Q3 2023 Kymera Therapeutics Inc Earnings Call
Okay.
Good day and welcome to marathon reputed third quarter 2023 results call.
All participants will be in listen only mode.
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After today's presentation will be an opportunity to ask questions.
Note that this event is being recorded.
I would like to turn the conference over to MS. Justine Koenigsberg, Vice President of Investor Relations. Please go ahead.
Good morning, and welcome to <unk> quarterly update joining me on this morning's call are now luminal feed founder President and CEO Jereb column, our Chief Medical Officer, and Bruce Jacobs, Chief Financial Officer, following our remarks and presentation. We will open the call to questions. During the Q&A portion of the call. Please limit your question to one.
And a related follow up so that we will have enough time to address everyone's questions. Please.
Please note that we will be referencing slides in our corporate presentation during Jerry's remarks.
The slides can be accessed in the investors section of our website under events and presentations and will be shown during the call for those on the webcast before we begin today's discussion will include forward looking statements about our future expectations plans and prospects. These statements are subject to risks and uncertainties that may cause actual results to differ materially from there.
Those projected a description of these risks can be found in our most recent 10-Q filed with the SEC any forward looking statements speak only as of today's date and we assume no obligation to update any forward looking statements made on today's call with that I would now like to turn the call over to Noel.
Thank you Justine and thanks, everybody for joining US today, we're excited to review our recent progress in several critical milestones that the company has achieved.
We are near the end of 2023 I'm extremely proud of the strong execution by our team that has led to continued progress in our clinical studies across multiple programs along with innovative pipeline advancement support that future growth.
Before we detailed that progress I wanted to share a few thoughts and work them. Ara is you know our mission to building a best in class fully integrated global be greater medicine companies in doing so I hope to provide you with an important lens through which you can view, our achievements and our strategic decisions regarding the portfolio.
Our unique approach to developing a new generation of medicines using T. P. D has resulted in a robust pipeline both in the clean economical way to the clinic highlighted by multiple programs there are guided by and consistent with our goal of creating groundbreaking.
I hope there is broader appreciation for all that came that was accomplished since our founding only seven years ago. We have taken put programs in the cleaning demonstrating see that'll give translation of PK PD and safety across each of those programs.
We have shown early clinical proof of concept for three of them as you will hear soon our unique strategy has allowed us to achieve multiple TPB firsts, including conducting the first.
And I studied has people in tears and patients with K T. Four seven for targeting Iraq for.
In addition, we'd be the first speak rate and an elusive transcription factor likes that three.
More strategically for T T four seven and four we formed the critical collaboration with one of the leaders in the Ini space and that program is now advancing in phase two development with the first patient in the first trial.
<unk> recently dosed, we've built industry, leading knowledge and capabilities that we're leveraging each and everyday.
And we have developed a best in class pipeline of innovative and highly valuable program some of which we would be excited to share with you over the coming months.
An important cornerstone of <unk> success has been our unique approach to target selection, which has several key tenants. The guide their strategy and of course, our research and development efforts. Our focus is and has always been on genetically validated targets that are either on drug or inadequately truck within pathways.
Clear validation.
And we're keeping the best or only solution importantly, we target large market opportunities, where the unmet needs are significant and where we believe that there is a greater probability and opportunity for significant commercial success.
With regards to therapeutic areas their programs have progressed over the last several years and as you can see from the pipeline slide on our website and in our corporate presentation slide six our portfolio is increasingly lean towards immunology.
This is a purposeful strategy orientation guided by several factors that have influenced our strategic and investment decisions.
Here a more complete overview of these focused at our R&D day on January 4th, but today I'd like to highlight a few.
First it is clear that I and I is an area, where the understanding of the underlying biology has increased dramatically.
The large commercial opportunities with Eni and I are mostly dominated by biologics that have had validated key pathways and targets, but also create an opportunity for other more convenient modalities and a loss at least for today to that point, we believe that T. P. D can provide a unique solution with strong efficacy.
Subjects like specificity, but with the flexibility of oral small molecules.
Importantly, we hope you all I appreciate that we have demonstrated early but convincing evidence of bar potentially 90, and I would keep T 474.
In fact, we believe strongly that the success, we've had with Iraq War program will help shape. How we approach. These new opportunities we have Congress learnings from that program, starting with the development of the molecule itself, including our extensive preclinical work and the key insights we've gained from running what we believe is there.
Our largest add people in tears seafood patient starting the TPP space.
And now Keith T post to them for he's undergoing phase two studies with our partner Sanofi. These wealth of experience and knowledge gives us high degree of confidence in our ability to execute on many new opportunities some of which we would be sharing with all of you in the coming months.
We've also made important progress in the clinic with K T 333, which targets that three M. P. T 253 R. M. D. M. Two degree either Jared will provide updates on both programs later during the call and highlight well we're very excited that K T 333 will appear in the nausea abstract laser this morning, it would be fine.
In a poster presentation with updated clinical data at the Ash meeting in December it's important to know that we're seeing early signs of clinical activity even at those levels that we're not predicted to be clinically active but where we are nonetheless seeing robust start three degradation Jared will share a few highlights on this.
