they would need to come off of those treatments and we have an appropriate washout period for different therapies that are written in the protocol. So they will not be able to come onto the study.

And be on concurrent medications will have to come off of those before they can go on to <unk> 474.

The other question was about the Q I'm sorry in terms of the Qt and what's sort of Qt excursions will be required for monitoring and as Alex said.

Unknown Executive: Going back to regulatory, what we've seen based on FDA-based databases as well as work, that we've done ourselves is that for 10 to 20 milliseconds, QT changes.

Had extensive discussions with our cardiology consultants and they all unanimously believed that for a 10 to 20 minutes I can change there would be no need for cardiac monitoring probably.

Unknown Executive: Usually what we've seen as maybe the most impactful kind of label for this particular, impact, we've seen some warning and precaution statement that says usually, you know, this drug can extend QT. Be aware in case you take other drugs that can extend QT.

Unknown Executive: And in terms of commercial success, I mean, what we've seen is, I mean, also talking to prescribing doctors in this space is that with this type of profile, there is no expectations of having to have monitoring associated with prescription of the drug.

Excursion that is routinely sort of going beyond say 40 milliseconds or greater.

Unknown Executive: And in the absence of monitoring, then I think the uptake should be should be just as any other drug that might not have this particular finding.

As a level that might require some degree of cardiac monitoring, but again it really all depends on what's happening to the Qt interval itself is going beyond 500 milliseconds. When does the risk of cardiac arrhythmia that would all have to be looked at in totality by FDA ultimately in order to determine what would be the labeling implications and whether any sort of cardiac monitoring would be necessary.

Jared Gollob: And maybe Jared, you can comment on what are the subset of patients that, you know, we might be not selecting in our clinical development plan?

Yeah.

Jared Gollob: Yeah, I mean, I think we feel as though this should affect very few patients in the target, indications, you know, patients who have, you know, a prolonged QT at baseline, and there are rare patients with sort of hereditary syndromes resulting in QT prolongation or patients who are on other drugs that they cannot come off of that are clearly shown to prolong the QT interval.

Jared Gollob: Those would be the sort of patients that would not be able to, you know, go on to our study, it might be excluded from use of the drug, you know, if it approved and commercially available, but we expect that to be a very small fraction of the total patients who would be eligible for this sort of treatment.

The next question is from Vikram pure journey with.

Morgan Stanley . Please go ahead.

Good morning, Thanks for taking my questions.

Jared Gollob: And then going back to the Part C, you know, again, maybe we'll double team here as well.

Unknown Executive: Just at the high level, I just want to reiterate the goal of the study, as we've been saying, for now, you know, two years, although obviously, the focus has been more recently, given that now the study is in progress.

Unknown Executive: But we've always said that the desire here, the goal was to demonstrate that transitioning this technology from healthy volunteers to patients, and I just want to remind everybody, we actually haven't said that, but I've said it on social media, this is the first drug that has gone in patients outside of oncology, coming from a heterobifunctional degrader mechanism.

So maybe looking at your earlier stage pipeline beyond 474 could you comment a bit on the antenna development plan for 253 once the IND is filed later this year and what you would expect the news flow for the <unk> program to look like in 2023.

Unknown Executive: So the actual, the reason for running the patient studies, exactly for that reason, we wanted to see that going from healthy volunteer to patients, where again, there is a plethora of cell type that contribute to the pharmacology, we wanted to make sure that degradation profile was maintained. So this was the initial design, reason for designing the study.

Unknown Executive: And you know, I'll remind everybody, the initial study design was 14 days.

Unknown Executive: Now, we've learned from the healthy volunteer study, new things.

Unknown Executive: And so we adopted the study to the new things that we've learned.

Then secondly could you give us an update on your efforts with.

The molecular glu programs, you've alluded to before and when do you anticipate having.

<unk> candidate there to talk about.

Yes, Thanks, Vikram, maybe I'll try and answer this question more broadly and then if we need to.

Gerry can help me to.

So the reason why we start with the MDM to program because we felt it was an area of.

Clinical investigation and commercial opportunity that had been there has been untapped bye bye.

Bye.

The space I think the biology of <unk>.

Tumor.

