Q4 2024 Monte Rosa Therapeutics Inc Earnings Call and Pipeline Update

[inaudible]

Philipp: Remember, our trial was not designed to enroll only biomarker-positive patients, but rather enroll patients with the tumor types expected to be enriched for the presence of HI, L, and NMIC expression.

Greetings and welcome to Monte Rosa Therapeutics conference call to discuss the company's pipeline updates and clinical results. At this time all participants are in a listen only mode. A question and answer session will follow the formal presentation.

Philipp: Instead, we performed a retrospective biomarker assessment in patients treated on the trial where biopsies or archival tissues were available. The graph on the left depicts the frequency of L and NMIG high expression in 46 patients with available tumor tissue.

As a reminder, this conference call is being recorded it is now my pleasure to introduce Andrew Funderburke Senior Vice President Investor Relations and strategic finance at Monterrey. So thank you Andrew you may begin.

Philipp: To keep it brief, we saw considerably lower than expected frequencies of tumors with high L or NMIG, especially in non-spousal lung cancer and spousal lung cancer as compared to preclinical data we had obtained. Pleasingly, in that biomarker-positive population where we had paired tumor biopsies, we saw optimal target GSPT1 protein degradation of approximately 60 percent, which was consistent with our practical data.

Filip Janku: To keep it brief, we saw considerably lower than expected frequencies of tumors with high L or N-MYC, especially in non-small cell lung cancer and small cell lung cancer as compared to preclinical data we had obtained. Pleasingly, in that biomarker-positive population where we had paired tumor biopsies, we saw optimal target GSPT1 protein degradation of approximately 60%, which was consistent with our preclinical data. Slide 38 summarizes the clinical response data in the dose escalation cohorts. There were 48 patients where expression in tumor tissue was obtained at baseline, and we also included patients with known L or N MYC amplification, even if tissue was not available to assess expression. Of these 48 patients, 37 patients were available for response as per RECIST 1.1. From this group, 13 patients, so about one-third, were determined to be biomarker positive.

Speaker Change: Thank you good morning, everyone and thank you for joining our conference call to discuss the clinical and preclinical updates across our pipeline.

Speaker Change: With us on today's call are Mark a swarm of Chief Executive Officer, Philip Yonker, Chief Medical Officer, Sharon Thompson, Chief Scientific Officer, and Phil Nixon Chief business and legal officer.

Philipp: Slide 38 summarizes the clinical response data in the dose escalation cohorts.

Speaker Change: Before we begin I would like to remind everyone that any statements, we make or information presented on this call that are not historical facts are forward looking statements that are based on our current beliefs plans and expectations and are made pursuant to the safe Harbor provisions of the private Securities Litigation Reform Act of 1095, please refer to our <unk>.

Philipp: There were 48 patients where expression in tumor tissue was obtained at baseline, and we also included patients with known L or N-meg amplification, even if tissue was not available to assess expression. Of these 48 patients, 37 patients were available for response as per ARESIS 1.1. From this group, 13 patients, so about one-third, were determined to be biomarker positive. Of these 13 patients, there was one confirmed partial response and four patients with stable disease, resulting in disease control rate of 38%. Of the 24 biomarker negative patients, there was one unconfirmed partial response and three patients with stable disease, for a disease control rate of 17%.

Marcus: We will report and other filings, we make with the SEC for risk factors and other information with that I'll turn the call over to Marcus.

Marcus: Thank you Andrew and thanks, everyone for joining us this morning.

Filip Janku: Of these 13 patients, there was one confirmed partial response and four patients with stable disease, resulting in disease control rate of 38%. Of the 24 biomarker-negative patients, there was one unconfirmed partial response and three patients with stable disease for a disease control rate of 17%. Moving to slide 39, as I mentioned earlier, we have also initiated two combination arms studying MRT-2359 with enzalutamide in castration-resistant prostate cancer and with fulvestrant in hormone receptor-positive breast cancer. On this slide, we summarize initial data in the castration-resistant prostate cancer cohort, again, a patient group where we believe c-MYC overexpression is critical in driving androgen receptor dependence and therapeutic resistance, and where there is a significant unmet need for new, safe oral therapies.

Greetings and welcome to Monte Rosa Therapeutics conference call to discuss the company's pipeline updates and clinical results.

Marcus: <unk> has a to provide today exciting updates across our clinical entry clinical programs.

Marcus: I'll kick it off by just outlining some of the highlights go through in this call today.

Marcus: First we talk about besides from our phase one healthy volunteer study almost <unk> 61 60.

Philipp: Moving to slide 39, as I mentioned earlier, we have also initiated two combination arms studying MRT2359 with enzalutamide in castration-resistant prostate cancer and with fulvestrans in hormone receptor-positive breast cancer. On this slide, we summarize initial data in the castrate-resistant prostate cancer cohort. Again, a patient group where we believe CMIG overexpression is critical in driving androgen receptor dependence and therapeutic resistance, and where there is a significant unmet need for new, safe oral therapies.

Marcus: It's very clearly support our path into broad phase III development of this asset.

Marcus: Jennifer discuss these results in a minute by Hertz up it really strengthen our conviction in the potential of MFC 61 60.

Marcus: As a broadly applied and other treatment approach for immune mediated diseases.

Marcus: You May then briefly touch on our next seven program, which is on track for 90 submission in the first half of this year on <unk>.

Marcus: We're also going to provide some details today on the IND, enabling studies on some results there.

Marcus: Our thoughts on clinical development for this program.

Philipp: As of March 10, 2025, we have released this 1.1 assessment available for three patients, and very encouragingly, among them, we saw one confirmed partial response and two stable diseases. Notably, all three patients were heavily pretreated and had mutations typically associated with resistance to androgen receptor antagonists, such as enzalutamide, including mutations in the androgen receptor ligand binding site or expression of ARV7 transcripts. PSA response assessments were available for two patients showing one PSA response of 90% in the patient with a confirmed recent PR. The safety profile observed has been favorable. We are continuing to enroll and evaluate patients with castrate-resistant prostate cancer with the potential to expand enrollment to 20 to 30 patients if we continue to observe a positive efficacy signal.

Filip Janku: As of 10 March 2025, we have RECIST 1.1 assessment available for 3 patients. Very encouragingly, among them, we saw 1 confirmed partial response and 2 stable diseases. Notably, all 3 patients were heavily pretreated and had mutations typically associated with resistance to androgen receptor antagonists such as enzalutamide, including mutations in the androgen receptor ligand binding site or expression of AR-V7 transcript. PSA response assessment were available for 2 patients, showing 1 PSA response of 90% in the patient with a confirmed RECIST PR. The safety profile observed has been favorable. We are continuing to enroll and evaluate patients with castrate-resistant prostate cancer with the potential to expand enrollment to 20 to 30 patients if we continue to observe a positive efficacy signal. We expect to present additional results, along with the data from the hormone receptor-positive breast cancer cohort in H2 2025.

Marcus: And then as sort of a lag.

Marcus: Yes.

Marcus: <unk> contribution from the <unk> side on a road show you a few slides on how we're using our <unk> platform.

Marcus: To expand our portfolio of oral iron ini drugs.

Marcus: Lastly of course, we would also get into our oncology programs.

Marcus: I will talk about some of those details.

Marcus: During this presentation.

Marcus: So now, let's turn to the <unk> program, starting with <unk> hundred 60, 160, <unk> directed <unk>, who would be greater.

Marcus: And so as you can see.

Marcus: On slide five <unk> is a signaling molecule critical in both TNMP service at the stimuli. Therefore, unregulated secretion of key new monetary cytokines, including IL, two IL 17, interferon gamma and <unk>.

Philipp: And we expect to present additional results along with the data from the hormone receptor positive breast cancer cohort in the second half of 2025.

Marcus: <unk> six.

Marcus: And by doing so.

Marcus: If one is really critical for the interplay of T cells in particular th 17 cells with T cells and immune mediated diseases.

Philipp: Here on slide 40, we have, as a vignette, a heavily pretreated patient with castrate-resistant prostate cancer and androgen receptor H875Y mutation, which is typically associated with resistance to androgen receptor inhibitors, such as enzalutamide. After initiation of therapy with MRT2359 and enzalutamide, the patient developed a rapid and deep response, with PSA dropping by 85% after cycle one and by 90% by cycle four. More importantly, the recent imaging demonstrated a partial response of 46% after cycle two and 57% after cycle four, and the patient continues on treatment on cycle five. We are particularly encouraged to see this early response in a heavily pretreated patient.

Filip Janku: Here on slide 40, we have, as a vignette, a heavily pretreated patient with castrate-resistant prostate cancer and androgen receptor H875Y mutation, which is typically associated with resistance to androgen receptor inhibitors such as enzalutamide. After initiation of therapy with MRT-2359 and enzalutamide, the patient developed a rapid and deep response, with PSA dropping by 85% after cycle 1 and by 90% by cycle 4. More importantly, the RECIST imaging demonstrated a partial response of 46% after cycle 2 and 57% after cycle 4, and the patient continues on treatment on cycle 5. We are particularly encouraged to see this early response in a heavily pretreated patient. To summarize, we are encouraged by the early signs of clinical response in heavily pretreated castrate-resistant prostate cancer patients with androgen receptor alterations associated with resistance to androgen receptor inhibitors.

Marcus: Although there is a clear evidence that backbone is critical for hyper activation of these pass throughs.

Most importantly, with the overlap of <unk> 61, 60, its mode of action with those known.

Marcus: Four approved biologics.

Marcus: We think this could be an exciting alternative for many of these therapies and so we believe 60 160.

Marcus: As mentioned before the very broad potential applications in immune mediated diseases.

Marcus: Yeah.

Marcus: We signed 61 60 is a highly selective MTBE targeting that one even more.

To expand our portfolio of oral drugs.

Lastly of course, we're not forget into our oncology programs.

Marcus: Moved it into a phase one healthy volunteer study last year in August.

But I'll talk about some of those details later in this presentation.

Marcus: In October the broad potential for this target across immune mediated diseases. We were very pleased to announce our exclusive strategic development agreement with Novartis.

Philipp: To summarize, we are encouraged by the early signs of clinical response in heavily pretreated castrate-resistant prostate cancer patients with androgen receptor alterations associated with resistance to androgen receptor inhibitors. We see MRT2359's activity in castrate-resistant prostate cancer as an exciting opportunity in a large, high-unmet need population. Schemic expression in this population is widespread, so this indication will not require patient selection up front, simplifying our further clinical development.

And so now let's turn to the <unk> program, starting with <unk> 61, 60 hour back one directed molecular beauty greater.

Marcus: By collaborating with the key player in the Ini space with a company that has outstanding clinical development organization.

So as you can see on slide five RF, one is a signaling molecule critical in both T. L. T cell receptor signaling therefore unregulated secretion of key in your model of choice cytokines, including IL two.

Filip Janku: We see MRT-2359's activity in castrate-resistant prostate cancer as an exciting opportunity in a large, high unmet need population. c-MYC expression in this population is widespread, so this indication will not require patient selection up front, simplifying our further clinical development. We look forward to presenting additional data in the second half of this year. In light of the promising data in castrate-resistant prostate cancer and the data we have seen from our dose escalation cohorts, we have made a strategic decision not to open expansion cohorts in lung cancer and high-grade neuroendocrine tumors. While we believe our results in these cohorts, particularly in the biomarker-positive subset, are supportive of the clinical activity of MRT-2359, considering our other opportunities, in particular castrate-resistant prostate cancer, we believe the low biomarker positivity in these small L and N-MYC indications doesn't support expansion cohorts in these populations.

Marcus: We believe we can accelerate and broaden the scope of potential development for <unk> 61, 60 by retaining substantial value for months erosion.

Filip: So with that I'm pleased to turn the call over to Filip, Our Chief Medical Officer to review the actual data.

IL 17, interferon gamma and IL.

<unk> six.

And by doing so by.

<unk> is really critical for the interplay of T cells in particular th 17 cells with T cells and in UK.

Philipp: We look forward to presenting additional data in the second half of this year. In light of the promising data in castrate-resistant prostate cancer and the data we have seen from our dose escalation cohorts, we have made a strategic decision not to open expansion cohorts in lung cancer and high-grade neuroendocrine tumors.

Marcus: We have from our phase one study.

Filip: Thank you Marcus and thanks, everybody for joining.

Filip: We are really pleased with the data from our phase <unk> study of <unk> $6 six in healthy volunteers as shown on slide eight and Marty six around six stable dose and five single ascending dose cohorts and three multiple ascending dose cohorts.

Jesus.

I agree there's a clear evidence that basketball is critical for hyper activation of these pathways.

Most importantly, with the overlap Okay. Marty 61, 60, its mode of action with those known.

Philipp: While we believe our results in these cohorts, particularly in the biomarker-positive subset, are supportive of the clinical activity of MRT2059, considering our other opportunities in particular, castrate-resistant prostate cancer, we believe the low biomarker-positive in these small L and N make indications doesn't support expansion cohorts in these populations.

Four four approved biologics.