Cool and we will be able to say more once the accepted abstract it's publicly released which should be shortly after our call concludes this morning.
We're also excited by the early data emerging from car T to five three phase one dose escalation study with demonstrated book both proof of mechanism and early signs of clinical activity in Indonesia dose levels, even earlier than we expected that.
The early clinical activity lack of thrombocytopenia neutropenia in the presence of antitumor activity makes us optimistic about the translation of our degree the rationale of increased therapeutic index and full realization of our P 53 pathway potential.
With regards to K T 413 out of Iraq can meet degree there we have decided to discontinue the program. Let me first say that this decision is not driven by any clinical data safety concerns that we have with the program. We are degrading the targets in blood as we'd expected and we are not experiencing dose limiting toxicities.
Rather our decision to discontinue K T 413 reflects our commitment to the program that more closely fit the previously mentioned strategic focus of the company.
More specifically when we evaluate the evolving health care landscape, especially in oncology and the market opportunity and the competitive landscape in the fuse large b cell lymphoma, and juxtapose that with the enormous opportunities we have in our emerging pipeline. We have decided the right strategic decision is to focus our resources on those.
High value programs.
You should also be noted that we did not take this decision lightly nor did we make it without thinking about the potential impact on patients.
But as many of you already know the DLP Seattle market is well served today with numerous active agents and we believe promising therapies will continue to emerge in the relapsed refractory and frontline settings.
Ultimately, we believe that came there I can have the greatest impact by focusing on areas of significant unmet patient need what T. P. D can have the greatest impact we have built a team with leading expertise in drug discovery and development capabilities, which we believe provides can't manner with a strong competitive advantage and perhaps most important.
As I've already highlighted we have shown our ability to execute with the development of <unk> T for seven four which is achieved another significant milestone with the dosing of the first patient in the phase II study.
As our immunology R&D day in January we would provide an even clearer picture of the strategic forces focus that we're outlining today highlighted by what we believe are both important and exciting pipeline disclosures.
We're confident than when we shared the details around our next programs and our strategies for building <unk> into an industry, leading fully integrated biotech company you will appreciate our enthusiasm for the enormous opportunities those programs represent.
I can tell you now and are we likely repeat these when we got there in January I've never been more encouraged and excited by the pipeline of opportunities on which came area is poised to capitalize.
Finally, humira remains very well capitalized which puts us in a strong position to execute on the opportunities our pipeline presents as we noted in today's press release, we've extended our runway into the first half of 'twenty to 'twenty six.
This takes us well beyond several key catalysts and data readouts that we expect to be important derisking event for our clinical and preclinical pipeline, including face today, you don't K T 474.
For the POC readouts for our oncology programs and important updates on our pipeline more details about which will be shared at our upcoming immunology R&D day, let me pause pause here and turn the discussion to Jared.
Thanks Noah.
The focus of my comments today will be primarily on K T 333, and K T to five three and new clinical data we are announcing this morning.
As Noah mentioned, we're very happy that our clinical abstract relating to K T 333, our first in class small molecule at the greater of Stat. Three was accepted for a poster presentation at ash.
The full abstracts will be available online shortly but I will share a few highlights shown on slide 29.
And we of course will be available for follow up once the full abstract is released.
For context July 10th with our abstract data cut off date.
As of that date 21 patients have been treated across five dose levels of which 12 were evaluable for disease response.
The patients included a variety of liquid and solid tumors.
All of our comments today are based on that July 10th cutoff date.
Yeah.
The data in the abstract show continued evidence in blood of robust stat, three protein degradation in humans with associated staff III pathway inhibition.
With dose level, three and beyond expect it to be clinically active.
Along with potential early signs of anti tumor activity.
As mentioned there were 12 evaluable patients in dose levels one through four.
Of which just to where liquid tumors at dose level two.
Of those two liquid tumor patients treated at dose level. Two we saw one partial response after two cycles in a patient with C. T C L.
Cell lymphoma, where we saw substantial activity, where the statutory integrator and our preclinical statutory dependant mouse model.
Among the 10 solid tumor patients available for disease assessment, which is a group where we do not expect to see monotherapy clinical activity based on our preclinical studies, we saw a stable disease in three patients after two cycles at dose level three and four.
Importantly from a safety perspective, no D. L. Ts were observed and no drug related Aes were reported.
Safety M. P D were consistent with previous updates.
These early findings are encouraging and support the potential of headroom by functional integrators for targeting previously undruggable transcription factors implicated in diseases.
Okay.
Accrual is ongoing and therefore, we expect to present additional data in patients with Hematological malignancies, including T cell lymphomas, and leukemias and solid tumors beyond what is in the abstract.
We look forward to providing more details both after the publication of the abstract today as well as next month at the Ash meeting at the time of the poster presentation.
Additionally, in September we announced that the FDA granted fast track designation for K T 333 for the treatment of relapsed refractory cutaneous T cell lymphoma, and relapsed refractory peripheral T cell lymphoma.