Key tumor suppressor gene and the ability to stabilize P 53 in a variety of tumor has been the focus of many efforts, but I think has been.

Maybe from it for me not be appropriate not using the appropriate technology. So we discover that.

In order to replicate the cancer genetics.

Lead removal of MGM two was needed.

And so the applicability of this concept of removing MDM to the stabilized.

Three an impact a broad variety of tumor.

Is is large.

The team is focusing on at the moment these how we select and prioritize indications.

So I think as Jerry had mentioned earlier.

Very very strong keys or degrading MDM too in AML, given existing data given cancer genetics and given some preclinical data that we've generated that.

Very very elegantly demonstrates that MDM to degradation is up there.

The mechanism is a mechanism to go after especially in refractory or resistant to be neither blocks patients, which is an area that we're trying to expand but obviously, we would not develop this asset <unk> was the only place to go and so we're we're we're expanding our.

Investigation and many other tumors. Both leap. We then saw there then we'll we'll disclose more data as we as we commit to those area of investigation, So I would say.

First.

Kind of first in human study will start.

Towards end of the year early next year.

With.

Probably both the solid in AML.

Approach and then there would be expansion cohorts in different indications I expect that in terms of news flow and we will have again a molecule derisking early on so as we've done as we've been discussing for four <unk> hundred and 333 is 250, <unk> degrading the target with kinetics and safety.

We believe based on preclinical model is therapeutically relevant so there will be the early proof of mechanism, which.

I don't want to start now setting up expectations, but I expect that that would be something that will focus on next year and then soon after that we'll be talking about in which indication we expect to see proof of concept.

Going back to your broader question. So we have.

Rather TBD is normally three-legged discovery that is applied both too.

Normally three legged enabled hydro by functional degradation as well as novel, it's relying ACD, both molecular glues driven degradation.

I think it is fair to say that.

These programs are still in the discovery stage.

And I think once we're ready to disclose the program I think it would be when we're close to the clinic. So we're going to we're going to choose to keep our cards close to the best on the early early discovery pipeline, because it's a highly competitive space and to be honest I don't think were given.

Any credit for anything that is early so I think it's probably not a smart thing to share at this point.

The next question is from Marc Frahm with Cowen. Please go ahead.

Unknown Executive: So we moved from a 14 days to 28 days. And the reason for moving from 14 days to 28 days has been because, for two reasons. One, we've seen that skin degradation in two weeks has not reached steady state.

Hi, Thanks for taking my questions.

Wanted to just.

Start off on 474.

Given the degradation dynamics that youre really not maybe going to get maximal degradation.

Degradation in the skin for two weeks.

Appropriate to compare to four week data for all sorts of other programs that happened in NHS or should we be thinking more like two to three week end points for those trials.

Unknown Executive: And so we wanted to make sure we reach steady state so that when we select phase two dose, we do with that information in hand.

Unknown Executive: The second one, we uncovered this QT finding in the healthy volunteer study, we saw that between day seven and day 14, we had reached steady state or plateau of this mechanism, we wanted to confirm by extending the study by two more weeks, so that we would the risk running a 12 to 16 weeks phase two study.

Well Mark Thats, a great question I'll, only spend 10 seconds and I pass it to Jay.

The reality is.

We just don't know like first of all we're early in the trial. So we really don't know.

And then second.

I think it's a very good question and I think only our ability to assess how the data evolves will tell us and pitch us I think what we're seeing here is to see maximal scheme pharmacology, we need to wait for the second part of the 28 day study so maybe week three week four.

Sure.

And.

Again, the studies mall there is no placebo, so I would've just be transparent and we're not trying to downplay expectations like nothing has really changed from the last quarter. We were only thing is we can set the expectation on a study where there are so many variables, which make the study based on expectation.

On efficacy completely empowered what we're seeing is less focused on things that we put a lot of expectations on <unk>.

Critical go no go expectations on which is PD and safety and the other let's keep it exploratory I fully appreciate that the investor community.

We would like to have clear.

Targets for for those exploratory endpoint, but we're just being very transparent in saying that it's really hard for us to do that.

Unknown Executive: So this is really the backdrop.

The next question.

Jack Hu with Baird.

Please go ahead.

Unknown Executive: So the goal is confirming PT and confirming safety.