Filip: <unk> endpoints of the study are safety and Tolerability. Other endpoints included pharmacokinetic, Pharmacodynamic and which included upfront degradation levels in Dnb fellas as well as assessment of ex vivo response to T cell and B cell receptor stimulation.

This could be an exciting alternative for many of east therapies. So we believe 61 60 <unk>.

Sure it before but a very broad potential applications in immune mediated diseases.

We signed 61 60 is a highly selective MTBE targeting backbone.

Filip: Here on slide nine you can see the analysis of plasma concentration of <unk> 61, 6% over time, which in healthy volunteers demonstrated a dose dependent pharmacokinetic profile.

Sharon: I'll now hand the call back over to Sharon to walk you through some updates to our CDK2 and Cyclin E1 programs. Sharon? Thanks, Philipp. I'm excited to now share some promising preclinical data from both our Cyclin E1 and CDK2 programs. As many of you know, Cyclin E1 and CDK2 are key drivers of cancers caused by changes in the CDK pathway.

Filip Janku: I'll now hand the call back over to Sharon to walk you through some updates to our CDK2 and Cyclin E1 programs. Sharon?

They moved it into a phase one healthy volunteer study last year in August.

In October the broad potential for this target across immune mediated diseases. We were very pleased to announce our exclusive strategic development agreement with Novartis.

Sharon Townson: Thanks, Filip. I'm excited to now share some promising preclinical data from both our Cyclin E1 and CDK2 programs. As many of you know, Cyclin E1 and CDK2 are key drivers of cancers caused by changes in the CDK pathway. However, for both targets, there have been challenges for conventional inhibitor approaches, and we believe our highly selective MGDs could have key advantages here. Slide 44 highlights some of our in vivo findings for our Cyclin E1 program, where we assessed our selective degrader, MRT-50969, in Cyclin E1 amplified gastric cancer and breast cancer models. In both instances, we're seeing quite potent monotherapy effects in these difficult-to-treat tumors, including near complete tumor regression in the Cyclin E1 amplified breast cancer model.

Filip: Multiple ascending doses resulted in an approximately two fold increase in exposure at steady state and no food effect were observed.

Filip: Okay.

By collaborating with the key player in the <unk> space with a company that has outstanding clinical development organization.

Filip: As shown on slide 10, both of them degradation was offset by flow cytometry of CD <unk> T cells and CD 19, B cells. In addition, ex vivo stimulation of whole bustles performed to assess the in diesel functions, including CD 69 up regulation measured by flow cytometry, and cytokine secretion measured by immunoassay.

Sharon: However, for both targets, there have been challenges for conventional inhibitor approaches, and we believe our highly selective MDDs could have key advantages here. Slide 44 highlights some of our ambivalent findings for our Cyclin E1 program, where we assessed our selective degrader 50969 in Cyclin E1-amplified gastric cancer and breast cancer models. In both instances, we're seeing quite potent monotherapy effects in these difficult-to-treat tumors, including near-complete tumor regression in the Cyclin-E1 Amplified Breast Cancer model. Moving to our CDK2 program on slide 45, we assess the therapeutic effects of our CDK2 degrader 51443 in combinations with a standard of care regimen of ribocyclib and fulvestrin in two ER positive breast cancer models.

If we can accelerate and broaden the scope of potential development for M 61, 60 by retaining substantial value for much erosion.

So with that I'm pleased to turn the call over to Filip, Our Chief Medical Officer to review the actual data we have from our phase one study.

Filip: Yes.

Filip: As we show on slide 11, <unk> $6 six to achieve dose dependent <unk> degradation in peripheral bumpy cells, which exceeded 90% after a single and multiple dose administrations, except for those level of Saab Verde gets to 80% degradation.

Filip: Thank you Marcus and thanks, everybody for joining.

Filip: We are really pleased with the data from our phase one sad and Mad studies of MRP 61, six days in healthy volunteers as shown on slide eight it might be $60 six tables. Those same five single ascending dose cohorts and three multiple ascending dose cohorts.

Filip: We were very pleased to see this level of potency consistent with our preclinical studies and matching our target profile. In addition, both on protein production of our sustained into the post treatment detailed this dose dependent recovery. Following defend similar results were observed in b cells.

Filip: The primary endpoint of the study are safety and Tolerability. Other endpoints included pharmacokinetic Pharmacodynamic and which included degradation levels in Dnb fellas as well as assessment of ex vivo response, the T cell and B cell receptor stimulation.

Sharon Townson: Moving to our CDK2 program on slide 45, we assessed the therapeutic effects of our CDK2 degrader, MRT-51443, in combinations with a standard of care regimen of ribociclib and fulvestrant in two ER-positive breast cancer models. In both models, the results demonstrated profound tumor regression for the triple combination relative to standard of care treatment. In summary, we are very excited with the strong preclinical results we are seeing from both our cell cycle programs. Our focus going forward is on benchmarking our MGDs for both CDK2 and Cyclin E1 to determine the optimal molecule to advance to an expected IND submission in 2026. With that, I am happy to turn the call back over to Marcus for a summary and concluding remarks before we open up the call to Q&A. Marcus?

Filip: Next we evaluated the impact of MRP $6 six day under functional inhibition of dnb cells as measured across several well characterized in your markets.

Filip: Here on slide nine you can see the analysis of plasma concentration of MRP 61, 6% over time, which in healthy volunteers demonstrated a dose dependent pharmacokinetic profile of multiple ascending doses resulted in approximately two fold increase in exposure at steady state and no food effect observed.

Sharon: In both models, the results demonstrated profound tumor regression for the triple combination relative to standard of care treatment.

Filip: In our clinical study.

Filip: The creation by MLP 61, 6% resulted in a significant functional inhibition of <unk> and b cells. Following axial stimulation a whole block for example, following the move of TCR stimulation, we observed significant attenuation of CD 69 up regulation, a key marker of D and be selective Asian, indicating.

Sharon: In summary, we're very excited with the strong preclinical results we're seeing from both our cell cycle programs. Our focus going forward is on benchmarking our MGDs for both CDK2 and cyclin E1 to determine the optimal molecule to advance to an expected IND submission in 2026.

Filip: Okay.

Filip: As shown on slide 10, both of them degradation was offset by flow cytometry of CD <unk> T cells and CD 19, B cells. In addition, ex vivo stimulation of the whole blockbuster performed to assess b and b cell function, including <unk> 69 up regulation measured by flow cytometry, and cytokine secretion measured by immuno.

Filip: <unk> inhibition.

Marcus: With that, I'm happy to turn the call back over to Marcus for a summary and concluding remarks. Before we open up the call to Q&A, Marcus. I thank Sharon and Philip for sharing these exciting updates with us this morning.

Filip: Furthermore, <unk> $6, 6% to <unk> significantly inhibited secretion of the inflammatory cytokines.

Filip: Hello can do interferon gamma and interleukin <unk> from whole blood derived T cells. Following ex vivo stimulation of the T cell receptor demonstrating interactions up to 99% from the pre COVID-19 levels.

Markus Warmuth: Thanks, Sharon and Filip, for sharing these exciting updates with us this morning. In summary, I'd like to state we're very proud of the progress we've made throughout 2024 and, as a matter of fact, in Q1 of this year, with a number of significant milestones, of course, still coming up throughout this year and next. Let me just quickly summarize on this slide, what you've seen today, and also give you some guidance on what to expect moving forward. Today we shared encouraging clinical data with you on MRT-6160. These data are mapping a clear path, as mentioned before, to phase II studies.

Filip: Please.

Filip: As we show on Slide 11, <unk> $60 60, <unk> achieved dose dependent upon degradation in peripheral blood T cells, which exceeded 90% after single and multiple dose administrations, except for those levels of Saab Verde gets to 80% degradation.

Marcus: So in summary, I'd like to state we're very, very proud of the progress we've made throughout 2024. And as a matter of fact, in the first quarter of this year, with a number of significant milestones, of course, still coming up throughout this year next. So, let me just quickly summarize on this slide what you've seen today, and also give you some guidance on what to expect moving forward. So, today we share encouraging clinical data with you on MRT616. These data are mapping a clear path, as mentioned before, to Phase II studies. While I can't give you guidance on exact timing for the Phase II initiations, I can say that we are working with our collaborators at Novartis to advance this program as efficiently as possible, building on the promising data we shared with you today.

Filip: Also following b cell stimulation MRP $6 6 billion substantially accumulated interleukin six at the higher dose levels collectively our pharmacokinetic and Pharmacodynamic assessments into clinic are in line with but I clinical studies that suggest that the robot functional effects on cytokine production. This 80 person and Hyatt.

Filip: We were very pleased to see this level of potency consistent with preclinical studies and matching our target profile. In addition, Bob on protein production of our sustained into the post treatment period.

Filip: Foundation of above one, which we have clearly achieved the doses that's within this trial.

Filip: Dependent recovery following treatment similar results were observed in b cells.

Filip: Yeah.

Filip: Moving to slide 13, we are of course also looking into duration of these functional eplex, both those Inc and <unk>.

Filip: Next we evaluated the impact of MRP $60 six day under functional inhibition of dnb cells as measured across several well characterize immune markers.

Markus Warmuth: While I can't give you guidance on exact timing for the phase II initiations, I can say that we are working with our collaborators at Novartis to advance this program as efficiently as possible, building on the promising data we shared with you today. As discussed, we're also quite encouraged with what we see early on for our cohort of heavily pre-treated, castrate-resistant prostate cancer patients. It's a small sample size, but given how heavily pre-treated these patients are, certainly encouraging. In light of that, we made the strategic decision to focus on that cohort, not open any other cohorts at this point for all the reasons we've discussed. We expect additional data for this program in the H2 of this year. As to NEK7, we also look forward to an IND submission for MRT-8102, and that's going to happen H1 of this year.

Filip: <unk> administration of <unk> $6 six day resulted in a marked and sustained suppression of T cell receptor mediated CD 69 activation similar results were observed synthetics are above the sales following bcf stimulation.

Filip: In our clinical study.

Filip: Degradation by MRV $60 six day resulted in a significant functional inhibition of the b cells. Following ex vivo stimulation a whole block for example, following T cells similar TCR stimulation, we observed significant attenuation of CD 69 up regulation, a key marker of T and b cell activation, indicating.

Marcus: As discussed, we're also quite encouraged with what we see early on for our cohort of heavily pre-treated castrate-resistant prostate cancer patients. It's a small sample size, but given how heavily pre-treated these patients are, I'm certainly encouraging. And so in light of that, we made the strategic decision to focus on that cohort, not open any other cohorts at this point, for all the reasons we've discussed. We expect additional data for this program in the second half of this year. As to NEC7, we also look forward to an IND submission for MIT 8102, and that's going to happen first half of this year, and then a potential IND for our CNS-optimized NEC7 program next year.

Filip: With regards to cytokine secretion as shown on slide 14, <unk> $6 six demonstrated a sustained effect of Dci mediated cytokine production following single and multiple dose administrations and ex vivo TCR stimulation.

Filip: Functional inhibition.

Filip: Furthermore, MRP six around 6% significantly inhibited secretion of the inflammatory cytokines.

Filip: <unk> 61, 6% to <unk> significantly and deeply inhibited interleukin two interferon gamma and <unk> accretion consistent this will be have shown you earlier and just ask for CD Sixty-ninth depression, the effects were sustained into the post treatment period.

Filip: Interleukin two interferon gamma and interleukin 17, a from a whole blood derived T cells. Following ex vivo stimulation of the T cell receptor demonstrated reductions up to 99% from the <unk> levels also following b cell stimulation MRP 61 6 billion substantially.

Filip: In summary, the effect of <unk> 61, 6% on both Cd's extent on activation as well as cytokine production provides further evidence for the impact of degradation on downstream <unk> biologics.

Filip: That is that looking at the higher dose levels collectively our pharmacokinetic and Pharmacodynamic assessments in the clinic are in line with preclinical studies that suggest that robot functional effect on cytokine production. This 80 person and higher degradation of one which we have clearly achieved was the doses in this trial.

Markus Warmuth: A potential IND for our CNS optimized NEK7 program next year. Our cell cycle programs are projected to have an IND in 2026 as well, and we hope to share more on the exciting work coming from our QuEEN platform, in particular in the I&I space, in the context of more oral I&I drugs in relatively near future. Lastly, as stated on this slide, importantly, we do think we are well-positioned to advance these programs with a very strong balance sheet and providing cash runway anticipated into 2028. With that, I would like to open up the call for any questions you have. Operator?

Filip: Okay.

Marcus: Our cell cycle programs are projected to have an IND in 2026 as well, and we hope to show more on the exciting work coming from our clean platform, in particular in the INI space, in the context of more oral INI drugs in relatively near future.

Filip: Moving onto the safety summary on slide 15, we are pleased to report that the MLP $60 6 million was volatility that was lower reported serious adverse events.

Filip: Observe treatment emergent adverse events, which included combined treatment related and unrelated universe, even better credit relatively mild and self limited.

Filip: Yeah.