We're happy that FDA gave this designation to the program as it further highlights the promise of degrading stat three.
Protein that has historically been undruggable for the treatment of patients with C. T. C O M. P. D C L.
Yeah.
Turning now to Katie 253 hour M. D M. Two to greater we are disclosing clinical data from arm a of the ongoing phase one trial for the first time this morning.
We are pleased to report that we have demonstrated K T to five three clinical proof of mechanism and initial signs of clinical activity in just the first two dose levels in patients.
We have slides that highlight some of our results and the corporate presentation posted in the IR section of our website.
I will briefly summarize and we can take questions in Q&A.
As shown in slide 32, K T to five three degrades M. D. M. Two crucial regulator of the most common tumor suppressor P 53.
P 53 remains intact and close to 50% of cancers, meaning that it retains its ability to modulate cancer cell growth.
While small molecule inhibitors had been developed to stabilize and unregulated P 53 expression.
They have been found to induce a feedback loop that increases M. D. M. Two protein levels, which can repress P 53, and therefore limit their efficacy.
In preclinical studies K T to five three has shown the ability to overcome the M. D. M. Two feedback loop and thereby robustly activate the P 53 pathway, even with brief exposures.
Adult patients with relapse refractory high grade myeloid malignancies, a L L.
Almost and saw the tumors receive IV doses of Katie 253, once every three weeks.
The study is intended to evaluate safety Tolerability P. K P. D. An initial clinical activity and allow us to identify the recommended phase two dose.
It is comprised of two arms with a sending doses of Katie 253 in each arm.
R. A as in patients with advanced solid tumors in lymphomas and R. B as in patients with relapse refractory high-grade myeloid malignancies, including a M. L M. A L L.
<unk>, our first patient in May and have fully enrolled the first two dose levels in our may with enrollment to dose of a three ongoing.
Enrollment onto arm D has also been recently initiated following demonstration of on target pharmacology and the first two dose levels of arm a.
As of the October 20th data cut off date, a total of nine patients with solid tumors had been enrolled onto dose levels one through three of RMA.
And have received a mean of 2.3 cycles with a range of one to six cycles.
As shown in slide 36 proof of mechanism has already been demonstrated in the first two dose levels with exposure dependent upregulation, a plasma gd at 15 levels.
G D. A 15 at that transcriptional target of P 53, and as such it serves as a downstream biomarker of P 53, Upregulation following empty two degradation.
In addition to the dose proportional increase in plasma T. T 253 levels between dose levels, one and two and cycle one.
The G D. A 15 maximum fold increase over baseline during cycle, one was 10 and dose of of one and 30 and dose level too.
The kinetics of Gd at 15 changed following the cycle. One dose is shown in slide 36 for a subject on dose level, one where brisk upregulation over the first 24 hours. After dosing was followed by recovery towards baseline over the subsequent six days.
This was consistent with a pattern of P 53 activation in preclinical models associated with K T 253 anti tumor activity.
[noise] clinical response results for all patients within a dose cohort were available for dose level, one and are shown in slide 37.
Even though based on exposure that we did not expect this dose level to be clinically active we were encouraged to see that among the three solid tumor patients treated on dose of it. One there was one confirmed partial response after four cycles with treatment continuing after six cycles.
One confirmed stable disease after four cycles with the patient subsequently discontinued from the study after six cycles for lack of response.
And one patient with disease progression after cycle one.
The patient with a partial response had merkel cell carcinoma, metastatic to abdominal lymph nodes and skin, who had previously been treated with chemotherapy as well as multiple different immune checkpoint inhibitors.
As shown is like 37, the lymph node metastases, we're responding after the first two cycles of treatment as well as the skin metastasis and after four cycles. There was an approximately 60% reduction in nodal tumor burden and resolution of the skin metastasis.
There were no dose limiting toxicities.
As shown in slide 38, most common drug related eight east occurring in two or more patients.
Included grade one to nausea in grade one diarrhea.
One patient at those other one had an SAE of grade three hypotension during cycle for that was due to diminished oral intake deemed related to study drug.
Treatment included IV fluids in the patient remains on study without dose reduction or recurrence of hypertension.
There were no neutropenia or thrombocytopenia, a he's even in patients who had received up to six cycles of therapy.
In summary on slide 39, these promising interim clinical data showing evidence of target engagement and P. 53 pathway activation along with initial signs of anti tumor activity without dlt's, including typical hematological toxicity are supportive of our therapeutic hypothesis for MDM two degraders.
And the potential to improve the therapeutic index compared to MDM too small molecule inhibitors.
As we continued to explore the safety and clinical activity of Katie 253, and both solid and liquid tumors in phase. One a we are also putting together a comprehensive preclinical and clinical data said examining the factors impacting in vivo response to intermittent dosing with K 2253 across multiple different solid and liquid tumor types.
In order to derive patient selection biomarkers to the next stage of development after phase one a.
Disclosure of additional clinical data as well as preclinical data informing a biomarker based patient selection strategy is planned for 2024.
Finally, a quick update on K T 474 hour Iraq for the greater which is now in phase two development under the direction of our partner Sanofi.