Great Good morning.

Thanks for taking my questions.

So first also on the Qt prolongation.

You mentioned this this is why it's probably.

It related to.

Specific to the molecule I was wondering if you have identified any liable structures within the molecule within the compound.

That's helpful dose and I guess the question is it really.

Ask whether other compounds in our pipeline.

At this time.

This liable structure.

To follow up on.

Unknown Executive: Now, given that we've extended to 28 days, and given other data with other molecules, where in 28 days, there has been some early sign of clinical efficacy, we have added these exploratory clinical endpoints.

On the potential efficacy of this Iraq for a class.

Unknown Executive: But again, our focus is on the PT and safety.

Help us understand kind of frame the efficacy expectation for Iraq.

Unknown Executive: And we'll be happy to collect and share any data on efficacy.

Okay.

Yes, I'm not looking for guidance, but just kind of broadly speaking in terms of different.

Modalities I think <unk> talked about.

They are not looking for.

Okay.

Biologic.

But they see a great potential for oral therapy.

Therapy, thanks very much.

Thanks to the first question, we understand really well.

Unknown Executive: But as Jared said earlier, given that, you know, we expect to reach maximal pharmacology only in the back second, you know, in the back two weeks of the study, it would be unfair to set expectations from that point of view.

Unknown Executive: But again, we remain committed to sharing that data, and we'll share it with all of, you.

What drives this very weak affinity for the <unk> channel and I want to reiterate in case I haven't said it before we do not degrade iron channels, we only degrade direct or also in Cardiomyocyte.

We understand really well we have no concern about the.

The impact of any other program, including the backup program. So we know exactly what we need to do and what we've done for other programs in our pipeline.

With regards to efficacy may be adjusted the high level I think that beyond one CLR pathway.

As shown impact in a wide variety of diseases by blocking either single cytokine, we have data without one.

33, 36 in some cases, even <unk>, we have data with Iraq for inhibitor in IRA and to some extent maybe some early data in Hs.

So this is one of the most validated innate immune pathways out there what were offering here is a molecule that can block the pathway I will say almost completely if not completely.

Should afford superior efficacy to all the other agents that I've mentioned, so far so the question is not.

It's not weather.

This is my opinion I want to say this is not whether this is going to be.

Active or not the question is where is it going to be active and how much.

In which disease. So is this going to be the best in class and a jet and then active dragonnade bear.

Best in class seen lupus and an active drug.

In Gi inflammation I'm just.

Putting things out there.

I think clinical investigation will be needed to assess the level of activity needed and I think the comments that were made by other companies, including our partner.

<unk>.

There is different expectations.

An oral drug with a good safety profile, where youre going to be driving your penetration on different expectation than a biologics where really the only case for biologics for high penetration has to be exceptional activity given the modality barrier that has.

With with patients compliance, but just any thoughts on the no no I mean I think.

I agree with what you said I mean, our aim ultimately is for this drug to have transformative activity in patients with these diseases with high unmet need, but it's not what I'm, saying, having oral drug with a very favorable safety profile. We can definitely see these drugs being taken up and commercialize are being successful.

Even if the activity is not necessarily a superior to what's out there right now, but our expectation is that for certain indications. We should have superior activities that should be again transformative for patients. So we're told we got to move quickly. So led to some quick Q&A from now on we have two minutes left.

Chris Shibutani: The next question is from Chris Shibutani with Goldman Sachs.

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

Chris Shibutani: Please go ahead.

Hey, guys. Thanks, so much for taking my question.

Just a stat three I guess, what are you expecting to see from a PD perspective, and proof of mechanism perspective, such as the percent degradation at the update later this year just based on the doses you're studying I understand that it's still a dose escalation and then just in terms of that three I guess, what have we learned from kind of some other stats.

Preclinical programs, whether its inhibitors or anti <unk> programs targeting stat, three just from a clinical perspective in terms of any efficacy.

In the oncology setting and lessons learned there and I guess kind of.

What we've learned about why it's so important to degree versus inhibit.

Thanks.

Thanks, Elisa will do this really quickly so pre clinically we have seen that if we get around 90% degradation of that <unk> in a patient population that is dependent on that target.