Filip: Moving to slide 13, we are of course also looking into duration of these functional effects. Both those inc.

Marcus: And so, lastly, as stated on the slide, and importantly, we do think we are well positioned to advance these programs with a very strong balance sheet and providing cash runway anticipated into 2028.

Filip: Treatment emergent adverse events observed in two or more subjects treated with <unk> $6 6 billion included pain from blood those headaches and other aes as detailed on the slide.

Filip: <unk> administration of <unk> $6, six day resulted Denmark and sustained suppression of T cell receptor mediated <unk> 69 activation.

Filip: The results were observed in peripheral blood T cells following Bcl stimulations.

Filip: Overall frequency of treatment emergent adverse events were similar between MRP $6 60 on placebo.

Operator: And so with that, I would like to open up the call for any questions you have, operator. Thank you. To ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again.

Filip: With regards to cytokine secretion as shown on slide 14, MRP $60 six demonstrated a sustained effect of TCR mediated cytokine production following single and multiple dose administrations and ex vivo TCR stimulation.

Filip: In summary, these are extremely pleased to see our pharmacodynamic and functional ex vivo study, suggesting significant effect, both cytokine production after marked and sustain degradation of Buffalo.

Operator: Thank you. To ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. The first question comes from Kelly Shi with Jefferies. Your line is open.

Kelly Shee: And the first question comes from Kelly Shee with Jeffries. Your line is open. Congrats on the progress and thank you for taking my question.

Filip: The graduation of <unk> consistent with levels required to induce efficacy in preclinical models and the functional impact from cytokine production was consistent with levels predicted to achieve efficacy in humans based on a benchmark of clinical data from other blocks targeting related phosphate.

Filip: It might be $60 six cities significantly and deeply inhibited interleukin two interferon gamma and into Logan 17, Asa creation consistent with what we have shown you earlier and just ask for CD 69 suppression the effects were sustained into the post treatment period in.

Kelly Shi: Congrats on the progress, and thank you for taking my question. On VAV1, given that it is involved in multiple signaling pathways, how do you decide, and also with your partner, the most promising I&I indications to pursue based on now available panel of biomarker profiling data? Also have follow-up. Thank you.

Kelly Shee: So on VIVE-1, given that it is involved in multiple signaling pathways, how do you decide, and also with your partner, the most promising eye indications to pursue based on now available a panel of biomarker profiling data? Also have follow-up. Thank you.

Filip: You saw a highly favorable safety profile and we believe the phase one data. We have presented in addition to the chronic toxicology package supports the clear path into phase II studies, and both potential applications in multiple immune mediated diseases.

Filip: In summary, the effect of MRP 61, 6% on both <unk> 16, and activation as well as cytokine production provides further evidence for the impact of oven degradation on downstream PMT cell biology.

Filip: I will now turn to our next program in the Ini space focused on <unk> and its role in D&O RPC inflammable.

Filip: Moving onto the safety summary on slide 15.

Philipp: A great question, Kelly. And so, you know, obviously, you can tell, we're still preparing for those phase two studies. And so final decisions haven't been made. That said, as you know, I might remember lots of preclinical data that we have generated in the past two, three years, in particular, in indications that are driven by either T cells, in particular, Th17 cells or Tb cells combined. And so, to remember, we had a very strong data on preclinical data in UC, very interesting data in rheumatoid arthritis. I think there's, there's related diseases you could, you could think about and think the data we showed today from the Healthy Volunteer Trial, of course, in that context is very informative, because again, where this data, of course, this ex vivo stimulation, not in vivo data from patients, nevertheless, I think it gives clear indications that we are hitting the cytokines we want to hit and we can sort of modulate how deep we want to go in regards to inhibiting this decrease in.

Markus Warmuth: A great question, Kelly. Obviously, you can tell we're still preparing for those phase II studies, and so final decisions haven't been made. That said, as you know or might remember, lots of preclinical data that we have generated in the past 2, 3 years, in particular in indications that are driven by either T cells, in particular TH17 cells, or T B cells combined. If you remember, we had very strong data on preclinical data in UC, very interesting data in rheumatoid arthritis. I think there's related diseases you could think about, and I think the data we showed today from the healthy volunteer trial, of course, in that context is very informative because again, we're at this stage, of course, this ex vivo stimulation, not in vivo data from patients.

Filip: We used to report that it might be $6 six the most volatility with no reported serious adverse events.

Filip: On this slide.

Filip: Again, it is a quick overview of <unk> seven as a highlight that elevon therapeutic target in this space.

Filip: Observe treatment emergent adverse events, which included combined treatment related and unrelated adverse even better credit relatively mild and self limited treatment emergent adverse events observed in two or more subjects treated with <unk> 601, six that included pain from blood dose headaches and other aes as detailed on the slide.

RPC and funnel them as a key pathway activated in many inflammatory conditions. Some shown at the bottom of this slide and activation of the <unk> funnel, though we're critically depends on <unk> seven in this context <unk> functions as a scaffolding protein that facilitates assembly of the active <unk> and farmers are complex and a kinase independent.

Filip: Overall frequency of treatment emergent adverse events were similar between MRP $60 six on placebo.

Filip: Vanda.

Filip: And if some of it.

Filip: As illustrated on Slide 19 is being widely shown and also demonstrated by our own in vitro and in vivo work that <unk> seven and DNO RPC in pharma, though are critical for the production of interleukin one beta resulting in elevated CRP levels.

Filip: We are extremely pleased to see our pharmacodynamic and functional ex vivo studies, suggesting significant effects on cytokine production after marked and sustain degradation of above one.

Filip: Regardless of what one was consistent with levels required to induce efficacy in preclinical models and the functional impact from cytokine production was consistent with levels predicted to achieve efficacy in humans based on benchmark clinical data from other drugs targeting related phosphate.

<unk> is a known among other things as a key long term predictor of cardiovascular risk several anti IL, one and other <unk> inhibitors have shown promising introductions of CRP levels in clinical trials. Therefore, we saying next seven degrade that offers a unique opportunity to blow the assembly of annual occupancy and some of them.

Markus Warmuth: Nevertheless, I think it gives us clear indications that we are hitting the cytokines we want to hit, and we can sort of modulate how deep we want to go in regards to inhibiting their secretion.

Filip: We saw a highly favorable safety profile and we believe the phase one data. We have presented in addition to the chronic toxicology package support the clear path into phase II studies, and both potential applications in multiple immune mediated diseases.

Filip: Offering a new potential oral treatment modality for a variety of inflammatory diseases linked to IL, one beta and the subsequent elevation of CRP.

Kelly Shee: Thank you very much.

Kelly Shi: Thank you very much. 1 follow-up is we see pretty good biomarker inhibition by using this ex vivo simulation approach. Curious, how does it differ from the direct in vivo measurement to represent the treatment impact? What level of in vivo biomarker reduction could we expect in I&I patients based on this result? Thanks.

Filip: I'll now turn to our next program in the Ini space focused on Nyx, seven and its role in D&O RPC inflammable.

Philipp: And also, one follow-up is, we see pretty good biomarker inhibition by using this ex vivo simulation approach. Curious, how does it differ from the direct in vivo measurement to represent the treatment impact? And what level of in vivo biomarker reduction could we expect in INR patients based on this result? Thanks. Yeah, I mean, honestly hard to put a number out on what percentage to expect in the inpatients because that will actually depend on the type of disease you're targeting. I think what we find encouraging here is for a healthy volunteer trial, where we looked at what we thought an important benchmark of healthy volunteer trials were matching up.

Filip: Importantly.

Filip: <unk> three signaling pathway are clinically validated and extensive clinical data exists.

Filip: On this slide let's begin with a quick overview by VC next seven is a highly relevant therapeutic target in this space.

Filip: Support its relevance to multiple diseases in therapeutic anr spending cardio immunology, rheumatology and neurology as we detailed on slide 20.

Filip: Obviously in pharma with them as I keep Australia activated in many inflammatory conditions. Some shown at the bottom of this slide and activation of D&O RPC and farmers over critical it depends on <unk> seven in this context like several functions as a scaffolding protein that facilitates assembly of the active and a lot of D. C and farmers are a complex and a kinase independent.

Filip: So the existing data with <unk> targeting agents out there and to some degree the emerging data from first generation <unk> inhibitors give us great information work with focused clinically moving forward.

Markus Warmuth: Yeah. Honestly, hard to put a number out on what percentage to expect in patients, because that will actually depend on the type of disease you're targeting. I think what we find encouraging here is for a healthy volunteer trial, where we looked at what we thought an important benchmark healthy volunteer trials were, we're matching up.

Filip: Our team is on track to file our IND in the first half of this year and so on slide 21, we have outlined our proposed development path forward.

Filip: Banner.

Filip: As illustrated on Slide 19 is been viola shown and also demonstrated by our own in vitro and in vivo work that <unk>, seven and D&O RPC and farmers are critical for the production of interleukin one beta resulting in elevated CRP levels.

Filip: Following a planned Southmark phase one study in healthy volunteers, we plan to pursue the iOS to establish clinical proof of concept initially in individuals with high levels of CRP and then an additional immunology indications.

Filip: <unk> is a known among other things as a key long term predictor of cardiovascular risk several anti IL, one and other and a lot of PC inhibitors have shown promising introductions of CRP levels in clinical trials. Therefore, we think our next set of integrated offers a unique opportunity to blow the assembly of annual occupancy in pharma them.

Filip: We are also evaluating proof of concept studies in gout pseudo gout and it'll start items.

Kelly Shee: very, very well in regards to depth of cytokine secretion or inhibition of them. And so I think from here, I'm fairly confident that this molecule can hit the mark in vivo in patients as well. But again, the exact percentage, of course, will really depend on sort of the actual disease you're treating and the tissue where you're measuring cytokine secretion or levels or inhibition thereof. Congrats again. Thank you.

Markus Warmuth: Very, very well in regards to depth of cytokine secretion or inhibition of them. I think from here, I'm fairly confident that this molecule can hit the mark in vivo in patients as well. Again, the exact percentage, of course, will really depend on the actual disease you're treating and the tissue where you're measuring cytokine secretion or levels or inhibition thereof.

Filip: Clinical toxicology and Pharmacodynamic data of a chatter ability of you in a moment demonstrate amount of the 8100 two's excellent drug like properties and favorable safety profile and should give us confidence as we look to move forward into clinical development with that let me turn the call over to Sharon to review our preclinical work for the next seven program.

Filip: Offering a new potential oral treatment modality for a variety of inflammatory diseases linked to IL, one beta and the subsequent elevation of CRP.

Filip: Karen.

Sharon: Thanks Pat.

Filip: Shown on slide 22, we believe.

Filip: Importantly.

Filip: And the <unk> signaling pathway are clinically validated and extensive clinical data exists to support its relevance to multiple diseases in therapeutic anr spending cardio immunology and dermatology and neurology as we detailed on slide 20.

Filip: Leave the potency selectivity and long lasting PD profile of HR teams create potential differentiation from competitive approaches.

Kelly Shi: Congrats again. Thank you.

Edward Tenthoff: And the next question comes from Edward Tenthoff with Piper Sandler. Your line is open. Great. Thanks. Good morning and thanks for the very thorough and extensive update today. My question has to do with the prostate cancer, the focus on prostate cancer, which makes a lot of sense. Obviously, as men go through multiple cycles, including androgen deprivation therapy and enzalutamide and abiraterone, the mutational burden changes. Where do you think the ideal application is for 2359? And what kind of combinations do you think are worth exploring? Thank you.

Operator: The next question comes from Edward Tenthoff with Piper Sandler. Your line is open.

Filip: We have demonstrated potent mono selective degradation of next seven including no degradation of any of the other next family members.

Filip: So the existing data with <unk> targeting.

Edward Tenthoff: Great. Thanks. Good morning, and thanks for the very thorough and extensive update today. My question has to do with the prostate cancer, the focus on prostate cancer, which makes a lot of sense. Obviously, as men go through multiple cycles, including androgen deprivation therapy, and enzalutamide and abiraterone, their mutational burden changes. Where do you think the ideal application is for 2359, and what kind of combinations do you think are worth exploring? Thank you.

Filip: Our data also demonstrated that drug exposure results in a prolonged PD effect, which we think distinguishes our next 70 greater from analog Petri inhibitors.

Filip: <unk> targeting agents out there and to some degree the emerging data from first generation <unk> inhibitors give us great information to vertically focused clinically moving forward.

Filip: Our team is on track to file R&D in the first half of this year and so on slide 21, we have outlined our proposed development path forward.

Filip: Great clinical profile of <unk> has been highly favorable and supportive of continued development as shown on slide 23.

Filip: In the left panel we show after five days of dosing in centers in vivo next seven degradation leads to near complete inhibition of caspase, one activity and IL, one beta release and ex vivo stimulation assays.

Filip: Following a planned soft mob phase one study in healthy volunteers, we plan to pursue trials to establish clinical proof of concept initially in individuals with high levels of CRP and then Additionally, cargill immunology indications. We are also evaluating a proof of concept studies in gout pseudo gout I'll start items.