As we recently disclosed the first patient and the H S trial has been dosed and we are excited about the significant milestone four K mirror.
In addition, the 80 trial recently commenced and we will report news of the first patient dosed in that trial after it occurs.
The details around the study designs for both trials are available on Quintiles Dot Gov, and we have a summary on slide 20.
At a high level the trials of power to show a treatment effect relative to placebo and will also provide a comprehensive assessment of safety and on target PD.
Dose escalation was informed by the safety E. P D in clinical efficacy data from the patient cohort interphase won't study in both trials will evaluate Katie 474 versus placebo for 16 weeks.
The Hs study will enroll up to approximately 100 patients in the study up to 115 patients.
Both studies include standard endpoints measuring skin lesion burden in symptoms.
And the H S. Study. These include an count high score I H as four and pain measures while in the 80 trial. These include easy score along with the Iga D.
D and pruritus measures.
Both Hs and represent important indications with significant unmet patient needs and we're excited to see our partner Sanofi advanced the program interface too.
As noted in the Quintiles Dot Gov, posting both trials have primary completion dates in Q1 2025, anticipating completion of enrollment in 2024 and top line data and the first half of 2025.
Pause here and turn the discussion to Bruce to review the financials. Thanks.
Thanks, Jared as I review, our queue three financial highlights. Please reference the financial tables found in today's press release for the quarter, we recognize $4.7 million of collaboration revenue all of which was related to our sanity collaboration at the end of the quarter are deferred revenue total on the balance sheet was approximately $43.8 million that reflects sanity partner.
Ship revenue that we expect to recognize over the next several years, excluding the receipt of any potential future milestones as an ounce last week <unk> receive a 40 million dollar milestone payment triggered by the first patient dosed and the K E 474 Hs trial. We include this milestone in the next milestone we expect for the first patient dosed in the eighties study and Ah.
Cash runway guidance, although it is not reflected in the cash balances at the end of the quarter given that both of these payments are anticipated to occur in the fourth quarter of twenty-three. We expect both to initially be recorded as deferred revenue in to begin being recognized as revenue in the fourth quarter of 2023 with respect operating expenses R&D for the quarter was 48.1 million.
Of that approximately $5.8 million represented non-cash stock based compensation, making the adjusted cash R&D spend 42.3 million, which excludes that sock based cop and reflects a 5% increase from the comparable amount in the prior quarter on the G&A side are spending for the quarter was $14.1 million of which $5.
9 million represented non-cash stock based cop, the adjusted cashed G&A span of $8 2 million again, excluding stock based compensation reflects a 5% decrease from the comparable amount in the prior quarter. We ended the third quarter of 2023 with $435 million in cash and equivalents under our current operating plan, which again includes the format.
And portfolio actions, we expect our cash and cash equivalents to fund the company into the first half of 2026. This concludes our prepared remarks, and we'd be happy to know address any questions operator.
Thank you I'll I'll begin the question and answer session.
<unk> phone.
If you're using a speaker phone please pick up your handset before pressing the keys.
Withdraw your question please <unk>.
This time, we'll pause momentarily to pull some of the roster.
First question will be from Brian Kinney, Oh lets people. Please go ahead.
No as I read the explanation for the strategic shift away from the Iraq admit I couldn't help but think the same logic could be applied to stat three on the cancer side at least as we think about the amount of therapy potential in T cell lymphomas, so while I get that the stat. Three studies are also very useful as a proof of concept for your immuno.
Allergy developments should we still think of stat three is having legs for you in oncology and if so what form thank you.
Thanks, Brad.
Great question. So so first you know I just wanted to reiterate the 413 was a clear strategic decision based on how we prioritize our pipeline and again the landscaping in in diffuser B cell lymphoma, as you noticed that three that abroad development program that spans.
Both liquid tumor solid tumors as well as there is outside of their own column G. So I mean as you know we have a really high bar on how we make decisions on.
On investing in the next phase of development, So will always Ah Ah Ah Ah Ah at that point in the face of development, where we assess the opportunities ahead of US right now the way the Willow could start threes that is a multi prong development plan, which includes activities in liquid tumors, which we know.
With it but I think we are working boats into clean neekam preclinically to <unk> to flesh out the opportunities in solid tumors. As you know we've shown preclinically the activity that we've seen with the other agents, including P. D. One.
We are doing got phase one studies collecting a tumor biopsies to look at the signature in the tumor microenvironment with respect to how we modulate that then we're doing other studies that we haven't disclosed yet preclinically to Luka combination with this agent in solid tumors. So I think.
I wouldn't say that that the <unk> program is in the we're looking at is that three program. The same way that we have evaluated at 413 program. I think there is a broad opportunity that we're evaluating again, you know oncology and as we said in the past outside of oncology, having said that we will always be continuing to evaluate.
At every stage of development weather teases, he's playing out the way that we planned versus not and so for now we have full confidence in what this program can do and the data that we're sharing today and data that we haven't shared yet continuing to support their theses.
