Kymera Therapeutics Q2 2023 Earnings Call Transcript

Quartr
Provided by Quartr
August 3, 2023

There are 17 speakers on the call.

Operator

Hello, and welcome to the Chimera Therapeutics Second Quarter 2023 Quarterly Results Call. I'd now like to turn the call over to Bruce Jacobs. Mr. Jacobs, please go ahead.

Speaker 1

Good morning, everyone, and welcome to the Chimera Therapeutics quarterly conference call. I'm Bruce Jacobs, Chief Financial Officer at Chimera and I'll be joined today by Nela Manalffy, Founder, President and CEO Jared Gault, our Chief Medical Officer. I'm also excited to welcome Justine Koenigsberg, Chimera's new Head of Investor Relations to her first Chimera quarterly call. After our prepared remarks, we'll open the call to your questions as we always do. Before we get started, I'd like to remind everyone that some of the comments that management may make on this call include forward looking statements As outlined in the press release, actual events 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 Chimera's most recent filings with the SEC and any other future filings that the company may make with the SEC.

Speaker 1

You're cautioned not to place any undue reliance on those forward looking statements and Chimera disclaims any obligations to update such statements except as required by law. With that said, I'll now hand the call over to Nelo.

Speaker 2

Thanks, Bruce, and thank you everyone for joining us today. We're excited to review the progress we made over the last And discuss how it contributes to achieving our mission of building a best in class fully integrated global degrader medicines company. Over the past few months, we've shared updates on our clinical oncology pipeline and preclinical work, including multiple presentations at scientific meetings across the world Relating to KT253, KT413 and KT333, I will provide an overview of this And Jared will share more details during his remarks. Starting with the most recent addition to our clinical pipeline, We dosed the first patient in the Phase 1 study of our MDM2 degrader KT253, which addresses a critical and drug mechanism In cancer biology that has been pursued in the biopharma industry for many years. The data we presented at EHA in June Showed that 253 has the potential to overcome the inherent limitations of small molecule MDM2 inhibitors against this well validated In preclinical models of ALL and AML, a single dose of KT-two fifty three drove durable Tumor regressions and demonstrated differentiated pharmacology compared to a small molecule inhibitor.

Speaker 2

In June, 253 was also granted orphan drug designation by the FDA for the treatment of AML. This program exemplifies our unique approach of selecting targets with strong genetic validation in pathways where we believe Targeted protein degradation offers the best or only option for an effective treatment, and we look forward to investigating it in a variety of and sharing more on this program, including clinical proof of mechanism in patients later this year. With respect to KT-four thirteen, which targets IRAK4 and the image substrates, EGROS and ILOS and KT-three thirty three, which targets STAT3, Both are continuing in the dose escalation stages of their Phase 1 studies. As a reminder, our focus this year for these programs is to evaluate The degradation and the safety profile of these 1st in class mechanisms and their biological and clinical impact in the appropriate patient populations. We recently shared encouraging data from the trials showing fidelity of PKPD translation from preclinical models to patients.

Speaker 2

At the ICML meeting in June, we shared data demonstrating that both molecules were approaching or were already at the target degradation levels we believe Based on preclinical models are sufficient to achieve anti tumor activity without any dose limiting toxicities observed. Later this year, we intend to provide additional data evaluating anti tumor activity in the target patient populations for these two programs. Our first in class ARROC 4degrader, KT-four seventy four, is in development with our partner Sanofi for the treatment of TLR IL-1R driven immune inflammatory diseases with high unmet medical needs such as hydrothanitis suppurativa, atopic dermatitis and potentially others. We're very excited about the potential of KT-four seventy four for patients with inflammatory diseases who currently lack An effective oral medicines with a good safety profile, and we expect the Phase 2 studies in both HS and AD to initiate in the Q4 of 2023. This degrader 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 our RAC4 kinase inhibitors By eliminating both the kinase scaffolding functions of IRAK4, Jared recently presented the Phase 1 data From this program at the EADV Symposium in Seville, which demonstrated that 474 administered to Yes, and AD patients had tolerability PK and PD similar to healthy volunteers achieved robust direct 4 degradation in blood and skin Associated with the systemic anti inflammatory effect and showed promising clinical activity in both HS and AD.

Speaker 2

In parallel to our clinical programs, we continue to drive the science of targeted protein degradation and identify 1st, best in class opportunities to transform the treatment of disease. We have several exciting programs in our preclinical pipeline that are designed to address Well validated pathways in areas of significant patient need with multibillion dollar revenue potential. We look forward to Sharing more details on these programs later this year early next in an R and D day. Along with our clinical and scientific progress, we've worked to ensure that we have The people and resources to build a sustainable fully integrated company. To that end, we recently appointed Doctor.

Speaker 2

Jeremy Chadwick as Chief Operating Officer, who will serve as a key member of our leadership team, help guide the development of our 1st in class programs and scale our capabilities to support our growth. Jeremy joins us from Takeda where he held leadership roles in Global Regulatory Affairs, Drug Safety, Global Clinical Supply Chain and Development Operations. As Bruce mentioned, we're also very happy to welcome Justine Konigsberg as Vice President and Head of Investor Relations. Justine has spent more than 25 years in the industry and she'll be engaging with many of you on the call in the upcoming weeks. Let me pause here and turn the call over to Jared, who will now cover in more details recent progress from our clinical oncology programs Before turning the call over to Bruce for a financial update.