Filip: The preclinical GOP toxicology study suggest that considerable safety margin for <unk>.

Filip: Preclinical toxicology and Pharmacodynamic data of a chatter of ability are you in a moment demonstrate amount of <unk> 81 to reduce excellent drug like properties and favorable safety profile, which gives us confidence as we look to move forward into clinical development with that let me turn the call over to Sharon to review our preclinical work for the next several program.

Filip: No observed adverse effect level was the highest dose tested in both <unk> and sandoz, but the grades have been children default exposure margin over the projected human efficacious dose in both speaking importantly, there were no <unk> related clinical signs no changes in immuno phenotyping.

Filip Janku: Yeah, thank you for that. It's a great question. I think logically, I think starting off with the second line and the combination with drugs like enzalutamide, so essentially androgen receptor inhibitors is probably a good starting point, but I think the potential applications are definitely beyond that. Essentially, in a way, your target might be ended up with the coverage of the same population as enzalutamide currently covers, which is actually both castrate-resistant prostate cancer, as well as the castrate-sensitive prostate cancer. I actually think the ultimate patient population you can target with this is actually quite broad.

Philipp: It's a great question. I think logically, I think starting off with the second line and the combination with drugs like enzalutamide, so essentially androgen receptor inhibitors is probably a good starting point, but I think the potential applications are definitely beyond that. So, essentially. In a way, I mean, your target might be ended up with the coverage of the same population as enzalutamide currently covers, which is actually both castrate-resistant prostate cancer as well as the castrate-sensitive prostate cancer. So actually, I think the ultimate patient population you can target with this is actually quite broad.

Filip: Karen.

Filip: Philip.

Filip: And now growth of clinical pathology findings at any dose level.

Filip: As shown on slide 22, I believe the potency selectivity and long lasting PD profile of HR to create potential differentiation from competitive approaches we.

Filip: Okay.

Filip: We also studied <unk> in a rapid GAAP model to better characterize its effects on inflammatory diseases.

Filip: We have demonstrated potent mono selective degradation of next seven including no degradation of any of the other next family members.

Filip: As shown on slide 24 daily oral dosing of <unk> hundred two at 50 makes the cake, which is pathogenic effects associated with gas, including reduction in giant swelling and histopathology score.

Filip: Our data also demonstrated that drug exposure results in a prolonged PD effect, which we think distinguishes our next 70 greater from analog Petri inhibitors.

Filip: Overall, we are highly encouraged by the preclinical profile of AQR team I look forward to filing <unk> 90 in the first half of this year.

Philipp: And would you envision combination trials in the future? The combination trials beyond the combination with enzalutamide, it's certainly a possibility. I mean, there doesn't seem to be any significant addition of toxicity by combining these two drugs together. So I think it's definitely combinable. I think the first step would be to develop this as a combination of this androgen receptor agent and potentially, again, either in the second line or even in the first line, when there is a possibility to potentially replace a combination of androgen receptor inhibitors with chemotherapy. Great.

Edward Tenthoff: Would you envision combination trials in the future? Thanks.

Filip: Great clinical profile of <unk> has been highly favorable and supportive of continued development as shown on slide 23.

Filip: This now brings us to the potential for expansion of our next seven program and the optimization of our next 70 greatest with CNS penetration.

Filip Janku: The combination trials beyond the combination with enzalutamide. It's certainly a possibility. There doesn't seem to be any significant additional toxicity by combining these two drugs together. I think it's definitely combinable. I think the first step would be to develop this as a combination of this androgen receptor agent and potentially, again, either in the second line or even in the first line, when there is a possibility to potentially replace combination of androgen receptor inhibitor with chemotherapy.

Filip: In the left panel we show after five days of dosing in centers in vivo next seven degradation leads to near complete inhibition of caspase, one activity and IL, one beta release and ex vivo stimulation assays.

Filip: Given the large therapeutic potential we see for next seven we've been advancing mgd, specifically optimized for CNS penetration.

Filip: Just to show you a few highlights on slide 26, we're achieving very compiling level over the next seven degradation pbms.

Filip: The preclinical GOP toxicology study suggest that considerable safety launches Almaty AQR to the no observed adverse effect level was the highest dose tested in both rat and centers with a greater than 200 fold exposure margin over the projected human efficacious dose and boats.

Filip: Similar to those shown for MLP, <unk>, which corresponds to near complete suppression of IL, one beta following ex vivo stimulation as shown on the right.

Filip: As you can see in the Middle we also see deep reduction of next set of <unk> in the CSF, suggesting significant exposure with our MTBE in the brain.

Filip: Importantly, there were no <unk> related clinical signs no changes in immuno phenotyping and now growth of clinical pathology findings at any dose level.

Edward Tenthoff: Great. Thanks, Filip.

Colleen: Thanks, Colleen.

Filip: Going forward, we believe having a CNS optimized molecule creates a lot of optionality for us and the opportunity to address indications at both peripheral and central components.

Mark Fromm: And our next question will come from Mark Fromm with TV Co. And your line is open. Thanks for taking my questions, and thanks for the very comprehensive presentation. Maybe on Vav1...

Operator: Our next question will come from Marc Frahm with TD Cowen. Your line is open.

Filip: We also saw the eight you wanted to you in a rabbit model to better characterize its effects on inflammatory diseases.

Marc Frahm: Thanks for taking my questions and thanks for the very comprehensive presentation. Maybe on VAV1, just the kind of cytokine changes that you're able to show in the ex vivo simulation and can you put this into context of maybe what's been achieved with maybe a B-cell-directed therapy like a BTK or on the T-cell side with more of the T-cell specific therapies like the IL-17 inhibitors and other kind of single cytokine mechanisms, just to kind of put the context of this broad inhibition, what are you achieving on each side of the equation? With the dosing, just the PK, and the MAD dosing, it looks like you're getting very sustained suppression of VAV1. Should we think about extended dosing beyond once daily to maybe test out weekly or anything like that in some of these trials that are to come?

Filip: Top of the peripheral inflammatory indications we mentioned earlier.

Filip: As shown on slide 24 daily oral dosing of <unk> 250 makes the keg Rajiv pathogenic effects associated with gas, including reduction in giant swelling and histopathology score.

Mark Fromm: the cytokine changes that you're able to show in the ex-vivo simulation, and can you put this into context of maybe what's been achieved with maybe a B-cell-directed therapy, like a PTK, or on the T-cell side with more of the T-cell-specific therapies, like the IL-17 inhibitors and other single cytokine mechanisms, just to kind of put the context of this broad inhibition. What are you achieving on each side of the equation? And then also with the dosing, just the PK and the MAD dosing, it looks like you're getting very sustained suppression of Avalon.

Filip: So to wrap up the ini part of this presentation I would like to now briefly discuss the opportunity you see more generally across the <unk> space.

Filip: Yes.

Filip: Based on everything we've learned to date, we believe our mgd's are uniquely suited to address key unmet needs in INR indication as showed on slide eight.

Filip: Overall, we are highly encouraged by the preclinical profile of AQR to I look forward to filing <unk> 90 in the first half of this year.

Filip: Yeah.

Filip: This now brings us to the potential for expansion of our next seven program and the optimization of our next seventh graders for CNS penetration.

Filip: High expression of <unk> and immune cells enables robust target degradation, which when combined with the exquisite selectivity of our on GDS allows for a high therapeutic index a key potential advantage demonstrated in both our backlog and next seven programs.

Filip: Given the large therapeutic potential we see for next seven we've been advancing mgd, specifically optimized for CNS penetration.

Philipp: Should we think about extended dosing beyond once daily to maybe test out weekly or anything like that in some of these trials that are going on? Yeah, I mean, I'll start with your with your second question. I think the high level short statement here is, yeah, I think what you saw in today's presentation, of course, creates a lot of optionalities in regards to those regimens. I think that's certainly a strength of molecular blue degraders in general, obviously the catalytic mechanism. Of course, depending a little bit on sort of what the resynthesis rate of the protein is, you know, daily dosing is not the only option you have.

Filip: Just to show you a few highlights on slide 26.

Furthermore, the catalytic mechanism of action drive sustained pathway modulation reinforcing our strong therapeutic rationale as seen in these programs.

Filip: Keeping very compelling level over the next seven degradation pbms.

Filip: Similar to those shown for MLT 81, which corresponds to near complete suppression of IL, one beta following ex vivo stimulation as shown on the right.

Filip: Okay.

Filip: As we continue to build a portfolio of oral ini attracts I'll highlight a few exciting areas of immunology that we are homing in on.

Filip Janku: Yeah. I'll start with your second question. I think the high-level short statement here is, yeah, I think what you saw in today's presentation, of course, creates a lot of optionalities in regards to those regimens. I think that's certainly a strength of molecular glue degraders in general, with the catalytic mechanism. Of course, depending a little bit on sort of what the resynthesis rate of the protein is. Daily dosing is not the only option you have, and I think that can create interesting opportunities. On how we compare to other molecules, I would say really very wide. Sure, we looked at what does a BTK inhibitor do at clinical doses, what are the IL-17 and the IL-23 antagonists doing? Again, I think we compare very favorably here.

Filip: As you can see in the Middle we also see deep reduction of next set of protein in the CSF, suggesting significant exposure with our mgd in the brain.

Filip: While we are not yet disclosing specific targets, we see compelling opportunities in pathways critical to b cell modulation in auto antibody production and inflammation as well as in key pathways relevant to asthma and allergies.

Filip: Going forward, we believe having a CNS optimized molecule creates a lot of optionality for us and the opportunity to address indications at both peripheral and central components on top of that peripheral inflammatory indications we mentioned earlier.

Filip: Consequently belief, we believe our mgd's have broad therapeutic potential across the <unk> space and.

Marcus: And we are excited to share future progress as our early stage programs advanced with that I'll turn the call back over to Marcus.

Filip: So to wrap up the ini part of this presentation I'd like to now briefly discuss the opportunity we see more generally across the <unk> space.

Marcus: Thank you Sharon and so just to recap the ini part of this call and we just showed you very encouraging data for 60 160 healthy volunteer trial.

Philipp: And I think that can create interesting opportunities.

Filip: Okay.

Filip: Based on everything we've learned to date, we believe our mgd's are uniquely suited to address.

Philipp: how we compare to other molecules. I would say really very wide. I mean, you know, sure. I mean, we looked at what does a BTK inhibitor do at clinical doses, what are the IL-17 and the IL-23 antagonists doing? And again, I think we can be very favorable here. Obviously, not every healthy volunteer trial in that space has been reported out. And not every assay protocol is the same. We've used interferon gamma a lot, because that seems to be the one everyone looks at. And I would say we clearly hit the mark here with up to 99% inhibition.

Filip: It needs an INR indication as shown on slide eight.

Marcus: Really got through the <unk>.

Marcus: 80% plus.

Filip: High expression of <unk> and immune cells enables robust target degradation, which when combined with the exquisite selectivity of our on GDS allows for a high therapeutic index a key potential advantage demonstrated in both our backlog and that seven programs.

Marcus: Degradation of Revlon and cytokine modulation of the.

Marcus: <unk> hundred 99%.

Marcus: Very encouraging data set and messing, a clear path into phase III trials.

Marcus: And we're also looking at <unk> in the first half of this year for our next seven degreed or <unk>, two targeting a pathway of uniloc between Samsung.

Filip: Furthermore, the catalytic mechanism of action drive sustained pathway modulation reinforcing our strong therapeutic rationale as seen in these programs.

Filip Janku: Obviously, not every healthy volunteer trial in that space has been reported out, and not every assay protocol is the same. We've used interferon gamma a lot, because that seems to be the one everyone looks at. I would say we clearly hit the mark here with up to 99% inhibition. Again, it doesn't mean that we need to get to 99%, but I think it's great.

Marcus: Getting more and more attention.

Marcus: When we talk about creating more opportunities for us to utilize our discovery engine onto goods highly differentiate differentiated portfolio of oral ini drugs.

Filip: As we continue to build a portfolio of oral ini drugs I'll highlight a few exciting areas in immunology that we are homing in on.

Filip: While we are not yet disclosing specific targets, we see compelling opportunities in pathway, it's critical to b cell modulation in auto antibody production and.

Philipp: Again, it doesn't mean that we need to get to 99%, but I think it's great. to have that, to see that, and then obviously adjust the dose as you want to get to whatever level you think is best for your indication.

Marcus: So now, let's turn to our oncology programs equally exciting in the second half off the call.

Filip: Inflammation as well as in key pathways relevant to asthma and allergies conflict.

Marcus: We will provide you an update on <unk>.

Markus Warmuth: To have that, to see that, and then obviously adjust the dose as you want to get to whatever level you think is best for your indication.

Marcus: Our MLP $23 59 development program.

Marcus: Consequently belief, we believe our mgd's have broad therapeutic potential across the <unk> space and we are excited to share future progress as our early stage programs advanced with that I'll turn the call back over to Marcus.

Marcus: And we will show you some early encouraging data interest ratio resistant prostate cancer, a tumor type characterized by widespread expression of <unk> on top of all of course.