Okay. That's helpful and maybe it's a <unk> a follow up on M. D. M. Two it's nice to see no trigger chemo Benz, but could you just got a bit more about the kinetics of the platelet changes you're seeing because for deal one at least you've gone up to six cycles. So are you are seeing a return to baseline for those accounts by the start of the subsequent dose and I'm just trying to get a <unk>.
For the potential of any compound impact over cycles on counts as he moved to those more potent dose levels. Thank you.
<unk> the question I mean, so far within the first two dose levels, we have not seen any.
Thrombocytopenia or neutropenia, so we have not seen any reduction in platelets or neutrophils.
Thanks, so much.
Mmm.
Thank you Yeah. That's a reminder, interest of time, please limit yourself to one question and one for awhile.
The next question will be fraud.
<unk> Oh Morgan Stanley. Please go ahead.
Good morning, everyone honest with Gospel uncle Vikram.
But we have one question given to release measures book has taught it company on immunology moving forward.
Do you plan to keep the <unk> and M D M two programs beyond.
Echinacea clinical data sets.
Awkward those programs the whole set off partner up thank.
Thank you.
Okay. Great question. So so just just to be clear I think we're seeing two important things today. One is that as we have continued to say over the years, we want to make sure that we deploy our platform against the.
Ah Ah clear unmet needs and doing so like going off their targets that ended up being dragged the drug well. We also said today and we said it over the years that our focus is.
On you know a large problems so problems that have not been solved by other technologies and more importantly in in patient population that we believe are a sizeable.
So when we talk about immunology, we believe that that is an area that there is primed for these technology, we believe that you'll hear much more in January.
Oral degree there magazines in immunology.
Could author really amazing opportunities for lots of busy there now are either underserved or served only by injectable biologics instead.
Having said that there are areas of oncology steeled fulfilled the the the the investment pieces that I just outlined meaning we believe that we have programs that can Ah lok lots of opportunities by going off the targets that they have not been drugged Oh drug world by by other technology. So I think the <unk>.
<unk> theme is going after in these in these evolving landscape sizable opportunities and really deploying the technology, where it's best deployable. It's fair that Ah, we believe that the opportunities scene in immunology are probably both brother.
And and and actually.
I would say also Ah would less competition than than I think we see in a very very competitive oncology space and we will continue to evaluate whether the case continues to be as we continue to evolve this program.
So I think at this point, that's where that's where we are as we go into January I I think that the pipeline choices in the presentation will be even cleaver.
Oh, thank you.
Next question. Please. Thank you. The next question will be from <unk>. Please go ahead.
Hi, how are you there.
Oh.
Oh will come back to Mark next up we have to ask me to Bank of America. Please go ahead.
Hey, this is John Joy on for jazz Meacham.
Kind of looking at K T 474.
Cynical benchmarks and atopic dermatitis.
Still to fix them.
Oh, Great question. So we're looking with with our Eric four degree there, which is really thirsty in class magazine. There is trying to just just to go back a second the goal there is to block the path for the <unk> pathway with a single molecule.
And in doing so.
Being able to at least at the biological and hopefully clinical impact that Ah upstream biologics are not able to do and and basically demonstrate the clinical activity potentially all the upstream biologics new single molecule.
<unk> 413 pathway, so will look at it in Iraq for his abroad anti-inflammatory agent that can be both effective well tolerated and oral and so convenient for a broad patient population. So right now you know in the absence of conclusive phase III data that will that.
Will allow us to put in a position to drive commercially in incredible men are I think at this stage, what we've said in the past and continued to say he's the target further profiled 4474 is to be a normal active drug with a good safety profile and I would argue that that is not present right now he neither DHS or the demos.
And that's really the goal of the development program.
Okay Awesome. Thank you and then work like follow up so is there any read through or material in fact to come are from so no fees increase R&D spend announcement.
I think it's a positive readthrough from from where I stand, obviously I can't comment on some of his decision.
I think for me if I had to share my opinion I think it's refreshing to see a large pharmaceutical company, taking a bold move in investing in R&D, that's all I'm Gonna say.
Next question an operator, please [laughter].
Thank you next question will be from our farm unique Alan Please go ahead.
Hi can you hear me now.
Yes.
Okay, [laughter], sorry about that maybe for Jared.
The yeah, the description of the Asher a tractor in there.
Nine.
<unk> valuable patients I believe yeah can you describe those yeah, how many are still on trial and.
Maybe along with that the how many should we expect.
Where a single agent activity might actually be part of the hypothesis when we get to the <unk> presentation and all the politics.
Yeah. Thanks for the question Mark Yeah.
Can't comment on the sort of results beyond what is in the abstract and as you noted you know we've enroll 21 patients so far for the first five dose levels. We noted that 12 patients were valuable across the first four dose levels and then we talked about the.
The one P R and the C. T C L patient at this level, two and three solid tumor patients who were stable that those those three and four.
So our plan in December it ashes to obviously provide updates you know both on those patients as well on any additional patients who have enrolled onto the trial between that after I cut off date and the cut off date for the the ash poster.