Speaker 1

Thanks, Nela. I'll provide a brief recap of where we stand With our clinical programs and what to expect in the coming months. As Melo mentioned, we have begun dosing patients in the Phase 1 multi Enter open label dose escalation clinical trial evaluating our investigational MDM2degrader KT253 And recruitment in the trial is going well. MDM2 is the crucial regulator of the most common tumor suppressor p53. P53 remains intact or wild type in close to 50% of cancers, meaning that it retains its ability to modulate cancer cell growth.

Speaker 1

We believe 253 has the potential to be a highly potent degrader that unlike small molecule inhibitors has been shown preclinically To have the ability to overcome the MDM2 feedback loop and rapidly induce apoptosis even with brief exposures. 253 has the potential to be effective in a wide range of hematological malignancies and solid tumors with function in p53. We've shown pre clinically that 253 has superior activity compared to MDM2 small molecule inhibitors and demonstrated greater than 200 fold And additionally, we presented data at EHA in June demonstrating that a single high dose 253 administered intravenously in preclinical models of AML and ALL led to greater than 90% MDM2 degradation in tumors within 1 hour of dosing, strong p53 upregulation and induction of apoptosis within the 1st 8 to 24 hours And sustained tumor regressions. In contrast, lower doses of 253 administered more frequently Oral repeat dosing with an oral MDM2 small molecule inhibitor led only to relatively weak p53 activation and apoptosis induction And modest tumor growth inhibition. These preclinical results suggest that a pulse IV dosing regimen of 253 Has the potential for an improved efficacy and safety profile over MDM2 small molecule inhibitors currently in the clinic.

Speaker 1

The Phase 1 trial is evaluating the safety, tolerability, PKPD and clinical activity In patients with relapsed or refractory high grade myeloid malignancies, ALL, lymphomas and solid tumors. Patients in the Phase 1a dose escalation study are receiving IV doses of 253 administered once every 3 weeks. The open label study is intended to identify the recommended Phase 2 dose and is comprised of 2 arms with ascending doses of 253 in each arm. Arm A consists of patients with lymphomas and advanced solid tumors and Arm B consists of patients with high grade myeloid malignancies and ALL. Dosing in arm B will start once a pharmacologically active dose has been reached in arm A, at which time dose escalation will proceed in parallel across both arms And continue until the maximum tolerated dose is established for each arm.

Speaker 1

We plan to share initial safety and proof of mechanism data for Phase 1 clinical trial later this year. Now turning to our other 2 ongoing oncology trials. STAT3 is a transcriptional regulator that has been linked to numerous cancers as well as to inflammatory and autoimmune diseases. KT-three thirty three is being developed for the treatment of STAT3 dependent hematological malignancies and solid tumors. The Phase 1 clinical trial of 333 is designed to evaluate the safety, tolerability, PKPD and clinical activity of 333 dosed weekly In adult patients with relapsed and or refractory lymphomas, leukemias and solid tumors.

Speaker 1

In June, at ICML, with a data cutoff date of May 1, 2023, Chimera shared that 13 patients received a mean of 5 doses across the first four dose levels of the trial, Including patients with solid tumors as well as CTCL and PTCL. While the 4th dose level was still open for accrual at that time, Data reported from DL-one-three found plasma exposure increased with dose, reaching levels close to those predicted to be efficacious And demonstrated dose dependent STAT3 degradation with up to 88% mean maximum reduction in peripheral bloodline nuclear cells With evidence of SAD3 pathway inhibition and down regulation of inflammatory biomarkers in peripheral blood, degradation profiles at DL3 were near levels of knockdown that led to antitumor activity in preclinical models. We shared at ICML that there were no The Phase 1 dose escalation stage is ongoing recruiting broadly across solid and liquid tumors. KT-four thirteen is a novel hetero functional degrader that targets degradation of both IRAK4 and the image substrates iclos and allos. 413 was designed to address both the IL-1R TLR and the Type 1 interferon pathway synergistically to broaden activity against MyD88 mutant B The Phase 1 clinical trial is designed to evaluate the safety, tolerability, PKPD and clinical activity of 413 Administered as an IV infusion once every 3 weeks to adult patients with relapsed and or refractory B cell non Hodgkin lymphomas.

Speaker 1

In conjunction with the ICML meeting, we shared that as of June 1, the first three dose levels have been completed and the 4th was accruing patients. At that point, 5 patients were treated across DL-one-four and received a mean of 2.2 doses, including patients with transformed Activated B cell like diffuse large B cell lymphoma, follicular lymphoma, marginal zone lymphoma and plasmablastic lymphoma, All of whom were MYD88 wild type except for one who had a MYD88 gain of function mutation. Data reported across DL-one through 4 showed plasma exposure increase with dose, reaching levels close to those predicted to be efficacious. 413 achieved dose dependent degradation of up to 70 iRAC4 and 96% to 100% icaros and iLLOS in peripheral blood monomuclear cells after a single dose. Degradation profiles at DL-three-four were consistent with knockdown levels associated with antitumor activity and preclinical models of MYD88 mutant lymphomas.

Speaker 1

We showed at ICML that there were no dose limiting toxicities or drug related neutropenia observed in the study. The Phase 1 dose escalation portion of the trial is ongoing recruiting a broad population of B cell lymphoma patients. We look forward to sharing data evaluating the antitumor activity of KT-three thirty three and KT-four thirteen And their respective target patient populations later this year. Finally, the KT-four seventy four Phase 2 studies in both HS and AD, Which are being advanced by Sanofi are expected to commence in 4Q 'twenty three, first in HS and followed shortly thereafter in AD. We will share more details around the trials as we approach the dosing of the first patients.