Mark Fromm: Okay, that's very helpful.

Marc Frahm: Okay. That's very helpful. Maybe just on the prostate cancer expansion cohort. I recognize it's up to 20 to 30. Are there any interim gating factors that we should think about in terms of the enrollment through the rest of the year?

Philipp: Then maybe just on the prostate cancer expansion cohort, you know, I recognize it's up to 20 to 30.

Marcus: And we will discuss why we decided to prioritize this indication.

Marcus: Over other expansion cohorts, but bottom line you see this is a hugely exciting opportunity for <unk> 69, moving forwards on risk the added benefits of not having to develop a companion diagnostic in that setting.

Speaker Change: Thank you Sharon and so just to recap the ini part of today's call and we just showed you very encouraging data for 61 60 healthy volunteer trial.

Philipp: Are there kind of any interim kind of gating factors that we should think about in terms of the enrollment through the rest of the year? Yeah, I mean, it's assignment stage two design. So there's an interim efficacy readout again. Admittedly, this is early, but as we said, super, super encouraging with that response with the disabled diseases and You have to have just obviously to gain excitement and momentum on on enrollment. And so there's an interim efficacy Criteria that, you know, we look at for full expansion to 20 to 30. But of course, it's not as simple as looking at a response rate because I think you also need to look at how heavily are these being pre-treated.

Marcus: Gotcha.

Markus Warmuth: Yeah, it's a Simon's two-stage design, so there's an interim efficacy readout. Again, admittedly, this is early, but as we said, super encouraging with that response with the stable diseases. Still, you have just obviously to gain excitement and momentum on enrollment, and so there's an interim efficacy criterion that we look at for full expansion to 20 to 30. Of course, it's not as simple as looking at a response rate, because I think you also need to look at how heavily are these being pre-treated. Of course, needless to say, we've been looking at the early data, not the recently released data, the early phase I data from Pfizer, and the combination with their EZH2 inhibitor. To throw it out, I think our patient population here is more heavily pre-treated.

Marcus: 80% plus <unk>.

Marcus: Degradation of Athlon and cytokine modulation of.

Marcus: Towards the underground and also touch base on CDK tool and cycling the one or two very very interesting programs on highly validated targets and we'll provide you a quick update on our path to an IND submission in 2026.

Marcus: 80% to 99%.

Marcus: Very encouraging data set and making a clear path into a phase III trials.

Marcus: And we're also looking at <unk> in the first half of this year and for our next seven degreed or <unk> targeting a cast raytheon and Lockheed to inflammatory.

Speaker Change: And so we said I'll hand, it back over to <unk> to lead you through our updates on <unk> hundred $23 59.

Speaker Change: Thank you Marcos I'll start off with a brief recap four hour teleporting hypothesis for the GSP Bond program.

Marcus: We're getting more and more attention.

Marcus: And then we talk about creating more opportunities for us to utilize Korean our discovery engine onto goods are highly differentiate differentiated portfolio of oral ini drugs.

Speaker Change: <unk> is our inflation termination fact privilege has an important role and termination of the protein translation of interest we discovered that molecular glued to greater induced GSP deep underground nation is deeper and faster and make them ourselves compared to other cells, resulting impact protein translation synthetic rutile.

Marcus: So now, let's turn to our oncology programs equally exciting in the second half of the call.

Philipp: Of course, needless to say, we've been looking at the early data, not the recently released data, the early phase one data from Pfizer and the combination with the ETH2 inhibitor. And to throw it out, I think our patient population here is more heavily pre-treated. everyone, not just the ones where we have efficacy assessment, the ones that have been enrolled since have some form of a mutation in the androgen receptor pathway. And so obviously we have to put that into the equation.

Marcus: He will provide you an update on our MRI <unk> $23 59 development program.

Speaker Change: And ultimately I would use to make expression.

Marcus: I'm going to show you some early encouraging data in castration resistant prostate cancer or too much hard characterized by widespread expression of <unk> on top of AI of course.

Speaker Change: Therefore, GSP about the validation of <unk> offers a potential therapeutic modality drug make different cancers.

Speaker Change: The three different <unk> family members involved in multiple cancers, including loans, which are listed here on slide 33 in which we explored in our phase one two study of MLP to Etsy benign. This includes both small cell lung cancer non small cell lung cancer, driven by <unk> or <unk> high grade underground do motives.

Marcus: We will discuss why we decided to prioritize this indication.

Markus Warmuth: Everyone, not just the ones where we have equity assessment, the ones that have been enrolled since, have some form of a mutation in the androgen receptor pathway. Obviously we have to put that into the equation. I'm sure that was a lengthy answer to a relatively short question. The short answer is, yeah, there's an interim efficacy assessment to then go to the full 20 to 30.

Marcus: Over other expansion cohorts, but bottom line. We see this is a hugely exciting opportunity for <unk> 23, 59 moving forwards.

Marcus: Added benefits of not having to develop a companion diagnostic in that setting.

Philipp: I'm sure there was a lengthy answer to a relatively short question. And the short answer is yeah, there's an interim efficacy assessment to then go to the fall 2020.

Speaker Change: And under agenda receptor positive prostate cancer as well as hormone receptor positive breast cancer.

Marcus: Towards the end, we really got lots of touch base on CDK tool inside any one or two very very interesting programs on highly validated targets and then provide you a quick update on our path to an IND submission in 2026.

Speaker Change: By email.

Speaker Change: Based on our most recent data we started to focus on tumors that are primarily known to be semic, driven which has the added benefit of not requiring biomarker based selection of patients.

Marc Frahm: Okay. Thank you.

Robert Driscoll: And our next question comes from Robert Driscoll with Wedbush. Your line is open. Thanks, morning guys. Congrats on all the progress here. Just a couple of questions.

Operator: Our next question comes from Robert Driscoll with Wedbush. Your line is open.

Marcus: So with that I'll hand, it back over to affiliate to lead you through our updates on <unk> hundred $23 59.

Speaker Change: These tumor types with prostate cancer in which semic overexpression drives under agenda set the dependence and therapeutic and assistance in castration resistant prostate cancer.

Robert Driscoll: Thanks. Morning, guys. Congrats on all the progress here. Just a couple of questions. On 2359, for the breast cancer cohort, how are you thinking about the MYC biomarker there and, I guess, the potential patient population? Second question, just any extended thoughts on why there appears to be this discrepancy between the preclinical data and the clinical data for the MYC biomarker and the other cancer cohorts? Thanks.

Affiliate: Thank you Marcos I'll start off with a brief recap for our therapeutic hypothesis for the <unk> program.

Philipp: On 2359 for the breast cancer cohort, how are you thinking about the MIG biomarker there and I guess the potential patient population? And then second question, just any extended thoughts on why there appears to be this discrepancy between the preclinical data and the clinical data for the MIG biomarker and then the other cancer cohorts? Thanks.

Speaker Change: Our phase one two study of <unk> 15 on well designed to assess safety Tolerability pharmacokinetics, pharmacodynamics and preliminary clinical activity of <unk> 359 in patients with previously treated selected solid Cumulus, our monotherapy dose escalation cohort focused on selected <unk>.

Marcus: So <unk> is <unk>.

Marcus: <unk> termination factory, which has an important role and termination of the protein translation effect.

Marcus: We discovered that molecular glued to greater induced GSP von degradation is deeper and faster and make them ourselves compared to other cells, resulting in impaired protein translation synthetic let's I'll, let the and ultimately that it used to make expression.

Speaker Change: Such as non small cell lung cancer small cell lung cancer high grade neuroendocrine tumors and tumultuous L make amplifications.

Philipp: Yeah, so let's start with breast, right? So we look at breast in a very similar way as we look at a prostate, right? Like our pre-clinical data, which would be in satellites and PDXs. suggests that CMIC high expression is very widespread. So we don't think we need to hone in on a particular subpopulation, just like for CRPC. No need to have a companion diagnostic in that setting. And just like we alluded to this interplay between CMIC and AR, we see this for. She makes an ER as well.

Markus Warmuth: Yeah. Let's start with breast. We look at breast in a very similar way as we look at prostate. Our preclinical data, admittedly in cell lines and PDXs, suggests that c-MYC high expression is very widespread. We don't think we need to home in on a particular subpopulation. Just like for CRPC, no need to have a companion diagnostic in that setting. Just like we've alluded to this interplay between c-MYC and AR, we see this for c-MYC and ER as well. Again, this cohort lags a little bit behind, and so we don't really have any data yet from that cohort to share. In regards to biomarker positivity, sure, you always scratch your head when you see it then. We spent a lot of time looking at real-world data sets, not just cell line or PDX data, even real-world data sets.

Marcus: Therefore, gsp's declaration.

Marcus: A potential therapeutic modality to drug and make different cancers.

Speaker Change: Most patients at multiple dose levels using a five days online days off schedule as well as 21 days on seven days off schedule.

Marcus: The three different family members involved in multiple cancers, including ones, which are listed here on slide 33 in which we explored in our phase one two study of MLP $23 59. This includes both small cell lung cancer non small cell lung cancer, driven by <unk> high grade neuroendocrine tumors and <unk>.

Speaker Change: Last year, we announced that the schedule of 21 days on seven days off at the five milligram dose level would be our recommended phase two dose.

Speaker Change: Slide 35 shows you the patient demographics of the study population and I believe the most important takeaways here are that we weren't able to nicely balanced recruitment between different tumor types and also that we are dealing with that population.

Marcus: Androgen receptor positive prostate cancer as well as a hormone receptor positive breast cancer.

Marcus: Driven by <unk>.

Marcus: Based on our most recent data we started to focus on cumulative without primarily known to BC mix driven.

Speaker Change: On slide 36 outlines the adverse event profile observed for each of the dose levels and an expected frequencies.

Philipp: But again, this cohort lags a little bit behind and so we don't really have any data yet from that cohort to share. in regards to biomarker positivity. Sure, I mean, you ought to scratch your head right when you see them. We spent a lot of time looking at real-world data sets, not just cell line or pdx data, even real-world data sets. facets, I'm sure. I think you're probably looking at a situation where our clinical trial population is more heavily pre-treated than what you typically get in these real-world data sets, not mentioning the companies we got the data from, but definitely more heavily pre-treated.

Marcus: Has the added benefit of not requiring biomarker based selection of patients one.

Marcus: One of these tumor types as prostate cancer in which semic overexpression drives under agenda set the dependence and therapeutic assistance in castration resistant prostate cancer.

Speaker Change: Doses of <unk>, five milligram and one milligram per day into five nine schedule and doses of <unk> five milligram and <unk> 75 milligram in the 'twenty one sudden reschedule their volatility does this most of the low grade adverse events, while doses of one five milligram or higher above the maximum tolerated dose is thrombocytopenia being at that.

Marcus: Our phase one two study of <unk> hundred 59, well designed to assess safety Tolerability pharmacokinetics, pharmacodynamics and preliminary clinical activity of <unk> 33, 59 in patients with previously treated selected solid Cumulus.

Limiting toxicity.

Speaker Change: Importantly, dose limiting toxicity reported with non selective competitive GSP coupon degrade us such as hypocalcemia hypotension and cytokine release syndrome were not reported in our study of <unk> 2000, <unk> 59.

Markus Warmuth: I'm sure, I think we're probably looking at a situation where our clinical trial population is more heavily pre-treated than what you typically get in these real-world data sets, not mentioning the companies we got the data from, but definitely more heavily pre-treated. We're using a different assay, and again, sure, we try to make sure that these assays somehow match up, and it's not completely off, but sure, like small cell, 70% to 80% as predicted versus 30%, that is a huge difference and obviously made small cell lung cancer for us a lot more less attractive. On top of the fact that, again, sure, standard of cares in that population have changed, and certainly, your now current study population isn't any easier to treat. I think that's our best explanation.

Marcus: Automotive therapy dose escalation cohorts focused on selected <unk> water, such as non small cell lung cancer small cell lung cancer high grade neuroendocrine tumors and tumultuous.

Marcus: Make amplifications.

Now, let's talk about what we saw with regards to the <unk> biomarker analysis remember our trial was not designed to handle OLED biomarker positive patients.

Marcus: Dose patients at multiple dose levels using a five days online days I'll schedule as well as a 21 days on seven days off schedule.

Philipp: And we're using a different assay, and again, sure, we try to make sure that these assays somehow match up. And it's not completely off-bar, but sure, like small cell, 70 to 80% as predicted versus 30%. That is a huge difference, and obviously made small cell lung cancer for us. a lot more less attractive, on top of the fact that, again, true standard of cares in that population has changed. And certainly, you know, current study population isn't any easier to treat. I think that's our best explanation.

Marcus: Late last year, we announced that the schedule of 21 days on seven days off at five.

Speaker Change: And then what patients is the tumor types, we expect it to be enriched for the presence of high.

Marcus: Five milligram dose level would be our recommended phase II dose.

Speaker Change: And make expression and stat, we performed a retrospective biomarker assessment and a patient as detailed on the dial or biopsies on archival tissues were available.