Maybe maybe if I won't get in trouble with us Ah just one odd movie a couple of more things. So one I guess the the the the ones that were not a valuable.
Guess I don't know the details who's a mix of patient that progress through early and patients of steel.
There there dozing in the in the in the in the Lucky.
More recent cohorts and I think it's fair to say that for the ash abstract.
We do expect so that should be on the ice presentation. We do expect to see evaluation of more liquid tumor patients. We can't say, how many but we expect to see more than these first two one those level too.
Okay. That's helpful. And then you know as you laid out earlier in response to one of the other questions.
The bigger hypothesis here really is combinations for solid tumors.
Can you lay out what do you need to show.
In this trial to in order to kind of trigger those comments opening up this combination cohort.
Yeah.
Before we go to that I I I want to make sure.
I don't want it sounds overly positive, but I also wanna sounds realistic.
You know we have shown for the first time that they're gonna they shouldn't can help patients.
This has never been done before this way and so I think we need to just take a moment and I. Appreciate that disease. You know this is thirsty class data and you know why we can debate. Obviously you know the the sides of the patient population that the simulation activity. He's he's pursuing we should not forget.
That that's what we're here to do has been patients with innovative thirsty and clouds medicines. So I'm not reflecting your question. So I'm now going to your question. There are several things that we want to be able to to see to move into a.
A an expansion call or in a solid in solid tumors Ah first understand the degradation safety and any signs of Ah Ah any activity that we see as a single agent in solid tumors. As you know we don't expect to see seeing village activity, we have some stable.
They actually have been for quite a while you know we can't it's hard for us to know what we know how much of that is D. C beat the disease being slow progressive around much of that is the actual.
The relation of the three you know we'd like to think that it's probably a bit of both but so there is an aspect of that.
There is an aspect of as I mentioned earlier looking at tumor biopsies and understand if we can replicate what has been shown actually both preclinical into clinic with other agents are included in that and <unk>.
Ooh in terms of modulating into more migraine government and then as I mentioned, we have ongoing activities preclinically not only actually exploring the start three P. D. One combo, but also start three and other targeted therapies combos and and and I think.
What are we stand today, we have the we have optimism that Ah. This mechanism is a place in drug development in oncology is just for US too early to see what that is until we complete the series of studies as they say both clinical in preclinical.
Our next question. Please yes. Thank you next question will be fundamentally moral UBS. Please go ahead.
Hi, this is <unk>.
Thanks, So much for taking my question I keep heights, three how are you thinking about like kind of a dose response and the optimal levels of degradation do you think that the <unk> could be different and it's not like he married the Hematological modeling days and then they have <unk>.
Mhm.
Cause they're gonna take them yeah. Thanks, Yeah. It certainly is possible that there could be different recommended phase two doses for solid tumors lymphomas, which is the arm a of the face when a versus hydrated myeloid malignancies, including AML, which is R. M b.
We think ultimately you know activity is gonna be probably a function of M. D. M. Two day degradation and the level of P. 53 pathway activation that we're able to elicit you know either in solid tumors lymphomas or in AML, along with the sensitivity of those tumor types. Two P 53 mediated a popped up.
Also of course, you know is going to be the safety profile of the drug which may be the same you know in the greenfell tumors or it could be different. So these are all the things that will be investigating these.
These two arms on study I'm looking at safety looking at the degree of P. 53 pathway engagement, an activation that we're able to elicit with a drug and of course, then looking at clinical activity and that will determine what will be either the maximum tolerated dose of the recommended phase two dose that we bring into the next phase of development, which will be phased when b and and.
As you sort of noted if possible that we may end up having the same dose used across all those indications or there could be different doses across solid tumor lymphomas vs liquid tumors, but the study is designed to allow us to.
Assess that and make that determination by the end of phase when he.
Just the ones I know, we've got other questions, but I just want to highlight just as it did for 333 I mean the <unk>.
Theater 4253 was and continues to be we did the greater mechanism you can drive.
Tumor cells to a quicker Tajik responds.
And has a frequent dosing regimen that maximizes efficacy and safety and while we have limited data and I will say they get limited data it was extremely the.
The exciting for us to see that the theses displaying out in the way that we imagine probably even better at this point. So I was you know I would encourage everybody to keep an eye on this program because if the profile continues with all this way I think we'll have a really large opportunity to set in.
In an evolving patient certification theses that will share more of next year.
Awesome. Thank you and then as quickly on 333 and three stable does he says that you sign finally came rotation can you get any color on what Tim or types that sir.
We actually saw the stable disease across a variety of different you know solid tumor types and you know as I mentioned you know we have some patients who have had you know fairly prolongs stable disease as well I think we'll be able to provide I think more color on the actual fell a tumor types at the actual ask presentation in.
December but I think it's very encouraging that I'm a study we've been able to enroll a variety of different solid tumor types as well as a variety of different T cell malignancy types, including PDC L. C D C L and others.
Others as well so I think we'll look forward to providing more of those details and updates in December at the Ashbury rotation.
Thank you next question from Eric Joseph J P. Morgan. Please go ahead.