For a couple of days, we can then those again either a week after two weeks. After so having a profile that is approaching that or around that or that that level of degradation with a good safety profile for us would be a huge derisking event for this program.

In terms of external landscape to be honest I haven't seen any real good agent out there so it's difficult to compare.

Compare I don't think there are real that three agents that engage the target specifically.

So it's hard to to compare apples to oranges there.

That's the question.

The next question is Calgary Pepco. Please go ahead.

Chris Shibutani: Hey, Chris, we can't hear you if you're on mute.

Oh, Hey, good morning, Thanks for squeezing me in here.

Chris Shibutani: Can you hear me now?

Chris Shibutani: Yes.

Sure on the stack III program.

Chris Shibutani: Okay.

Chris Shibutani: Apologies for that.

Other drug developer recently demonstrated clinical activity in late line liver cancer.

Chris Shibutani: With the Part C study for KT474, on dosing and on patient selection, you made the modification, to do the 75 milligrams in the fed state.

Theyre inhibitor based approach as a mono therapy I guess based on these recent learnings should we expect you to enrich that solid tumor arm with liver cancer patients.

Chris Shibutani: Can you just make sure that we all understand the basis for that selection of the change?

Chris Shibutani: And then secondly, with the two types of patients, HS and AD, there should be a differential, in terms of the kinds of exploratory responses that you might see from this Part C group based upon your understanding of the kinetics of degradation, as well as kind of the kinetics of the pathophysiology of the different diseases states.

Chris Shibutani: I realize that we're only going out to 28 days, but if there's any basis for thinking, that there might be a difference between those two patient types, that would be helpful to know.

Chris Shibutani: And will you share that and break out that data based upon those patient types?

There are other solid tumors that you're eyeing or prioritizing in this for this program.

Joe do you want to take them quickly yeah, Talbott I mean, we've been exploring multiple different sort of solid tumor types of pre clinically and we use those data to then drive ultimately whether we have decided to enrich for those populations. So I think that will be based on our preclinical data and also again there within solid tumors our data.

Chris Shibutani: Thanks.

Our suggest that combination of our drug with anti PD, one agents may be the most effective way to use the drug in solid tumors, whereas in liquid tumors like T and NK cell malignancy that if that would be dependent on where expect expecting significant activity with our integrator as a monotherapy.

Well, yes delivered data is intriguing so obviously, we'll follow up on that.

Yes, let's do two quick questions and I will drop.

Unknown Executive: Thanks, Chris.

The next question comes from Eric Joseph with JP Morgan.

Go ahead.

Unknown Executive: Maybe, Thierry, do you want to take this one?

Hi, Good morning, guys, just a follow up on Scott three can you talk a little bit about the anticipated therapeutic index.

Unknown Executive: Yeah.

Unknown Executive: Hi, Chris.

Any expectations around Milo suppression or neutropenia based on their mechanism of what you're saying.

Botox package and then from a TD perspective, particularly in solid tumors can you just clarify if you're taking serial biopsies will you be able to look at not only <unk>.

Unknown Executive: And maybe starting with your first question, why the 75 milligram dose, just to clarify, which is that our aim all along has been to bring in what we call the sort of minimally efficacious dose into Part C, meaning the smallest dose that gives us maximal pharmacology that we think would be associated down the road with clinical activity.

Unknown Executive: From the Part B MAD, we determined that the 100 milligram dose, which was administered, in a fasting state, was giving us maximum knockdown in the blood, near maximal knockdown in the skin, and also significantly impacting ex vivo cytokine induction. So we really saw that as our minimally effective dose.

Unknown Executive: Now, in the Healthy Volunteers Study, you know, these subjects were all treated on an, inpatient basis.

Unknown Executive: In Part C, inpatients, this is all going to be done on an outpatient basis, 28 days of, dosing.

Target degradation in the periphery, but also.

Distribution activity.

Activity.

Impact in that tumor.

Samples as well Opex.

Unknown Executive: So it's not practical, really, to dose those subjects in the fasting state.

Yes, so we have.

Right.

<unk> for biopsies in the dose escalation. This is not a monday that given that it's an early dose escalation. So we're relying on really patients two to help us there and so.

Unknown Executive: So we wanted to make sure we could dose them in the fed state. We did observe a very modest food effect that led to a modest increase in plasma exposure, in the presence of food.