Speaker 1

I will now hand the call to Bruce, who will share some brief comments Our financial results for the Q2. Thanks, Jared. I will quickly cover the financials before turning the call back to Nelo for some concluding remarks. For the quarter, we recognized $16,500,000 of collaboration revenue. And at the end of the quarter, our deferred revenue total on the balance sheet was approximately $45,000,000 That reflects partnership revenue we expect to recognize over the next several years, excluding the receipt of any potential future milestones.

Speaker 1

With respect to operating expenses, R and D for the quarter was $45,800,000 Of that, approximately $5,700,000 represented non cash stock based compensation. The adjusted cash R and D spend of $40,100,000 which excludes that stock based comp, reflects a 7% increase from the comparable amount in the Q1 of 20 23. On the G and A side, our spending for the quarter was $14,100,000 of which $5,500,000 represented non cash stock based comp. The adjusted cash G and A spend of $8,600,000 again excluding stock based compensation reflects a 9% increase from the comparable amount in the Q1 of 2023. We exited the Q1 with a cash and equivalents balance of approximately $472,000,000 As we shared earlier in the year, we believe that our cash runway extends into the second half of twenty twenty five, a projection that includes milestones only related to the start of the first two Phase 2 trials for KT-four seventy four, Both of which we stated today are expected to occur in 2023.

Speaker 1

I'll now turn the call back to Nelo.

Speaker 2

Thanks, Bruce. As said, we're very excited to be soon in Phase 2 with KT-four seventy four in 2 indications as well as by the Progress we've made on our oncology clinical program. Our rapid progress in building our pipeline, generating clinical momentum and advancing the science of EPD gives us confidence that Chimera will be able to capitalize on the untapped potential of this powerful modality To enhance the treatment of disease and improving patients' lives. We look forward to sharing exciting updates on our clinical programs,

Operator

Thank you. At this point, we will open the call for questions. That being said, we will now take a moment to review your Thank you for waiting. Your first question comes from the line of Mark Frahm from TD Cowen. Sir, your line is open.

Speaker 3

Thanks for taking my questions. Maybe start off with PT-three thirty three, Monotherapy clinical responses are kind of expected to be only relevant for maybe a fraction of the opportunity and Yes, that segment is a bit of

Speaker 1

a different hypothesis than the

Speaker 3

rest of the population.

Speaker 1

Can you walk through kind of

Speaker 3

how you plan to approach dose selection Yes, as you get this larger data set later this year.

Speaker 2

Thanks, Mark. So Nalo here. So maybe I'll just take the first part of the question and then I'll pass it to Jared. So just to remind everybody, so our SAD III program, which encompasses a liquid tumor opportunity, a solid tumor opportunity and opportunities outside Of oncology, as started with our first clinical endeavor with KT-three thirty three. So obviously, it's a broader Opportunity across several potential indications and we have clear hypotheses that we're pursuing in the clinic.

Speaker 2

The first one which is In our mind, the earliest one that could lead to proof of concept is single agent activity in a subset of T cell lymphoma leukemias that we've discussed in the past, PTCL, CTCL, LGL leukemias, which obviously also have subsets. The reason why we have focused on those indications as a single agent opportunities is because we've seen pre clinically that When we dose our degrader KT-three thirty three once a week or even once every 2 weeks, we're able to achieve profound anti tumor effect A single agent. And we can actually rationalize it translationally by the fact that many Patients in those particular subsets have either STAT3 mutations or pathway activation. So we have a biomarker activity As well as biomarker sensitivity in those opportunities. The Phase 1 dose escalation includes Those particular subtypes as well as solid tumors.

Speaker 2

As I've said in the past, we said in the past, in solid tumors They are based on our preclinical data in combination. We've talked about combination with immune therapy. We've mentioned combination with targeted agents That we haven't discussed externally yet. And so now circling back to your question, just so that it's all clear, so In terms of responses, anti tumor activity that we expect to being able to talk about later in the year will come from a subset of patients From this Phase 1 dose escalation. And we said in the past, a handful of patients that might include CTCL, PTCL, LGL.

Speaker 2

With regards to how we think about selecting, I assume you meant the Phase 2 dose, maybe I'll let Jared comment on that.

Speaker 1

Sure. So, Mark, we've always sort of stated that our dose selection will be based on a combination of Of PD and Safety, we've looked at our preclinical data, especially in these STAT3 dependent T cell malignancies where we found that 90% or greater nocadamastat 3 for 48 to 72 hours is associated with antitumor activity. So our aim is to be able to get to a dose that gives us at least that sort of a profile, 90% or greater knockdown In peripheral blood and or in tumor where we can get tumor biopsy that's lasting 48 to 72 hours and that associated with Safety profile, that's the sort of PD profile that we want to be able to then take into the Phase Ib expansion. So our recommended Phase II dose will likely be Combination of being able to see that level of PD along with safety, if possible, as Nelo mentioned, if in a handful of Patients in the target patient population with these STAT3 dependent T cell malignancies, we can see a few responses at those doses that are giving us that sort of PD In safety, that would give us even more confidence in bringing that dose into the next phase, which are these Phase Ib expansions, which right now Are slated to be in these T cell malignancies like CTCL, PTCL and LGL as well as in solid tumors.

Speaker 3

Okay. That's very helpful. And then maybe a similar type of question, but for MDM2, just you kind of walk through the depth of The radiation you want to get and with that pulsedal dosing, but how long do you think you need to be at 90% kind of what's the minimum there?

Speaker 2

I mean, so I'll start this and then if needed Jared can add. So The nice thing about the MDM-two program and how we're developing it is really trying to replicate What we've seen in cancer genetics, which is ablation of the gene, in this case MDM2 leads to a rapid And complete reliance on this gene from a wide variety of cancer cells that have p53 wildtype. And what we've then observed experimentally, obviously, the gene deletion is irreversible. Protein degradation, as we all know, is reversible. So then the question that you're asking is how long do you need to deplete the target to see activity?