Hi, good morning.
Asking you to step a little bit into the January R&D day, but can you talk about how your experience with a K C. 333, so far informs the attractiveness of stat three within your Hurrell immunology pipeline planning relative to other targets of interest and.
Does your experience with 333, perhaps give you a head start on an aural Degrader you know first with some of the other targets that had been fun.
Yeah, I guess, if the other lessons so far from me Ivy formulation of making carryover Earl Thank you.
Yeah. So thanks, Eric.
Question too.
Not to not answer your question, but I would point to two things first I think what we learned the most about all of the greater as an immunologist from Ah K T. Four seven Ford program.
You know, we we took care of that.
Bold approach a few years ago to take targeted protean their relation in immunology and I think we've been rewarded by by that approach. We've shown how at the oral degree there can be six can be west tolerated can be effective that degrading the protein can have it really substantial until.
Planetary effect is measures by cytokinin inhibition and also has shown early signs of clinical activity. As you know, we we've been careful with over weighing on that cleaning all activity because of the small lands, but I think it's clear to say that if you look at the totality of the day that there is clearly there was clearly benefit impatient.
<unk> Ah and besides woods publicly available there is a lot that we've learned on drug development of Degraders in immunology going back to preclinical two talks to CMC two clinical trials strategies. So I think that has inspired us and is.
And is driven us to take that concept in in equally large clinical opportunities.
I think what we've been so you will see in January.
That the the day the programs and the data that we are generating impressive maybe I'll leave it at that with regards to 333 I think what we've learned for sure is that this is an extremely powerful mechanism and it seems to be it seems to have at least.
So far in oncology patients ego, the safety profile edge of the day that would disclose so far and so that that's probably told US that there are pathways are particular targets that you know will be or can be amenable to this approach even if you know the the safety.
Of that particular thoughts were there particular target and not been previously dearest either in the clinics or through human genetics. So maybe that's hopefully we'll give you an idea of what we will be talking about in January.
Just a reminder to have enough time to get to any reminder, can we'd like to ask that you limit it to one question.
Maybe I'll try to be faster than the answers.
Next question operator.
Thank you next question will be from Michael Samantha <unk>. Please go ahead.
Hey, Good morning. This is Paul on for Michael Thanks for taking the question month on K T. 253, just wondering if you could provide some color on the merkel cell carcinoma patient who had a P. R.
Patient have Indian too application or any biomarkers like C. D can to a lost that might be related to the response and where are you able to achieve your target degradation level in the station and just trying to understand the activity here at the little one thank you.
Yeah. Thanks for the question. This merkel solve patient was P 53, wild type and had the Mercosur polio virus. The majority of Americans cell carcinoma patient have that virus and R. P 53, while type.
That patient had previously been treated both with chemotherapy and in the past with anti P. D. One drugs, which have been shown to be effective in Morocco sell the patient had responded initially Dante P. D. One and they had progressed after their latest anti P. D. One before coming onto our study I think you know are almost study trial on dose level one.
On that patient you know did have very robust induction of G. D. F 15, which as we mentioned at the downstream biomarker of M. D. M. Two degradation and so that particular patient who had that has an ongoing a partial response.
Did show clear on-target pharmacology with elevation in G. D F 15.
And so we've been very encouraged that even at the very first dose level. We're seeing this sort of all responsive partial response you know in this type of solid tumor that had previously progress after anti P. D. One and that really until it does so far support our mechanistic and therapeutic hypothesis about being.
Able to affect that these 253 wealth a tumors with pizza three three activation and pathway Upregulation, where the safety profile, where we're not seeing any hematologic toxicity, which was the case with this patient as well.
After next question. Thank you next question will be from Deborah Deborah <unk> Oh towards Securities. Please go ahead.
Hey, guys. Thank you so much for taking my question I was at the typical contracts and one take a law it seemed to be that are one comment.
The date of the piano can be held at a higher standards for safety.
Let's start at least.
Do you think that is now a standard established and how do you evaluate safety in the field do you think it is a case by case, each drug and just broaden eating expecting to continue to evolve.
Cool and your purpose.
So there's not a great question, so I I I I I don't know.
I I think maybe your comments reflect the fact that this is a new generation of magazines and while I think it is not really broadly I. Appreciate that this is a new generation of magazines, probably because both the mechanism is not fully well understood by Ah distract observers. This is a new generation of magazines and so with.
That Ah obviously always comes the questions of the interplay between safety and efficacy. So I I think that's probably what's driving some of the questions personally.
I think it's been shown now extensively by approve drugs that are big readers and we've talked about you know the the image that have been on the market for years for decades, and and then all of the investigational drugs that have been into cleaning for years now from companies in the space.
That that you know any safety to do with a degree the program is.
Tied specifically to they're on target and off target.
50 profile and then there is no safety that we came era obscene that had to do with the actual technology. So obviously, if you have a west tolerated Ah Macanese menu don't have off target activities that thank you see molecules be well tolerated.