Unknown Executive: So we did an additional SAD food effect cohort to determine what is the dose in the fed state, that would give us the same plasma exposure as 100 milligrams in the fasting state.

Unknown Executive: And we found out from that cohort that that dose is 75 milligrams, and that's the dose, that we're bringing into Part C. With regard to your question around AD versus HS and the ability to detect a clinical signal, you know, we note that, you know, in studies using active agents where these subjects are treated for a long period of time, 12 to 16 weeks, you can see signs of clinical response as early as 28 days in either AD or HS.

So we can't commit that we will have the data, but we're trying to collect.

The tumor data and as you know.

No. We are very keen on as I've said on translation, but also the correlation between PK and PD in blood and in tumor is important so we'll try and get there hopefully.

I think the first question was on safety at Pharmacologically active doses. These components are quite well tolerated pre clinically.

Unknown Executive: So we don't expect, if we were to see any clinical signal, for there to be any advantage, of AD or HS, which is why we're planning on accruing approximate equal number of AD and, HS patients to Part C, restricting the enrollment to patients with moderate to severe disease.

So we expect to see a similar profile in the clinic, but we will continue to monitor things and.

Unknown Executive: Maybe I just want to add a couple of things.

Obviously the report is there are things to be concerned about.

Sounds like last last question.

Unknown Executive: Just to clarify, so we expect 75 mixed dose, to have the same activity in terms of PD of the 100 mixed dose in the MAD cohort. That's the goal.

Yes. The next question is from Mike Kratzke Kratky with SVP. Please go ahead SBB.

Unknown Executive: It's pure math, actually.

Unknown Executive: It's nothing to do with us.

Yes, hi, everyone really appreciate you fitting me in here.

Unknown Executive: The math of the exposure to 75 is the same as the exposure to 100, whether you eat food or not, depending on the two doses.

Unknown Executive: The other part is obviously, on the second part, the pathophysiology is very different.

Unknown Executive: The kinetics of erectile degradation's impact on pathophysiology of those two diseases might be different.

In terms of the previously disclosed <unk> finding is there any plan to run a thorough Qt Qt study and then have a follow up on efficacy can you just clarify whether you'll be reporting.

I mean reductions in easy at day 28, and if you may be reporting any other metrics section.

<unk> 15 year, 75% to 90 in those atopic dermatitis patients. Thank you.

Joe do you want to take that one yes in terms of the endpoints themselves, we will be analyzing those endpoints in a number of different ways. We haven't finalized exactly how we'll be looking at those endpoints such as the easy an AE.

So really we'll provide more color on that once the data emerge.

The first question.

The third of Q2.

Yes.

The fact that within our phase one we've had extensive ECG monitoring in the healthy volunteer portion of the equity Holter monitoring and we detected this subclinical modest Qt finding I think thats, what it precludes the need for any thorough Qt study in the future. We essentially know sort of what we're dealing with and we'll be able to sort of do routine sort of ECG monitoring to sort of follow that finding.

Great. Thanks, Joe maybe to wrap up.

Out of time, so no more questions.

I know, we're past that time, so I'll be very brief I just wanted to thank everybody for joining in on our call and for all the really good questions.

Unknown Executive: So we actually don't know, right?

Unknown Executive: The question is, that's why the 28-day study has to be focused on, does the molecule do what it's supposed to do?

Unknown Executive: Does it degrade and is it well-tolerated?

Unknown Executive: Because we want to leave the real answer to your question in a 12- to 16-week study, to be fair.

We are excited.

Unknown Executive: And the other maybe key point here is that one reason why we are not sort of placing, our focus so much on the clinical endpoints, more on the PDM points, is what's most important in either AD or HS in Part C is that we are able to observe, with IRAC4 knockdown in the skin, which we want to achieve at least 85% or greater knockdown, we can see an impact on the expression of pro-inflammatory gene transcripts. And those gene transcripts that are elevated at baseline could be different in AD versus HS, but the key is that we want to see downregulation of those transcripts in conjunction with downregulation of IRAC4 protein expression.

Unknown Executive: If we see that in AD as well as in HS, regardless of what we see in terms of clinical endpoints at four weeks, that will give us confidence moving forward that we should be able to impact the natural history of the disease.