Speaker 2

So what we've seen in our models pre clinically that As little as 4 to 8 hours of exposure to a degrader that leads to robust degradation is sufficient To drive profound commitment to apoptotic cell death. And so actually in a way it's As you know, we dose once every 3 weeks and while for other programs that degradation need to be sustained either for 48 hours or 72 hours. In this particular program, we only need a few hours, single digit hours in order to drive the strong apoptotic response.

Operator

Thank you. Your next question comes from the line of Brad Canino from Stifel. Sir, your line is open.

Speaker 4

Good morning. For KT-three thirty three, now that you're getting a handle on the clinical PKPD, Should we expect you to open a healthy volunteer study to dial in the STAT3 degradation degree in kinetics that you need based on your I and I models In order to prepare for a potential Phase III INI study or is this going to be pursued by a separate asset altogether?

Speaker 2

Brad, thanks. This is a great question that I'm going to answer High level now and then hopefully I think when we meet in an R and D day that as I said, most likely Late this year, but most likely early next, I think we will cover hopefully with more details that question. But I can say right now that We're evaluating opportunities both for a potential 333 transition Into immunology as well as other other particular assets or and Other formulation. So maybe I'll leave it at that. This is where we're investigating, but I think what we take from this Phase 1 study, which is Not to be underestimated is the really good translation that we've Not only in PK and PD, which to be honest with this company has been a constant now for multiple programs, But more importantly on safety.

Speaker 2

So we feel now we're in a place where we can come much more comfortably Plan outside of oncology clinical study for a first in class target that has obviously very broad biological Yes. So sorry if I can't answer with details, but hopefully this gives you an idea about what we're thinking about.

Speaker 1

That's all right.

Speaker 4

I look forward to that update. Let me also ask on MDM2. When you think about the safety data from the prior small molecule inhibitors and then Particularly knowing that your target population is AML where the blood count recovery is going to be important for those patients, what are you looking to see in terms of platelet impact, thrombocytopenia rates in this first look to gain confidence in the profile for continued development. Thank you.

Speaker 2

Yes. Thanks, Brett. I'll actually let Jared comment specifically on your question, but I do want to take the opportunity to add something to your question, Which is so our clinical development team has designed, I think, I would say elegant, Some people don't like this word, but I still use it. An elegant plan to evaluate the PKPD Safety and activity in both solid tumors, liquid tumors and these myeloid malignancies. And the idea was to split the AML, ALL type of dose escalation from the other indications because as you know And as you mentioned, the context is quite different.

Speaker 2

And so the plan is right now we're escalating in solid tumor and other liquid tumors Until we feel we've reached a clinically active dose and that enter the AML space only when we're clinically active already, so that The safety does not unnecessarily Or sometimes the more challenging safety assessment doesn't influence the readout on the clinical activity. One other thing that I will say is that the way that this molecule works, which is as we said, the rapid degradation with the recovery The degradation with the recovery within the 1st 3 weeks should allow us to build a therapeutic index They should allow us to evaluate the clinical activity of MDM2 degradation in MDM2p53 sensitive Two more types. And as with all the other programs in Chimera's pipeline, we believe we can answer this question in early In early clinical development, meaning in Phase 1 or late Phase 1 clinical investigation, our ability to build the therapeutic index It's really the goal of our Phase 1 study. And if we're able to show that and demonstrate that to ourselves, I think that will hugely derisk this program and will allow us to be confident in investing a lot of money to develop this program.

Speaker 2

If not, We obviously will be willing to make decisions and that's what the philosophy is around all of our programs. But Jared, maybe you can comment specifically How we're looking at thrombocytopenia and other possibly related events that one might expect from P53 upregulation?

Speaker 1

Sure. Well, I think as you just alluded to, with this hit and run approach of dosing once every 3 weeks, and based on our GLP talks data, Our expectation is that our sort of depth of myelosuppression and or the duration of myelosuppression will be less And what is seen with the small molecule MDM2 inhibitors, which as Nelo just said, should give us a superior therapeutic index. With that being said, in AML, of course, the tolerability of myelosuppression is much higher. In fact, one does expect To see a certain degree of myelosuppression as you're clearing blasts and having an effect on the bone marrow that usually would then lead clinical responses, hopefully complete responses. And so that's why we've separated out these two arms, the high grade myeloid malignancies and ALL, Separate from the arm looking at solid tumors and lymphomas because there is a different level of tolerability in terms clinicians view myelosuppression.

Speaker 1

So we may see myelosuppression in AML patients, which would be a good thing because that would be telling us that we're seeing a response to MDM2 inhibition. But Again, we do expect the depth and duration of that myelosuppression to be less and to give us a better therapeutic index. And likewise, in solid tumors, we do expect to see less myelosuppression in that particular population, which could allow us impression in that particular population, which could allow us more attraction in developing the drug in patients with lymphoma and solid tumors Compared to the small molecule inhibitors that have been limited in their dosing by the dose limiting toxicities of GI tox as well as myelosuppression.

Operator

Thank you. Your next question comes from the line of Chris Shibutani from Goldman Sachs. Sir, your line is open.

Speaker 5

Great. Thank you very much. Good morning. Two questions. So on KT-four seventy four, it certainly is Sounding reassuring that Sanofi has formally committed, if I understand the conversation that we've had in June with you guys.