And I think that has been consistent across across the the industry. Now. This is an extremely powerful technology and this is why we believe has huge potential and so specificity of our molecules has to be Paramount and and I think that's what I encourage obesity everybody to be.
Focused on.
Question Nick.
Thank you next question will be from.
Eric <unk> Wells Fargo. Please go in.
And thanks for taking my questions. Just one so just given the future focused on sizeable ini indications I guess, how does that change the calculus on cash runway and I guess is it fair to assume that you'll run more traditional phase two studies achieve a proof of concept for those programs. Thanks.
Yeah. So maybe I'll answer the question Bruce if you want to add anything to it. So I think it's it's no that that you know through you know being more financially responsible we you know we've set today, we've extended the runaway from the second half of 25, two now the first step.
Of 26 and that includes all the plans that we have for our expanding immunology pipeline and it just wouldn't be sure. That's clear we will develop those drugs with the goal to Ah Ah approve 2222 along.
<unk> Registrational studies as quickly as possible, while continuing to validate that are obviously investment pieces. He's is playing out but also in early development. So I think it will be a mix of validation that is needed right to continue to do large investments.
But also and I on a path to approval in this large indications that is you know with the evolve being <unk>.
Landscape is important is extremely important.
Next question. Please thank.
Thank you. The next question will be from Chris W. Danny Goldman Sachs. Please go ahead.
Great. Thank you many of the questions have been asked but again with regards to the immunology strategy in bursts are you thinking about ultimately.
Collaborating a partner in some of the more advanced clinical development and.
A protein degradation was brought up quite prominently in a recent R. D presentations and my wife's that far my Bristol and as we think about new medicines.
South therapy looking into immunology as well if you had to guess kind of where the puck named go and what might be unique about targeted protein degradation that will ultimately differentiate what might that be.
I think Chris it's as simple actually it's a very simple answer to this one and I don't want to give away too much of the January message, but I would say I would look at it through this land. So we've learned a lot about immunology in the past 15 years I would say there's been pathways that had been validated mostly.
Through targeted biologics, we've learned the rule of.
TNF, we've learned the role of US 17, I was 23.
Four at 13, and we've been able to do so using this injectable biologics they give us high speed.
In many cases excellent as you can see Ah, but maybe suboptimal convenience as well as high cost of goods.
We believe that degrees or can actually bring biologics like type of specificity strong advocacy and the convenience of small molecule or a small molecule, which traditional small molecule cannot do because they lost the ability to have this complete pathway.
<unk> and so that plays for oral ini.
Degraders will be solving the problem of oral convenient small molecule was tolerated drugs that have really strong efficacy that's really the place where we want to be an out of them believed that the <unk> technology that can effectively compete with that assuming we will fulfill the target.
[noise] profiles that we want.
Next question neck.
Thank you next question will be from culprits are Patel Whoopi rally. Please go ahead.
Yeah.
Yeah.
Good morning regarding the staff three degradation levels, you see relatively higher that three degradation or the one responder D. L. Two and the three patients with stable disease relative to the other applications and those cough arts.
Where those patients closer to that 80 or 90% degradation level that you are meaningful.
No. Thanks for the question, we've actually seen robust statuary degradation in the blood really across many of the dose levels that we've tested including those level two doses of a three dose level for you know.
The numbers are still small probably too small to make correlations between degradation in response, but so far I think it's fair to say that we've seen robust degradation in most of our patients that those those levels and we're not necessarily saying you know a correlation or connection between degradation and response.
[noise] next question. Thank.
Thank you next question will be from <unk> I have Jeffrey Please go ahead.
Hi, Good morning. This is for Kelly and this is actually a very <unk>.
Follow up questions to the comments that she just made it. So I believe you said that you saw a criminal activity at dose levels, you didn't expect to see such activities, but I understand that patient number still limited early but is that possible that there could be a disconnect between target protein degradation and clinical activity and.
Do.
Do you expect that patents potentially change when you start to look at combination therapy, and and implications of 40 immunology indications. Thank you.
No. Thanks, so just to be clear I mean, we're seeing those responses degradation.
Across the Ah start three cohorts and we're seeing those responses partly engagement slash the irritation in in in the ER MDM two programs I think it's important to note that we are degrading at 80% plus in some patients.
Already.
In the early cohorts for <unk>.
And as well as in the MDM to program, we already have robust pathway engagement and so what we're seeing what we're seeing here is that there are particular patients or subset of patients that might be so sensitive to these mechanism where food big really issue may not be required, but we have confidence.
That as we increase the dos and the engagement profile than the patient population that will respond will be larger than what we'd seen in the early those as as you'd expect for a technology that is really really strong control of targeting engagement. So I think these are just dream.
Bye.
You know the small ends in a in a few patients unstudied.
The strong legalization, we see already with the early doses.
Mmk. Thank everyone for just this morning, and we look forward to keeping you updated on our progress and in the meantime for a list of upcoming conferences that we will be attending please visit the events page and I would answer section of our website. Additionally details around our upcoming 90 day will be released into <unk>.
Remember and in the meantime, please don't hesitate to reach out if there are additional questions Uhm. This concludes today's call.
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