Marcus: Slide 35 shows you the patient demographics of the study population and I believe the most important takeaways here are that we were able to nicely balanced recruitment between different tumor types and also that we were dealing with the liquidity needs of the population.

Speaker Change: The graph on the left depicts the frequency of make high, especially in 46 patients with available tumor tissue to keep it brief we saw considerably lower than expected frequency. So few motors with hi, al or unmake, especially in non small cell lung cancer and postal lung cancer as compared to the preclinical data he has abstained.

Marcus: On slide 36, we outline the adverse event profile observed for each of the dose levels and their expected frequencies.

Philipp: And again, true a part of the Now focusing with all the data we have, the totality of the data we have on prostate cancer makes a ton of sense.

Markus Warmuth: Again, sure, part of the now focusing with all the data we have, the totality of the data we have on prostate cancer makes a ton of sense.

Marcus: Doses of <unk> five milligrams, one milligram per day into five nine schedule and doses of <unk> five milligram and <unk> 75 milligram in the 'twenty one sudden reschedule their volatility does this most of the low grade adverse evils well doses of one five milligram or higher above the maximum tolerated dose is still looks like the P&L being.

Speaker Change: Pleasingly in the biomarker positive population there we had a few more biopsies visa optimal targets the <unk> protein degradation of approximately 60%, which was consistent with our preclinical data.

Robert Driscoll: Perfect. Thank you.

Speaker Change: Slide 38 summarizes the clinical response data in the dose escalation cohorts that about 48 patients for expression in tumor tissue was obtained at baseline and we also included patients with known al or unmake amplification, even if the issue was not available to us as expression of these 48 patients 37 patients.

Michael Schmidt: And the next question will come from Michael Schmidt with Guggenheim. Your line is open. Michael, your line is now open. Thank you for taking my questions. Question on BASC-1. that safety profile of very. I think you described it.

Operator: The next question will come from Michael Schmidt with Guggenheim. Michael, your line is now open.

Marcus: Dose limiting toxicity.

Marcus: Most importantly, a dose limiting toxicity reported with non selective competitor GSP people integrate us such as hypocalcemia hypotension and cytokine release syndrome were not reported in our study of <unk> 23 59.

Michael Schmidt: Thanks for taking my questions. Question on VAV1. Obviously, the safety profile looked very clean as you described it. Are there any expected on-target side effects that you're paying attention to, for example, infections or other things that are interesting?

Speaker Change: Before response, that's better resist one one.

Now, let's talk about what we saw with regards to the biomarker analysis remember our trial was not designed to enroll only biomarker positive patients, but rather enrolled patients as the tumor types are expected to be enriched for the presence of high L and make expression and start we performed a retrospective biomarker.

Speaker Change: From this group 13 patients. So about one third were determined to be biomarker positive of the 13 patients <unk> confirmed partial response and four patients with stable disease, resulting in disease control rate of 38% of the 34 biomarker negative patients. There was one unconfirmed partial response.

Philipp: Are there any expected on-target side effects that you're paying attention to, for example, infections or other things that are interesting? So you were breaking up a bit, but I tried to answer based on what I thought I understood. So on target, potential on target toxicity. Um, I would say. really non-based on the pre-clinical data we have. Obviously, a four-week, four-week GOP tox study. showed nothing, no test article related findings, and we dosed extremely high. We talked about this data a while ago. We have margin T of 500 fold and above based on calculating this off either red or cyanose.

Markus Warmuth: You were breaking up a bit, but I tried to answer based on what I thought I understood. Potential on-target toxicities, I would say really none based on the preclinical data we have. Obviously, 4-week GLP tox study showed nothing, no test article-related findings, and we dosed extremely high. We talked about this data a while ago. We have margins here of 500-fold and above based on calculating this off either rat or cynos. All the information we have, we did immune phenotyping in cynos and suggested it is immune modulatory and not immune suppressive. Can you absolutely exclude infection risk? I'd say no. I think no one in this field, no one in I&I can actually confidently do this. I think it's always there as a risk. Again, based on everything we've seen so far, we're not concerned at all.

Marcus: This month in a patient treated onto tile or biopsies on archival tissues where available.

Speaker Change: And three patients with stable disease, but a disease control rate of 17%.

Ralph on the left depicts the secret sales.

Speaker Change: Moving to slide 39, as I mentioned earlier, we have also initiated two combination arms studying <unk> hundred $59. Some odd in calculation of resistant prostate cancer and if its fullest in hormone receptor positive breast cancer.

Marcus: Hi, especially in 46 patients with available tumor tissue to keep it brief we saw considerably lower than expected frequency. So few motives with high L or unmake, especially in non small cell lung cancer and fossil lung cancer as compared to the preclinical data we have obtained.

Speaker Change: On this slide we summarized initial data in the castrate resistant prostate cancer cohort again, a patient group, where we believe <unk> overexpression is critical in driving under agenda set the defendants and therapeutic and assistance and where there is a significant unmet need for new safe oral therapies.

Marcus: Pleasingly in the biomarker positive population there we had a few more biopsies visa optimal target GSP amount of protein degradation of approximately 60%, which was consistent with our preclinical data.

Marcus: Slide 38 summarizes the clinical response data in the dose escalation cohorts that over 48 patients were expression tumor tissue was obtained at baseline and we also included patients with known al or unmake amplification, even if the issue was not available to us as expression of these 48 patients 37 patients.

Philipp: All the information we have, I mean, we did immune phenotyping in SINOs, and suggested it's immune modulatory and not immune suppressive. Can you absolutely exclude infection risk? I'd say no, I think no one in this field, no one in I&I, can actually confidently do this. I think it's obvious here as a risk. But again, based on everything we've seen so far, we're not concerned at all. Obviously, we do have...

Speaker Change: As of March 10, 2025, we have received $1 one assessment available for <unk> patients and very encouragingly among them <unk> confirmed partial response and stable diseases, notably all three patients were heavily proceeded and has mutation typically associated assistance to under agenda receptor antagonist such as <unk>.

Marcus: A little blip for response, that's better resist one one.

Speaker Change: All of them, including mutations in the androgen receptor ligand binding site on expression of <unk> seven timeskip.

Marcus: From this group 13 patients so about one third were determined to be biomarker positive.

Marcus: These 13 patients <unk> confirmed partial response and four patients with stable disease, resulting in disease control rate of 38% of the 34 biomarker negative patients. There was one unconfirmed partial response and three patients with stable disease for a disease control rate of 17%.

Speaker Change: PSA response assessment available four to patients showing one PSA response of 90% and the patient is a confirmed PR.

Markus Warmuth: Obviously, we have long-term tox studies in hand as well. We haven't disclosed any details there. I think we did make a statement in today's presentation that clinical data combined with the long-term tox data we now have gives us a lot of confidence and that's a clear path.

Philipp: long-term talk studies in hand as well and we haven't disclosed any details there but I think we did make a statement in today's presentation that clinical data combined with the long-term tox data we now have gives us a lot of confidence and maps a clear path. then a question. one program, just reconciling some of the data that was presented today. Have you looked at correlating? TSPT1 degradation with clinical activity in the patients so far and I don't know if you disclosed. tumor type that one responder in the biomarker positive patients was the lung cancer patient or neuroendocrine and then same for the...

Speaker Change: The safety profile observed has been favorable we are continuing to enroll and evaluate patients discussed lethal resistant prostate cancer has the potential to expand enrollment to 20 to 30 patients continue to observe a positive I think is sustainable and we expect to present additional results along with the data from the hormone receptor positive breast cancer cohort.

Marcus: Moving to slide 39, as I mentioned earlier, we have also initiated two combination arms studying <unk> <unk> 59 is all the time is any calculation that resistant prostate cancer and it was full restaurant in hormone receptor positive breast cancer.

Michael Schmidt: Okay, great. Thanks. A question on the GSPT1 program, just reconciling some of the data that was presented today. Have you looked at correlating GSPT1 degradation with clinical activity in the patients so far? I don't know if you disclosed the tumor type, that one responder in the biomarker positive patients, was it a lung cancer patient or neuroendocrine? Same for the unconfirmed response in that biomarker.

Speaker Change: In the second half of 2025.

Speaker Change: Here on slide 40.

Speaker Change: As I vignette heavily pre treated patients with castrate resistant prostate cancer and understand that assessment at age 80, 75, why mutation, which is typically associated with resistance to androgen receptor inhibitor such as <unk>.

Marcus: On this slide we summarize initial data in the castrate resistant prostate cancer cohort again, a patient group, where he believes he can make overexpression is critical in driving under agenda assessed the dependence and therapeutic and assistance in various areas of significant unmet need for new safe oral therapies.

Speaker Change: After initiation of therapy, as MRP, Tennessee, fifty-nine uninstall optimize the patient developed at Opex and deepest bonds. This PSA dropping by <unk> 85 per cent out the cycle alone and by 90% by cycle for more importantly, the resist imaging demonstrated a partial response of 46% after cycle, two and a 57% up.

Marcus: As of March 10, 2025, we have repurchased 1.1 assessment available for three patients and very encouragingly among them <unk> confirmed partial response and two stable diseases, notably all three patients were heavily pretreated and have mutations typically associated with resistance to other agenda receptor antagonist such as <unk>.

Philipp: Yeah, so the PR that we saw in the biomarker positive patient during dose escalation, there was a neuroendocrine bladder characterized by extremely high expression of NMIC. I'm almost a, it's called a signature patient for the setting. But again, fail to see and we've discussed it. That sort of high N-myc population sadly was like rare, not as frequent as we had hoped, even in your endocrine tumors. But again, certainly a patient that gives us confidence that the drug works. And of course, in the patient we saw the 60-some percent degradation of the TSPT1. In totality, although it's not many patients, as you can tell, in the biomarker positives, we've seen very decent levels of degradation, 60-70% in line with the preclinical data and expectation.

Markus Warmuth: The PR that we saw in the biomarker positive patient during dose escalation, that was a neuroendocrine bladder characterized by extremely high expression of N-MYC. Almost a, let's call it a signature patient for the setting. Again, fair to say, and we've discussed it, that sort of high N-MYC population sadly was like rare, not as frequent as we had hoped, even in neuroendocrine tumors. Again, certainly a patient that gives us confidence that the drug works. Of course, in that patient, we saw the 60-some percent degradation of GSPT1. In totality, although it's not many patients, as you can tell, in the biomarker positives, we've seen very decent levels of degradation, 60% to 70%, in line with the preclinical data and expectation.

Speaker Change: Cycle afore and the patient continues on treatment cycle five.

Speaker Change: Political and are encouraged to see this earlier schools in a heavily pretreated patient.

Marcus: All of them, including mutations in the androgen receptor ligand binding site or expression of <unk> seven times kept.

Speaker Change: To summarize yes.

Speaker Change: Encouraged by the early signs of clinical response in heavily pretreated castrate resistant prostate cancer patients. This notion that are set to alterations associated with assistance to androgen receptor inhibitors.

Marcus: PSA response assessment available four to patients showing PSA response of 90% in the patient visit confirmed resist PR.

Marcus: The safety profile observed has been favorable we are continuing to enroll and evaluate patients discuss later resistant prostate cancer has the potential to expand enrollment to 20% to 30 patients. If we continue to observe a positive efficacy signal and we expect to present additional results along with the data from the hormone receptor positive breast cancer cohort.

Speaker Change: VC MLP, Tennessee fifty-ninth activity in castrate resistant prostate cancer is an exciting opportunity and a large high unmet need population.

Speaker Change: You make especially in this population at my expense. So this indication of <unk> via patient selection upfront simplifying our federal head of clinical development.

Speaker Change: We look forward to presenting additional data in the second half of this year.

Marcus: In the second half of 2025.

Marcus: Here on slide 48.

Speaker Change: In light of the promising data in castrate resistant prostate cancer and the data you have seen it from our dose escalation cohorts. We have made a strategic decision not to open expansion cohorts in lung cancer in high grade ore underground a few months, while we believe our results in these cohorts particle literally in the biomarker positive subset are supportive of that.

Marcus: As a vignette heavily pretreated patients with castrate resistant prostate cancer and understand that a subset of <unk> 875, why mutation, which is typically associated with resistance to other agenda set the inhibitors such as double demand after initiation of therapy with <unk> 5900 until the time the patient developed at Outback and <unk>.

Philipp: We have not received yet any data from prostate, mostly because, not just mostly, simply because we weren't able to get the paired biopsies. These are not. Trivia. Thanks again. We're always happy when we get the screening biopsies, and I think we've done really well. They are getting that second biopsy. Again, we have a very decent success rate there with about a third of the patients, but we're not getting that on everyone.

Markus Warmuth: We have not received yet any data from prostate, mostly because, not just mostly, simply because we were unable to get the paired biopsies run. These are not trivial things. Again, we are always happy when we get the screening biopsies, and I think we have done really well there getting that second biopsy. Again, we have a very decent success rate there with about a third of the patients, but we are not getting that on everyone. Sadly for prostate, we haven't gotten the paired samples yet.