Speaker 5

It seemed as if AD was a trial that was going to start in 2023, perhaps a little bit less clarity and possibly to following in HS. Perhaps I've gotten that mixed. But To be clear, I think the update today is that both trials will commence by the end of this year, is that the case? And then, Bruce, What kind of additional sort of timeline should we think about in terms of milestone payments as this program progresses? And are you guys advancing 474 or any of the other tool compounds through Phase 1 type work Potentially to look at additional indications.

Speaker 5

I know Nela, you've highlighted mechanistically, biologically rationales to go into other broader categories, RA, lupus, etcetera. Thank you.

Speaker 2

Yes. Thanks, Chris. So I'll answer some of these, and I think you had like 3, 4 questions in there that was very elegant. And then I'll let Bruce answer the milestone question. So first one, yes, just to clarify further, so what we've said for the past 9 months since December, 7 months, we said that Sanofi He was going to take over clinical development of KT-four seventy four and that there was commitment to initiate at least one Phase 2 study in 2020 That was named to be DHS Phase 2 study.

Speaker 2

They did commit also to initiate NAD Phase 2 study, but we were not As a collaborators, as collaborations, we did not point to the exact time of phase 2 It was not clear that it would have been in 2023. So what we're updating today was finally that also the Phase 2 Start of AD will happen in 2023. So HS will be 1st and AD will be 2nd. Both of them will start in 4th Quarter of 2023. And so we want to thank Sanofi for allowing us to share more details and also to Accelerating the initiation of the 2nd Phase 2 study.

Speaker 2

With regards to other indications before I'll let Bruce's comment on the milestones. I mean, we as collaborators continue to discuss Other opportunities, I think we both feel like I can probably speak for both. We both feel that there are There are both mechanistically and clinically that fit the profile of an RX-four degrader. We're just not at this moment able to share more details, but rest assured that as things progress, we will be Updating on those strategies.

Speaker 1

Yes. And thanks, Chris. This is Bruce. Just to clarify on the milestones. So what we've said in the past is that The first Phase 2 patient dose generate milestones by indication up to a certain number, and we said at least 2 and hadn't commented before that.

Speaker 1

Beyond that, I should say, the first two milestones for HS and AD are included in our runway guidance, but no other milestones. And then I think I heard you Ask about the additional program or the additional molecules that we might generate targeting IRAK4. That was contemplated in the In the initial collaboration agreement and so the work that is ongoing there has potential to generate milestones as well. We just haven't said Specifically what those critical events are and the timing, but I think that's something you'll hear updates from us on over time as well.

Speaker 5

Great. And you said initial collaboration agreement, there was an update to that collaboration agreement in November of 2022. So that's still contemplated in this most recent active agreement, Correct.

Speaker 1

Yes, exactly. When we discussed the amendment, we made the comment at the time That the aggregate milestones remain unchanged, and that includes with respect to the follow on Compounds molecules that may be generated as well, so that the aggregate total remains unchanged.

Speaker 5

Thanks. Confirmation, reassuring progress. Appreciate it.

Operator

Thank you. Your next question comes from the line of Michael Schmidt from Guggenheim. Good

Speaker 1

morning, sir.

Speaker 6

Hey guys, good morning. Thanks for taking my questions.

Speaker 1

I had one

Speaker 6

on KT-four thirteen We've seen the updated Phase 1 data at ICML recently, where it looks like you're achieving target degradation already at Dose level 3 or 4. Can you talk a bit about how the neutrophil recovery and neutropenia has tracked With your expectations based on the cyclic dosing and also perhaps talk about the scope of the clinical update later this year and Expectations for that. Thank you so much.

Speaker 2

Thanks, Michael. So maybe I'll start with the second part of your question and then I'll let Jared addressed the first part of your question. With regards to expectations, so for both programs, as we said, the goal is really to Continue and evaluate PKPD safety and potentially Complete the dose escalation portion of the Phase 1a study. And as you know, the goal of dose escalation would establish Safety, in this case also PKPD, but as you know in clinical development, especially in oncology, it is important To assess early signs of antitumor activity to solidify the hypothesis of These oncology programs providing benefits to patients. So as part of the dose escalation for both program, we expect that we'll have a handful of Patients for 413 to be myDAD mutant and out of the whole B cell lymphoma that we're recruiting and for 333 CTCL, LGL and PTCL are the whole lipid and solid tumor cohort in order for us to Again, establish early signs of antitumor activity.

Speaker 2

So again, in terms of expectation, we hope to being able to Report on the complete our close to complete data set on the PKPD and safety as part of the dose escalation study And then hope to have, let's say, a handful of patients from each of the studies that fit the sensitive patient population where we would be able to Evaluate the antitumor activity of these 1st in class mechanisms. What we're now going to be able to discuss is Obviously, extent of response rates and metrics just because we believe that those are More scientifically sound in a better designed study to evaluate the clinical activity, which we believe is expansion cohorts and beyond. Pat, again, anti tumor activity, validation of these mechanisms, ability to correlate degradation to impact on tumors He's what we hope to being able to share later in the year. So maybe Jared, you can talk about the neutropenia question.

Speaker 1

Sure, Mike. So in terms of your question about neutropenia, when we provided our update back in June around the ICML meeting, we indicated that we had not seen any of those toxicities or any drug related lymphopenia, which was very Encouraging to us, as you mentioned, because we were seeing strong IMIT activity with greater than 90% knockdown of vikarose and allos, But we're not seeing neutropenem. Yes, we're expecting to see some decrease in neutrophil count. We have seen some decrease in neutrophils followed by recovery, but it hasn't risen to the level of being neutropenia, which is in line with our Preclinical data, our GLP talks data, where we did see some decline in neutrophils, but that we saw recovery Prior to the next dose 3 weeks later. So the use of this every 3 week dosing schedule, at least so far in the clinic, Has been successful from a safety standpoint in helping us to mitigate any sort of dose limiting neutropenia, which we think is important because we do have this This potent IMID activity as part of KT-four thirteen, of course, along with the strong IRAK4 lowering activity That our ability to dose escalate without being limited by myelosuppression, especially neutropenia or by GI TON It's something which we see as being very encouraging so far.