Unknown Executive: For either of those diseases, we studied the longer duration that we would be able to test in Phase 2.

Beyond our expectation to be here in 2022 dosing patients with HSA deal improvement solid tumors leukemias with programs that were all de Novo first in class programs develop that chimera within our team.

Unknown Executive: The next question is from Richard Law with Credit Suisse.

Richard Law: Please go ahead.

Richard Law: Hi, guys.

Richard Law: Good morning.

Richard Law: Can you talk more about the type of patients that you're recruiting, for the Phase 1 Part C study regarding the use of prior?

Richard Law: Any additional information on this type of patients that you're recruiting will be great.

Richard Law: And also a follow-up question that would be, you mentioned earlier that the 10 to 20 millisecond, would not meet monitoring.

This is an amazing accomplishment, obviously, we haven't accomplished anything until we impact the lives of patients. So we're focused on how to do that in the most responsible data driven and thoughtful way and to continue to engage with you to make sure that there is continue.

Richard Law: Is there a threshold for QTC prolongation that you would meet monitoring from the FDA?

Richard Law: Thank you.

Unknown Executive: I think in terms of your first question, in terms of the patient population for Part C, these will be, you know, HS and AD patients with moderate to severe disease.

Unknown Executive: They could be treatment-naive patients or they could be patients who have had prior treatments, including prior biologic therapies.

Unknown Executive: If patients are on biologic therapies or really any therapies at the time that they're screened for the study, they would need to come off of those treatments. And we have an appropriate washout period for different therapies that are written in the protocol.

Unknown Executive: So they will not be able to come onto the study and be on concurrent medications.

Unknown Executive: So the reason why we started the MDM2 program is because we felt it was an area of clinical investigation and commercial opportunity that has been untapped by the space.

Unknown Executive: They'll have to come off of those before they can go onto KT474.

Unknown Executive: And we discovered that in order to replicate the cancer genetics, really removal of MDM2 was needed. And so the applicability of this concept of removing MDM2 to stabilize PCP3 and impact a broad variety of tumor is large.

Unknown Executive: The other question was about the QT.

Unknown Executive: What the team is focusing on at the moment is how we select and prioritize indications.

Unknown Executive: Oh, yes.

Unknown Executive: So I think as Jared mentioned earlier, there is a very, very strong case for degrading MDM2 in AML, given existing data, given cancer genetics, and given some preclinical data that we've generated that is, you know, very, very elegantly demonstrates that MDM2 degradation is up there in AML as the mechanism.

Unknown Executive: I'm sorry.

Unknown Executive: There is a mechanism to go after, especially in refractory resistant to venetoglax patients, which is an area that we're trying to expand.

Unknown Executive: In terms of the QT and what sort, of QT excursions will be required for monitoring, you know, as Noah said, you know, we've had extensive discussions with our cardiology consultants, and they all, I think, unanimously believe that for a 10 to 20 millisecond change, there would be no need for cardiac monitoring.

Unknown Executive: But obviously we would not develop this asset if AML was the only place to go.

Unknown Executive: You know, probably, you know, an excursion that is routinely sort of going beyond, say, 40 milliseconds or greater, you know, is a level that might require some degree of cardiac monitoring.

Unknown Executive: And so we're expanding our investigation in many other tumors, both liquid and solid, and we'll disclose more data as we commit to those areas of investigation.

Unknown Executive: But again, it really all depends on, you know, what's happening to the QT interval itself.

Unknown Executive: So I would say our, you know, our first kind of first in human study will start, you know, towards end of the year, early next year, with probably both the solid and AML approach.

Mark Fraim: The next question is from Mark Fraim with Cohen.

Unknown Executive: Is it going beyond 500 milliseconds?

Unknown Executive: So that will be the early proof of mechanism, which, you know, I don't want to start now setting up expectations, but I expect that that will be something that we'll focus on next year.

Unknown Executive: What is the risk of cardiac arrhythmia?

Unknown Executive: And then soon after that, we'll be talking about in which indication we expect to see proof of concept.

Unknown Executive: That would all have to be looked at in totality by FDA ultimately in order to determine, what would be the label implications and whether any sort of cardiac monitoring would be necessary.