Speaker Change: Clinical activity of <unk> hundred 59, considering our other opportunities.

Marcus: <unk> bonds. This BSA dropping by 85% at the cycle alone and by 90% by cycle for more importantly, the resist imaging demonstrated a partial response of 46% of the Otto cycle <unk> at a 57% off the cycle afore and the patient continues on treatment cycle of five we are particularly encouraged to see this.

Speaker Change: Dakota Castaneda resistant prostate cancer, we believe the low biomarker positive at the Indy small unmik indications doesn't support expansion cohorts in these populations.

Speaker Change: I'll now hand, the call back over to Cheryl to walk you through some updates to our CDK due and cyclin E. One programs Cheryl.

Marcus: Early response in a heavily pretreated patient.

Cheryl: Thanks Philip.

Marcus: To summarize yes.

Cheryl: Excited to now share some promising preclinical data from both our <unk> and CDK T programs.

Philipp: And sadly for prostate, we haven't gotten the paired samples yet.

Marcus: By the early signs of clinical response in heavily pretreated castrate resistant prostate cancer patients. This androgen receptor alterations associated with resistance to androgen receptor inhibitors.

Cheryl: As many of you know cyclin E <unk> and CDK to are key drivers of cancers caused by changes in the CDK pathway.

Michael Schmidt: Thank you.

Eric Joseph: The next question comes from Eric Joseph with JP Morgan. Your line is open. Thanks for taking the questions, good morning.

Operator: The next question comes from Eric Joseph with J.P. Morgan. Your line is open.

Marcus: <unk> activity in castrate resistant prostate cancer is an exciting opportunity and a large high unmet need population ischemic, especially in this population is widespread so this indication of elaborate client patient selection upfront simplifying our further clinical development, we look forward to presenting additional data in the <unk>.

However for both targets there have been challenges conventional inhibitor approaches and.

Eric Joseph: Thanks for taking the questions. Good morning. Maybe just one question on the VAV1 program. Anything you can share at this point in terms of how Novartis might be thinking about duration of an initial phase II trial? I wonder, here, just given the 7-day MAD portion of this study, is there any chance of, I guess I'm asking around comfort on the safety side, whether you expect any sort of intermediate length phase I-B type trial before moving into a longer randomized phase II program. On the GSPT1 program, just having focused in prostate cancer going forward, can you just talk a little bit about your sense of how MYC expression tracks with line of treatment? Whether there's any, I guess, variation as patients are more heavily pretreated. Thanks.

Eric Joseph: Maybe just one question on the VALV1 program.

Cheryl: We believe our highly selective mtv's could have key advantages here.

Philipp: Anything you can share at this point in terms of how Novartis might be thinking about duration of the initial phase two trial? And I wonder you know here just given the the seven-day mad portion of this study is there any chance of I guess I'm asking around comfort on the safety side, whether you expected any sort of intermediate length. Phase 1B type trial before moving into a longer randomized Phase 2 program.

Cheryl: Slide 44 highlights some of R&D the findings for our cyclin E <unk> program.

Cheryl: First our selectivity granted 596, nine and Ciphony, one amplified gastric cancer and breast cancer models.

Marcus: Second half of this year.

Marcus: In light of the promising data in castrate resistant prostate cancer and the data you have seen it from our dose escalation cohorts. We have made a strategic decision not to open expansion cohorts in lung cancer in high grade neuroendocrine tumors, while we believe our results in these cohorts political literally in the biomarker positive subset are supportive of that.

Cheryl: In both instances, we're seeing quite potently monotherapy effects in these difficult to treat tumors.

Cheryl: <unk>, a near complete tumor regression in the cyclin E amplified breast cancer model.

Philipp: And then on the GSPT-1 program, just having focused in prostate cancer going forward, can you just talk a little bit about your sense of how MIC expression tracks with line of treatment? Whether there's any, I guess, variation as patients are more heavily pre-treated Thanks.

Cheryl: Moving to our CDK to program on slide 45.

Marcus: Clinical activity of <unk> hundred 59, considering our other opportunities.

Seth: Seth and therapeutic effects of our CDK to degrade at five one small country in combinations with standard of care regimen of <unk> and <unk> ER positive breast cancer models.

Marcus: Little castrate resistant prostate cancer, we believe the low biomarker positive at the Indy small unmik indications doesn't support expenditure cohorts in these populations.

Seth: Both models the results demonstrated profound tumor regression for the triple combination relative to standard of care treatment.

Marcus: I'll now hand, the call back over to Cheryl to walk you through some updates to our CDK due and cycling he wanted programs Cheryl.

Seth: In summary, we are excited with the strong preclinical results, we're seeing from both hostile cycle programs.

Cheryl: Thanks Philip.

Cheryl: So I'd like to now share some promising preclinical data from both our cyclin E one and CDK T programs.

Philipp: Yeah, so I thought on the your back one question, and I think again, best answer I can give you is work in progress. Tri-designs are being rocked on.

Markus Warmuth: Yeah. I'll start on the VAV1 question. I think, again, best answer I can give you is work in progress. Trial designs are being worked on. No details disclosed. I think the best assumption here is pretty much going to be standard designs. I think with regards to the length of the treatment in MAD, yes, it's seven doses. Of course, the upside here is, as you were able to see in the presentation, VAV1 levels stay down for an additional seven days. From a safety assessment, with the additional one week of collecting safety observations, we've essentially recorded two weeks of low VAV1, with a total of three weeks observation. I think for whatever the length of the phase IIAs are, we're in reasonably good shape here.

Seth: Our focus going forward is a benchmark mgd's above CDK to and cyclin E. One to determine the optimal molecule. It's a battle to an expected IND submission in 2026.

Cheryl: As many of you know cyclin E <unk> and CDK to are key drivers of cancers caused by changes in the CDK pathway.

Cheryl: However for both targets there have been challenges for conventional inhibitor approaches.

Marcus: With that I'm happy to turn the call back over to Marcus for a summary, and concluding remarks before we open up the call to Q&A August.

Philipp: No details disclosed. I think the best assumption here is pretty much going to be standard design. I think with regards to the length of the treatment in MAD, yes, it's seven doses, but of course, the upside here is, as you were able to see in the presentation, RAC1 levels stay down for an additional seven days from a safety assessment. with the additional one week of collecting safety observations, right? We've essentially recorded two weeks of low VAP-1 with a total of three weeks observation, and so I think we're So whatever the lengths of the phase IIa's are, we're in reasonably good shape here.

Cheryl: And we believe our highly selective mtv's could have key advantages here.

Cheryl: Slide 44 highlights some of the R&D the findings for <unk> Cyclin E <unk> program.

Marcus: Thanks, Sharon and fairly poor sharing these exciting updates.

Marcus: This morning.

Marcus: <unk>.

Cheryl: First our selective degrade 596 nine in Ciphony, one amplified gastric cancer and breast cancer models.

Marcus: In summary.

Marcus: I'd like to stage, we're very very proud of the progress we've made throughout 2024.

Marcus: As a matter of fact in the first quarter of this year.

Cheryl: In both instances, we're seeing quite potent monotherapy effects in these difficult to treat achievement.

With a number of significant milestones of course show coming up throughout this year and next.

Cheryl: <unk> near complete tumor regression in cyclin E amplified breast cancer model.

Marcus: So let me just quickly summarize on this slide what you've seen today and also give you some guidance on.

Cheryl: Moving to our CDK program on slide 45.

Marcus: What to expect moving forward.

Marcus: Today, we shared encouraging clinical data with you on <unk> hundred 61 16.

Cheryl: Seth and therapeutic effects of our CDK to degrade a sidewalk ballpark three in combinations with standard of care regimen of <unk> and two ER positive breast cancer models.

Marcus: Is that a mapping a clear path as mentioned before two phase two studies.

Philipp: And so again, I've said it multiple times, might sound like a broken record, but this really gives us a clear path into these phase IIa trials. On 2359 and CMIC again, and that's why we are so excited about it, we've seen Shemek up and correlating to a arm really throughout. The life cycle of prostate cancer is kind of a weird name for a term and so I think that makes it a lot easier, as I said, as some of the smaller L and N make indications are because as soon as you have an AR driven cancer, CMIC seems to be a quite relevant and almost there, so no need to go in and define expression levels up front.

Markus Warmuth: Again, I've said it multiple times, might sound like a broken record, but this really gives us a clear path into these phase IIA trials. On MRT-2359 and c-MYC again, and that's why we are so excited about it. We've seen c-MYC up and correlating to AR, really throughout the life cycle of prostate cancer. It's kind of a weird name for a term. I think that makes it a lot easier, as I said, as some of the smaller L and N-MYC indications. Because as soon as you have an AR driven cancer, c-MYC seems to be quite relevant and almost there, so no need to go in and define expression levels upfront. Again, early, but so far, the data we're seeing in many ways sort of confirms that.

While I can't give you guidance on exact timing for the phase II initiations I can see that we are working with our collaborators at Novartis to advance this program as efficiently as possible.

Cheryl: Both models the results demonstrated profound tumor regression for the triple combination relative to standard of care treatment.

Cheryl: In summary, we're very excited with the strong preclinical results, we're seeing from both our sales cycle programs.

Marcus: Building on the promising data would be shared with you today.

Marcus: As discussed.

Cheryl: Our focus going forward is a benchmark mgd's above CDK to cyclin E. One to determine the optimal molecule to an expected IND submission in 2026.

Marcus: We're also quite encouraged with what we see early on for our cohort of heavily pretreated castrate resistant prostate cancer patients, it's a small sample size.

Marcus: Given how heavily pre treated these patients arm struck me encouraging.

Cheryl: With that I'm happy to turn the call back over to Mark for a summary, and concluding remarks before we open up the call to Q&A.

Marcus: And so in light of February at the strategic decision to focus on this cohort not open any other courts.

Cheryl: Yes.

Speaker Change: Thanks, Sharon and Philip for sharing this exciting updates with us.

Marcus: At this point for all the reasons you discussed.

Cheryl: This morning.

Marcus: We expect additional data for this program in the second half of this year.

Cheryl: <unk>.

Cheryl: In summary.

Cheryl: I would like to state, we're very very proud of the progress we've made throughout 2024 and as a matter of fact in the first quarter of this year.

Marcus: <unk> seven <unk>.

Marcus: We also look forward to an IND submission of <unk> hundred two and Thats going to happen first half of this year.

Philipp: And again, early, right, but so far, the data we're seeing in many ways sort of confirms them.

Cheryl: With a number of significant milestones of course, they are coming up throughout this year next.

Marcus: And then a potential IND for our CNS optimized next seven program next year.

Cheryl: So let me just quickly summarize on this slide what <unk> seen today and also give you some guidance on.

Marcus: Our sales cycle programs are projected to have an IND in 2026% to swell and behold.

Cheryl: What to expect moving forward so.

Philipp: Yeah, thanks for taking the question.

Eric Joseph: Okay. Thanks for taking the questions.

On the exciting work.

Cheryl: Today, we shared encouraging clinical data with you on <unk> hundred 61 16.

Marcus: Coming from our Korean platform in particular in the <unk> in the context offer more.

Jasmine: The next question comes from Ellie Murrell with UBS. Your line is open. Hi, this is Jasmine on for Ellie. Thanks for the update in our question a couple on next 7. 1st, can you remind us of the level of degradation that you'd like to see here to be potentially supportive of efficacy? And then 2nd, can you elaborate a bit on the decision to play on the phase 1 proof of concept in the pericarditis population versus some other options? Thank you.

Operator: The next question comes from Ellie Merle with UBS. Your line is open.

Cheryl: Is that a mapping a clear path as mentioned before two phase two studies.

Marcus: <unk> drugs in relatively near future.

[Analyst] (UBS): Hi, this is Jasmine on for Ellie Merle. Thanks for the update and our question. A couple on NEK7. First, can you remind us of the level of degradation that you'd like to see here to be potentially supportive of efficacy? Second, can you elaborate a bit on the decision to play on the phase I proof of concept in the pericarditis population versus some other options? Thank you.

Cheryl: While I can't give you guidance on exact timing for the phase II initiations I can see that we are working with our collaborators at Novartis to advance this program as efficiently as possible.

Marcus: And so last year as featured on this slide.

Marcus: Importantly, we do think we are well positioned to advance these programs with a very strong balance sheets and providing cash one we anticipated into 2028.

Cheryl: Building on the promising data would be shared with you today.

Marcus: And so what we said I would like to open up the call for any questions you have operator.

Cheryl: As discussed.

Cheryl: We're also quite encouraged with what we see early on for our cohort of heavily pretreated castrate resistant prostate cancer patients, it's a small sample size.

Marcus: Thank you to ask a question. Please press star one on your telephone and wait for your name to be announced.