Operator

Thank you. Your next question comes from the line of kaljit Patel from B. Riley Securities. Sir, your line is open.

Speaker 7

Yes. Hey, good morning and thanks for taking the question. For the Planned Phase 2 study in HF. Can you give us any color on the expected trial design And maybe what types of patients you're planning to include in that trial? Would you allow the use of Prior use of HUMIRA in that study and then I have a follow-up.

Speaker 2

A bit, thanks for the question. It's a great question. Unfortunately, We're not in the position to comment on it, but I think soon enough, I believe, there'll be updates on clinicaltrials.gov. That point, we might be able to add some color around what's been disclosed. That's what we've agreed with our partner at this point.

Speaker 7

Okay, got it. And what are you looking in terms of expectations for that trial in HS? Are you looking to beat or match what HUMIRA has performed historically? Or do you think there's a slight wiggle room here that you don't need as much efficacy because you have an oral option?

Speaker 2

Another great question. I'm glad we're starting now setting expectations. So let's start with what we've seen so far. We've seen some really encouraging At TBD, I would say in both HS and AD. Obviously, your question was focused on HS, which is okay, but I would say on both Indications.

Speaker 2

In both indications, lack at this point a well tolerated potent oral option that Can help patients manage these really difficult diseases, especially obviously the moderate to severe cases. And our goal is to have an oral option that is well tolerated and that works and helps patients. And that we believe Can be competitive with other agents that have been approved in those patient populations. I think once we complete the study And we have a data set that is placebo controlled and solid. I mean, we can then start to discuss If that type of data set is repeated in the Phase 3 study, where is the commercial strategic Placement of this particular drug, but I think right now he's premature to discuss the commercial option.

Speaker 2

All I can say in terms of clinical And Patient Impact, we are planning to develop this drug and to be honest, others that you hear about in the future To fill a need, which is an oral option for patients that don't have one that is both well tolerated and active And our limited experience, I would say limited again, in both HS and AD running studies in patients It's been that regardless of the activity of existing options, patients are looking for well tolerated, Easy to take oral drugs and that's what Chimera is going to be focused on in the next few years.

Operator

Thank you. Your next question comes from the line of Vikram Paroy from Morgan Stanley. Sir, your line is

Speaker 8

open. Hi, good morning. Thanks for taking our questions. So one follow-up and apologies if this was discussed and we missed it. But on the topic of additional potential indications for 474 beyond HS and AD, What is your Sanofi's kind of cadence of decision making there?

Speaker 8

Is that going to be dependent on data from The planned Phase 2 studies in these two indications or is that a separate decision making process that you're going through with Sanofi at this time? And then secondly, I'm not sure to the extent you can talk about this now, just given your recent remarks on the other question around HS, but Has your Insanuby's thinking around the design for the HS study and the patients you might enroll been impacted at all by recent competitive developments in that indication?

Speaker 2

Thanks. Yes. Thanks, Vikram. Both great questions and I think I can address both. So the first one, I can't Speak for Sanofi, unfortunately.

Speaker 2

So what I can say though that we are As any responsible drug development organization, and in this case, partnership are discussing what potential other opportunities For an asset like this and as you know, Tenere on our own have been doing this for now a few years. So obviously, we don't have to reinvent the wheel that many times, but the conversations are around, what are the other potential opportunities Beyond HS and AD, I can't speak to the decision making process, but maybe from my perspective, what I can say is that obviously generating exciting data in HS and AD Might influence some other indications that are very close mechanistically and biologically to HS NAD, But it will not, in my mind, again, influence indications that are biologically And pathologically differentiated from HS and AD, and if you look at the list of potential indications that even we have on our Web You can imagine that there are numerous opportunities that fit the 1st bucket and the 2nd bucket. So maybe I'll leave it at that at this point. For the second question, which was around have other studies impacted our clinical Trial design, the short answer is no.

Speaker 2

The way that we and Sanofi had designed the Phase 2 study is to evaluate The clean obviously safety as you know, safety and the clinical activity of an RF 4D grader in HS and in AT, And we believe that our design is going to be able to answer that question. The question is whether the drug is superior or inferior clinically to other drugs, That's not the goal of our Phase 2 study. I've put it out there already. So as you can imagine, again, and this goes back We believe there is a clear need in HS, in AD, I would argue in asthma and COPD, in IBD Well tolerated and these again, these are my words of oral well tolerated active drugs and that's what we're trying to develop here.

Operator

Thank you. Your next question comes from the line of Eric Joseph from JPMorgan. Sir, your line is open.

Speaker 9

Thanks. Thanks for taking the questions. And just a couple from us on 253. And just this point of differentiation where you expect to be bypassing the feedback Regulation of MDM2. Maybe can you just remind us the kinetics of that feedback and is looking at sort of Degradation after cycle 1, enough to support Having a differentiated degradation profile, would you perhaps need to look at degradation with subsequent cycles to get A better understanding of the MAX degradation profile and use that to optimize the emission schedule selection.