Unknown Executive: Thank you very much for joining us for this evening's discussion of E3LiGaSe.

Vikram Purohit: The next question is from Vikram Purohit with Morgan Stanley.

Unknown Executive: I think one of the things that brought activity in is novel E3LiGaSe discovery that is applied both to novel E3LiGaSe-enabled heterobifunctional degradation, as well as novel E3LiGaSe-enabled molecular-glue-driven degradation.

Vikram Purohit: Please go ahead.

Unknown Executive: I think it is fair to say that these programs are still in the discovery stage, and I think once we're ready to disclose a program, I think it will be when we're close to the clinic.

Vikram Purohit: Good morning.

Communication with the external community so that we can advance this.

Unknown Executive: So we're going to choose to keep our cards close to the vest on the early discovery pipeline because it's a highly competitive space, and to be honest, I don't think we're given any credit for anything that is early, so I think it's probably not a smart thing to share at this point.

Mark Fraim: Please go ahead.

Vikram Purohit: Thanks for taking my questions.

Mark Fraim: Hi.

Vikram Purohit: So maybe looking at your earlier stage pipeline beyond 4.7.4, could you comment a bit on the intended development plan for 2.5.3 once the IND is filed later this year and what you expect the news flow for the MDM2 program to look like in 2023?

Mark Fraim: Thanks for taking my questions.

Vikram Purohit: And then secondly, could you give us an update on your efforts with the molecular glue programs you've alluded to before and when you anticipate having a development candidate there to talk about?

Mark Fraim: I wanted to just start off on 474.

Vikram Purohit: Thanks.

Mark Fraim: Given the degradation dynamics and that you're really not maybe going to get maximal degradation in the skin for 2 weeks, is it appropriate to compare the 4-week data for all sorts of other programs, that have happened in ADNHS, or should we be thinking more like 2- to 3-week endpoints for those trials?

Hopefully game changing therapies and all of the new generation program that we haven't disclosed yet and May <unk>. This fully integrated commercial stage company in the next few years. So thanks again and have a good day.

Unknown Executive: Yeah, thanks, Vikram.

Mark Fraim: Right, Mark, that's a great question.

Unknown Executive: Maybe I'll try and answer this question more broadly.

Unknown Executive: I'll only spend 10 seconds, and I'll pass it to Jared.

Unknown Executive: And then if we need to go into specifics, Jared can help me.

Unknown Executive: The reality is we just don't know.

Unknown Executive: First of all, we're early in the trial, so we really don't know.

Unknown Executive: And then second, I think it's a very good question, and I think only our ability to assess how the data evolve will tell us and teach us.

Unknown Executive: I think what we're seeing here is to see maximal skin pharmacology, we need to wait for the second part of the 28-day study, so maybe week 3, not week 4.

Unknown Executive: What we're only saying is we can't set the expectation on a study where there are so many variables which make the study based on expectation on efficacy completely unpowered.

Unknown Executive: What we're saying is let's focus on things that we put a lot of expectations on, critical go-no-go expectations on, which is PD and safety.

Unknown Executive: And the other, let's keep it exploratory.

Unknown Executive: I fully appreciate that the investment community would like to have clear targets for those exploratory endpoints, but we're just being very transparent in saying that it's really hard for us to do that.

Unknown Executive: The next question is from Zicom Shu with Berenberg.

Zicom Shu: Please go ahead.

Zicom Shu: Great.

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

Zicom Shu: Good morning.

Zicom Shu: Thanks for taking my questions.

Zicom Shu: I have a question for you.

Zicom Shu: First, also on the QT prolongation, you mentioned this one is probably related specifically to the molecule.

Zicom Shu: I was wondering if you have identified any liable structures within the compound that is responsible for this.

Zicom Shu: And I guess the question is really to.., ask whether other compounds in your pipeline have this liable structure.

Zicom Shu: To follow up on the potential efficacy, of this IREC-IV class, can you help us understand, kind of frame the efficacy expectation for IREC-IV in AD and HS?

Zicom Shu: I'm not looking for guidance, but just kind of broadly speaking in terms of different modalities.

Zicom Shu: I think Sanofi talked about, they're not looking for as efficacy as a biologic, but they see a great potential for oral therapy.