Speaker 2

Yes, another great question. We're very fortunate here to have great, great questions today. So the 253, What is the kinetics of the feedback loop and where does the overcoming of the feedback loop impact the biology of I might add a kind of a follow-up point to your first point. What we have experimentally Demonstrated that the feedback loop needs to overcome on it needs to be overcome, Which means we need to retain high level of MDM2 degradation only for the first few hours. Actually beyond the first few hours, It doesn't matter anymore whether you're degrading MDM2 or not, because once you degrade it for the 1st few hours, Sales have a irreversible commitment to that.

Speaker 2

And so that's the hypothesis here. Small molecules, it actually doesn't really depend on the dose. I had a really hard time overcoming that just because It's limited by how much compound you can give and the pace of the every synthesis of p53 of MDM2, we being a catalytic, it doesn't really matter exactly what the dose is, we're able to degrade a large amount of MDM2 every minute The compound is on board. So we should be able to evaluate mechanistically our ability to suppress MDM2 And to lead to cell death on cycle 1. Now multiple cycles might We needed to have maximal antitumor effect, but that as you know is just standard oncology drug development.

Speaker 2

And importantly, For us, the hypothesis is MDM2 degradation leads to apoptosis, leads to cancer cell death, leads to anti tumor activity before We hit dose limiting toxicity, which does not happen with small molecule inhibitors. And that's why I said earlier, we should be able to show that in a Phase 1 study. Again, We're not going to be able to talk about what is the response rate in population X, Y and Z with big numbers just because it's a dose escalation study, But we should be able to demonstrate that in patients there and tumor types that are sensitive to this mechanism, at the right dose, we should be able to see anti tumor activity Before we hit dose limiting toxicity and that will be the definition of success, at least early success For this program that other MDM2 inhibitor programs haven't been able to demonstrate convincingly, at least in our eyes.

Operator

Thank you. Your next question comes from the line of Ellie Merle from UBS Financial. Your line is open.

Speaker 10

Hey, guys. This is Jasmine on for Ellie. Thanks so much for taking our question. We saw from the update in June that the majority just so far with 413 has been ID88 file type and not unit. So How should that like inform our expectations for any potential anti tumor effects you're expecting to see?

Speaker 10

Do you expect that proportion And then I have a follow-up.

Speaker 2

So I didn't hear it very well, but I think you asked I think I'm going to answer anyway and you tell me if I understood your question. So it's true that as of the ICML update, which I want to remind everybody the cutoff date I believe was June 1. All the patients but one We're MyD88 wild type and actually the only patient that was MyD88 mutant was the 1st patient in dose level 4, which in a way I think it was a bit of coincidence, but it was a fortunate coincidence, meaning that the only or the first patient with myD88 Mutant or mutation was at a cohort that we believe should be or could be clinically active. We do expect to see activity only MyD88 mutant patients. That's based on our preclinical data Where really strong activity was seen only in myDAD mutant patients.

Speaker 2

So, our ability to demonstrate anti tumor activity, as I said earlier In this program, we'll be driven by our ability to have Multiple MYD88 mutant patients, as I said, a handful as part of the dose escalation to evaluate the clinical activity, while the rest of the patients, I assume we'll be mostly generating PKPD and safety data, which is again really the Official goal of the Phase 1 study, but hopefully that answers your question.

Speaker 10

Yes, thank you. And then on the 3 33 program, how should we think about the discontinuation rate you expect going forward? And then 1st events classified as related to the research that you showed in the ICML poster, do you see those as like related to Do you expect to see any of those going forward?

Speaker 2

I think I'll see Jared answer this one. Jared, hopefully you heard it Well.

Speaker 1

Yes, I sort of heard part of it. A little bit of it wasn't entirely clear.

Speaker 2

So maybe Jared, I'll summarize the potential discontinuation rates in 333 and then What did we see in terms of relatedness of adverse events in the 333 study Up to the ICML disclosure, that's my addition.

Speaker 1

Yes. I mean, we really haven't seen much in the way Discontinuation due to adverse events. We have had people who eventually have come off The study, but not due to adverse events. So in terms of what do we expect in terms of future discontinuation rate, hopefully, it will be low In terms of adverse events, patients may come up for other reasons like disease progression, for example, but hopefully not for adverse events. If we look preclinically at what we saw In terms of safety, as we push to higher doses in preclinical studies, we did see GI side effects there and relatively modest Effect on platelets.

Speaker 1

So far, we've seen relatively little of that as we've been dose escalating. And we have had adverse events, many of which have been related to disease as opposed to being related to the drug itself. But as we continue to dose escalate, we'll be watching carefully for any adverse events that are thought to be related To treatment and see how those line up with what we saw preclinically. But I think that's the whole point really of Phase 1 really is as we dose escalate to really see how well The level of STAT3 NOCTO that we're seeing is tolerated by these patients. It is difficult sometimes in these early Phase 1 When you have very heavily pretreated patients to be able to sort out events that you're seeing that are related to the disease itself versus those that are related to the drug and the investigators at the sites Ultimately, we have to make the call there.

Speaker 1

But so far, the safety profile has been encouraging, and we'll just continue to watch as we continue to enroll patients onto the trial. Operator, in the interest of time, can we ask the questions just to keep the one question so we can try to get through the rest of the queue?

Operator

Understood. Thank you. Now your next question comes from the line of Kripa Devarackonda from Truist Securities. Your line is open.

Speaker 11

Good morning. Thank you so much for taking my question. I know a lot of them have been With respect to Sanofi initiating programs in HS and AD, but given Sanofi's footprint in that space and also the evolution of competitive landscape in HS as well as in AD, would be great to get your thoughts on potential for combos that could be SynergisTek, for instance, would an antibody targeting a downstream cytokine in the pathway be a potential combo partner? Thank you.

Speaker 2

Yes. No, great question. So I mean, I would start with again saying what I said earlier, which is in both indications and others, Patients still need effective therapies. If you look at even Dupixent, which is One of the most successful drugs in immune inflammatory diseases has a really limited penetration. And so I think there Still a need for effective therapy that are simple to use and that are well tolerated.

Speaker 2

If I want to indulge your question on the scientific merit, yes, sure, there are Opportunities to synergize across these multiple immune mechanisms. And I can't speak to Those plans, because to be honest, have not been discussed. But one would say, let's say an observer of How the understanding of immune inflammatory diseases is evolving with time that yes, there could be potential synergies across More than one mechanism, but that's just a scientific observation at this point from my standpoint.

Operator

Thank you. Your next question comes from the line of Derek Archila from Wells Fargo. Your line is open.

Speaker 12

Hey, good morning and thanks for taking my questions. Just a follow-up to an earlier question on KT-three thirty three or potentially another STAT3 degrader you might develop for I and I indications, is this something that you would explore yourself or is this purely for think that you would look to partner KT-four seventy four. Thanks.

Speaker 2

No, I mean, Our strategy is not to partner immunology programs. We did partner KT or I should say iREC4 in 2020 And that at the time was the right thing to do for the company, but that is not what our strategy our base case strategy is. So You should not expect that the next immunology program is going to be partnered. I think you will depend on Many factors, but I think you should not expect that we our base case is to partner these programs before they reach key inflection point in general.

Operator

Thank you. Your next question comes from the line of Kelly Hsieh from Jefferies. Your line is open.

Speaker 13

Hi, this is Shantan on for Kelly. Thanks for taking our question. So one of your Quanti's 3 objective is to deliver 2 new INDs. Can you provide more color in terms of the indication and targets and how the learning from the current clinical programs have instructed your plan. Thank you.

Speaker 2

Yes. No, it's a great question. I'm not going to go into the specifics of the numbers there, but just generally what I said earlier is that we've learned a lot From the first 7 years of this company, I think it's fair to say we're pioneering protein degradation and for sure we're pioneering Protein degradation in immune inflammatory diseases, lots of learnings on how to develop It's early to discover an early development of immune inflammatory degraders that have the potential to be best in class Oral Auctions. And so I think the expectation to have is that there'd be a lot of focus on those particular Type of programs, large opportunities, unmet needs, oral immune inflammatory drugs and other indications. I would say that the expectation is a lot of focus in that particular area.

Operator

Thank you. Your next question comes from the line of Rich Law from Credit Suisse. Your line is open.

Speaker 14

Good morning. This is Grace on for Rich. Thank you for taking our question. Just wondering for the program 4,004, How are you thinking about positioning that in lines of therapy in the Phase 2 study? Are you still trying to play stay broad or will you narrow to a more specific patient

Speaker 2

So thanks. I kind of addressed this earlier. At this point, we're developing a drug that we believe will be Has the potential to be safe, active and access a broader population of patients that right now are not served by existing therapies. Again, when we talk about labels and commercial positioning, that will happen further in clinical development. Right now, we don't have any reason to believe that will be limited by any factors at this point.

Operator

Thank you. The last question on the queue comes from the line of Geoff Meakin from Bank of America. Your line is open.

Speaker 15

Good morning. This is Hao Shing calling in for Geoff Meacham. Thank you for the question. So just a follow-up on BD, Other than immunology, are you looking for these for the assets in your other therapeutic areas? And if so, what maybe some of seeing top of your mind when you're making these type of decisions.

Speaker 2

Question is on BT. Did you say BD like business development or AD?

Speaker 15

Yes, BD like KT474 type of collaboration.

Speaker 2

Yes. So, I mean, we've commented on this particular topic, Lance, in the past. So, I'll try and keep this short. I mean, at the company with a broad pipeline that has an enabling platform that can deliver Sustained innovation will continue to entertain potential synergistic partnerships. I would say that's a broad concept.

Speaker 2

I don't think right now we're in the position to discuss specifics about Indications area programs, but I think that statement apply probably will apply always for a company like Chimera that has this Such an effective engine to deliver innovative potentially innovative therapies.

Operator

Thank you. Showing no further questions in the queue. I'll now hand the call over to Justine for closing remarks.

Speaker 16

Thank you, Justin, and thank you, everyone, for participating on today's call. I am very excited to join the Chimera team I look forward to working with many of you going forward. In the meantime, please don't hesitate to reach out to me or Bruce If you have any follow-up questions, thank you and this concludes today's call.

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Key Takeaways

  • Chimera dosed the first patient in the Phase 1 study of KT253, its MDM2 degrader, following preclinical data showing durable tumor regressions and FDA orphan drug designation for AML.
  • In the Phase 1 dose-escalation trials of KT413 (IRAK4 degrader) and KT333 (STAT3 degrader), patients have approached target degradation levels with no dose-limiting toxicities, and anti-tumor activity readouts are expected later this year.
  • Under its partnership with Sanofi, the IRAK4 degrader KT474 showed robust target engagement, good tolerability, and promising activity in hidradenitis suppurativa and atopic dermatitis, with Phase 2 studies set to start in Q4 2023.
  • Chimera continues to advance multiple preclinical, first- or best-in-class degrader programs across oncology and inflammation, focusing on genetically validated targets with multi-billion-dollar potential.
  • For Q2 2023, collaboration revenue was $16.5 million, R&D expenses were $45.8 million, G&A expenses were $14.1 million, and cash of $472 million supports operations into the second half of 2025.
AI Generated. May Contain Errors.
Earnings Conference Call
Kymera Therapeutics Q2 2023
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