Zicom Shu: Thanks very much.

Unknown Executive: Thanks, so to the first question, we understand really well what drives this very weak affinity for the ERD channel.

Unknown Executive: And I want to reiterate in case I haven't said it before, we do not degrade ion channels.

Unknown Executive: We only degrade IREC-IV also in cardiomyocyte.

Unknown Executive: We understand really well, we have no concern about the impact of any other program, including the backup program.

Unknown Executive: So we know exactly what we need to do, and what we've done for other programs in our pipeline.

Unknown Executive: With regards to efficacy, maybe just at the high level, I think that the IL-1 TLR pathway has shown impact in a wide variety of diseases.

Unknown Executive: By blocking either single cytokines, we have data with IL-1, IL-33, IL-36, in some cases, even IL-18.

Unknown Executive: We have data with IREC-IV inhibitor in RA, and to some extent, maybe some early data in HS.

Unknown Executive: So this is one of the most validated, innate immune pathways out there.

Unknown Executive: What we're offering here is a molecule, that can block the pathway, I would say almost completely, if not completely, that should afford superior efficacy to all the other agents that I mentioned so far.

Unknown Executive: So the question is not, you know, it's not whether this is my opinion, I want to say.

Unknown Executive: This is not whether this is going to be active or not.

Unknown Executive: The question is where it's going to be active, and how much and in which diseases.

Unknown Executive: So is this going to be the best in class in HS, and an active drug in AD, best in class in lupus and an active drug in GI inflammation?

Unknown Executive: I'm just, you know, putting things out there.

Unknown Executive: It's just, I think clinical investigation will be needed, to assess the level of activity needed.

Unknown Executive: And I think the comments that were made, by other companies, including our partner, has been there is different expectations if you have an oral drug with a good safety profile where you're going to be driving your penetration on different expectations than a biologics where really the only case for a biologics for high penetration has to be exceptional activity given the modality barrier that has with patient compliance.

Unknown Executive: But Jared, any thoughts on this?

Unknown Executive: No, no, I mean, I think I definitely agree, with what you said.

Unknown Executive: I mean, our aim ultimately is for, you know, this drug to have a transformative activity, you know, in patients with these diseases with high unmet need.

Unknown Executive: But as Noah was saying, you know, having an oral drug, with a very favorable safety profile, one can definitely see these drugs, you know, being taken up in commercialized and being successful, you know, even if the activity is not necessarily superior to what's out there right now.

Unknown Executive: But our expectation is that for certain indications, we should have superior activities that should be, again, transformative for patients.

Unknown Executive: So we're told we got to move quickly.

Unknown Executive: So let's do some quick Q&A from now on.

Unknown Executive: We have two minutes left.

Unknown Executive: The next question is from Eliana Merle with UBS, please go ahead.

Eliana Merle: Hey guys, thanks so much for taking the question.

Eliana Merle: Moving just to stat three, I guess, what are you expecting to see from a PD perspective, and proof of mechanism perspective, such as the percent degradation at the update later this year, just based on the doses you're studying?

Eliana Merle: I understand that it's still a dose escalation.

Eliana Merle: And then just in terms of stat three, I guess, what have we learned from other stat three clinical programs, whether it's inhibitors or anti-sense programs targeting stat three, just from a clinical perspective in terms of any efficacy seen in the oncology setting and lessons learned there, and I guess kind of what we've learned about why it's so important to degrade versus inhibit stat three.

Eliana Merle: Thanks.

Unknown Executive: Thanks, Allie.

Unknown Executive: So we'll do this really quickly.

Unknown Executive: So preclinically we've seen that if we get around 90% degradation of stat three in a patient population, that is dependent on that target for a couple of days, we can then dose again either a week after or two weeks after.

Unknown Executive: So having a profile that is, you know, approaching that or around that or that, you know, that level of degradation with a good safety profile for us would be a huge de-risking event for this program.

Unknown Executive: In terms of external landscape, to be honest, I haven't seen any real good agent out there, so it's difficult to compare.

Unknown Executive: I don't think there are real stat three agents that engage the target specifically, and so it's hard to compare apples to oranges there.

Unknown Executive: Next question.

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