Philipp: I mean, I start with the expected degradation of another thought is a favorite question from folks. And I'd say, again, if you just look at the the data we have in this stack and previous stacks, 80% degradation. at least in the ex vivo stimulation assay, can give us pretty much 100% inhibition of secretion of IL-1-betum, and so I'd say 80% is probably what we're aiming for in single and multiple ascending dose studies. As always, I throw out sort of the precautionary, this will also depend a little bit on assay line. I think what we have in this presentation is based on VEST germs. As we go into the clinic, obviously, we will switch over to flow cytometry because that has proven very robust in our VAP1 trial, definitely less noise here than with VEST or even targeted mass spec, which we had actually used for GSBT1 and are still using.

Markus Warmuth: Yeah, I mean, I'll start with the expected degradation, and I know that's always a favorite question from folks. I'd say, again, if you just look at the data we have in this stack and previous stacks, 80% degradation, at least in the ex vivo stimulation assay, can give us pretty much 100% inhibition of secretion of IL-1 beta. I'd say 80% is probably what we're aiming for in single and multiple ascending dose studies. As always, I throw out sort of the precautionary. This will also depend a little bit on assay. I think what we have in this presentation is based on Westerns. As we go into the clinic, obviously we will switch over to flow cytometry because that has proven very robust in our VAV1 trial.

Cheryl: Given how heavily pre treated these patients are certainly encouraging.

Marcus: To withdraw your question. Please press star one again.

Marcus: And the first question comes from Kelly <unk> with Jefferies. Your line is open.

Cheryl: And so in light of February at the strategic decision to focus on this cohort not open any other cohorts.

Kelly: Congrats on the progress and thank you for taking my question.

Cheryl: This point for all the reasons just.

Cheryl: As discussed on the <unk>.

Speaker Change: So one given that it is involved in multiple or signaling pathways.

Cheryl: Additional data for this program in the second half of this year.

Cheryl: <unk> seven.

Cheryl: We also look forward to an IND submission of <unk> 81, or two and Thats going to happen first half of this year.

Speaker Change: Do you decided and also we've got patent Eric amongst a promising and indications to pursue.

Speaker Change: I am now available in Panama for biomarker profiling data.

Cheryl: And then a potential IND for our CNS optimized next seven program next year.

Speaker Change: Thank you.

Cheryl: Our sales cycle programs are projected to have an IND in 2026, as well and we hope to share more on the exciting work coming.

Kelly: A great question Kelly onshore.

Speaker Change: Obviously, you can share.

Speaker Change: We are still preparing for those fees.

Cheryl: Coming from our Korean platform in particular in the <unk> in the context offer more.

Speaker Change: These two studies and some final decisions haven't been made.

Speaker Change: That said.

Cheryl: <unk> ini drugs in relatively near future.

Speaker Change: As you know might remember lots of preclinical data that we have generated in the past two three years.

Cheryl: And so lastly, as stated on the slide.

Cheryl: Importantly, we do think we are well positioned to advance these programs with a very strong balance sheets and providing cash one anticipated into 2028.

Markus Warmuth: Definitely less noise there than with Westerns or even targeted mass spec, which we had actually used for GSPT1 and are still using. Filip, do you want to address the pericarditis question?

Speaker Change: In particular in the indications that are driven by either.

Speaker Change: In particular, the th 17 cells or <unk> combined and so <unk>.

Philipp: Do you want to address the pericarditis question? Yeah, so, so pericarditis is obviously like one of the indications, but I mean, for NEC7, the indication even in the cardio immunology space is actually much, much, much broader than that. What is actually nice about pericarditis is that the development pathway is actually relatively well defined, and definitely scalable. Does that answer your question? Or did I leave something out? Yeah, another couple. Thank you.

Cheryl: And so what we said I would like to open up the call for any questions you have operator.

Speaker Change: You remember, we had a very strong data and preclinical data in.

Filip Janku: Yeah. Pericarditis is obviously one of the indications, but I mean, for NEK7, the indication even in the cardio immunology space is actually much broader than that. What is actually nice about pericarditis is that the development pathway is actually relatively well-defined and definitely scalable. Does that answer your question, or did I leave something out?

Speaker Change: Thank you to ask a question. Please press star one on your telephone and wait for your name to be announced.

Speaker Change: You see.

Speaker Change: Very interesting data in rheumatoid arthritis.

Speaker Change: I think there is dose related diseases, you could you could think about and I think the data we showed today from yikes, who volunteer trial of course.

Speaker Change: To withdraw your question. Please press Star one one again and the first question comes from Kelly <unk> with Jefferies. Your line is open.

Speaker Change: In that context.

Speaker Change: Very informative because again.

Kelly: Congrats on the progress and thank you for taking my question.

Speaker Change: At this stage of course, this ex vivo stimulation not in vivo data from patients. Nevertheless, I think it gives us.

Kelly: So one given that it is involved in multiple or signaling pathways.

[Analyst] (UBS): Yeah, no, that's helpful. Thank you.

Speaker Change: Clear indications that.

Markus Warmuth: Great.

Speaker Change: We are hitting.

Kelly: Do you decided and also they've got pattern American looked promising and indications to pursue.

Speaker Change: The cytokines, you want to hit and become sort of modulate how do you prevent you'd want to go in regards to.

Derek Archilla: The next question will come from Derek Archilla with Wells Fargo. Your line is open.

Operator: The next question will come from Derek Archila with Wells Fargo.

Kelly: Now available in China off of biomarker, providing data also has a lot. Thank you.

Speaker Change: Inhibiting <unk> accretion.

Yvonne: Good morning, this is Yvonne for Derek. Thanks for taking our questions. A couple from us.

[Analyst] (Wells Fargo): Good morning. This is Yvonne for Derek. Thanks for taking our questions. A couple from us. First, on the VAV1 program, what are the gatekeeping steps remaining to initiate the phase II studies? Have you shared, is there any specific milestone trigger by the initiation of the studies? On the GSPT1 program, just how much data should we expect in the H2 update for the prostate cancer cohort? Thanks.

Speaker Change: Thank you very much and also welcome a lot happening we feel pretty good.

Kelly: Yeah, Great question Kelly on solar.

Philipp: So first on the VAP-1 program, kind of like what are the gatekeeping steps remaining to initiate the phase two studies? And have you shared, is there any specific milestones triggered by the initiation of the studies?

Speaker Change: Biomarker.

Kelly: Obviously, you can share.

Speaker Change: Inhibition.

Kelly: We are still preparing for those fees.

Speaker Change: By using these extra vivo accumulation approach curious how does it differ from what you are asking David Merrill Lynch. Two represented the treatment impaction and it will level off by email biomarker reduction.

Kelly: Phase two studies and so final decisions haven't been made.

Kelly: That said.

Kelly: As you know I'll remind remember lots of preclinical data that we have generated in the past two three years.

Philipp: And on the GSPT-1 program, just how much data should we expect in the second half of the year update for the prostate cancer cohort thing? So on that one I mean, you saw the the clinical data, right? So everything we need to know from the FATMAT, including safety, of course, which looks very favorable is here. There's a couple of bridging studies that are being done around formulation, so to get to a... something that's more scalable for larger trials or even for later commercialization. And then you know, the typical things that need to be done, protocols need to be written and presented to the FDA, so.

Speaker Change: We expect E ini patients.

Kelly: In particular in the indications that are driven by either T cells in particular th 17 cells or T b cells combined and so.

Speaker Change: Based on the shrink out thanks.

Markus Warmuth: On VAV1, you saw the clinical data, everything we need to know from the VAV1, including safety, of course, which looks very favorable here. There's a couple of bridging studies that are being done around formulation, so to get to something that's more scalable for larger trials or even for later commercialization. The typical things that need to be done, protocols need to be written and presented to the FDA. I think like most of the work's done, clear path into phase IIA studies now. Can you repeat the MRT-2359 question?

Speaker Change: Yes.

Speaker Change: Honestly hard to put a number out on.

Speaker Change: What percentage true.

Kelly: As you remember, we had a very strong data and preclinical data in.

Speaker Change: Expect in patients on the cross.

Kelly: You see.

Kelly: Very interesting data in rheumatoid arthritis.

Speaker Change: That will actually depend on the type of.

Speaker Change: Just use your youre targeting I think what we find encouraging here.

Kelly: I think there is dose related diseases, you could you could think about in.

Speaker Change: For our healthy volunteer trial.

Kelly: The data we showed today from the healthy volunteer trial of course.

Speaker Change: Where we looked at.

What we saw.

Kelly: That context is.

Speaker Change: Important benchmark.

Kelly: Very informative because again.

Speaker Change: Volunteer trials.

Kelly: At this stage of course, this ex vivo stimulation not in vivo data from patients. Nevertheless, I think it gives us.

Speaker Change: Matching up.

Speaker Change: Very very bad in regards to depths of cytokine secretion or subtract inhibition of N and so.

Kelly: Clear indications that.

Philipp: Again, I think like most of the work's done, clear path into Phase IIa studies now.

Kelly: We are hitting.

Speaker Change: From here I'm fairly confident that.

Kelly: The cytokines, you want to hit and become sort of modulate how do you prevent we'd want to grow in regards to <unk>.

Speaker Change: This molecule can hit their mark in vivo in patients with <unk>, but again the exact percentage of course, it really depend on.

Philipp: Can you repeat the 2359 question? Oh, actually, sorry, back to Ralph Vaughan milestones. Yes, there are. face-to-initiation milestones in our agreement. Thanks.

Filip Janku: Question on the milestone.

Kelly: Inhibiting their secretion.

Markus Warmuth: Actually, sorry. Back to VAV1 milestones. Yes, there are phase II initiation milestones in our agreement.

Kelly: Thank you very much and also welcome a lot happening we feel pretty good.

Speaker Change: Sort of the actual disease, you're treating to tissue.

Kelly: Biomarker.

Speaker Change: Who are you measuring cytokine secretion or levels or inhibition there off.

Kelly: In addition.

Kelly: By using these activate or simulation approach I'm curious how does it differ from the directing vivo Merrill Lynch two represented the treatment impact and it will level off by email biomarker reduction.

Speaker Change: Congrats again, thank you.

[Analyst] (Wells Fargo): Thanks. The GSPT1 question was, how much data should we expect in the H2 update for the prostate cancer cohort?

Philipp: And the GSPT-1 question was, how much data should we expect in the second half of the year update for the prostate cancer cohort? Yeah, I mean, again, hesitant to give you a specific patient number on beyond what we said, right, I think we can expand here, based on on pre specified criteria into 20 to 30 patients. Um I think the excitement from the investigators is there, and so I think that's going to be a sizable upgrade by the second half of the year in regards to number of patients we will have treated. But again, I'm hesitant to give you a specific patient number.

Speaker Change: And the next question comes from Edward 10 thoughts with Piper Sandler Your line is open.

Kelly: Could we expect in <unk> patients.

Edward: Great. Thanks, good morning, and thanks for the very thorough and extensive update today.

Markus Warmuth: Yeah. Again, hesitant to give you a specific patient number beyond what we said. I think we can expand here based on pre-specified criteria into 20 to 30 patients. I think the excitement from the investigators is there. I think there's going to be a sizable upgrade by the H2 of the year in regards to number of patients we will have treated. Again, I'm hesitant to give you a specific patient number.

Kelly: Just on the streets out thanks.

Speaker Change: My question has to do with the prostate cancer.

Speaker Change: Yeah, I mean honestly hard to put a number out.

Edward: Focus on prostate cancer, which makes a lot of sense.

Kelly: What percentage true.

Kelly: Expect an impatience because.

Edward: Obviously as many go through multiple cycles.

Kelly: That will actually depend on the type of.

Andrew Funderburke: Including Andrew.

Kelly: This year's Youre targeting I think what we find encouraging here.

Andrew Funderburke: The androgen deprivation therapy.

Duluth.

Kelly: For our healthy volunteer trial.

Andrew Funderburke: Apparat around.

Andrew Funderburke: Their mutational burden exchanges, where do you see the.

Kelly: Revenue looked at.

Kelly: What we saw at <unk>.

Kelly: <unk> benchmark healthy volunteer trials.

Andrew Funderburke: Ideal.

Andrew Funderburke: Application is for two or three product line and work kind of combinations do you think are worth exploring thank you.

Kelly: We're matching up.

Kelly: Very very valid in regards to depths of cytokine secretion or.

[Analyst] (Wells Fargo): Thanks.

Operator: I show no further questions at this time.

Operator: I show no further questions at this time. I would now like to turn the call back over to Markus for closing remarks.

Kelly: So in fact inhibition of N and so.

Andrew Funderburke: Yeah. Thank you.

Marcus: I would now like to turn the call back over to Marcus for closing remarks. That's great. Yeah, thanks. And just like we thank you to everyone for dialing in today and obviously look forward to presenting more and updating you in the course of this year. Thanks everyone.

Kelly: Think from here I am fairly confident that.

Andrew Funderburke: It's a great question I think logic, clearly I think starting off starting off with the second line.

Kelly: This molecule can hit their mark in vivo in patients with <unk>, but again the exact percentage of course, it really depend on.

Markus Warmuth: That's great. Yeah, thanks. I'd just like brief thank you to everyone for dialing in today. Obviously look forward to presenting more and updating you in the course of this year. Thanks, everyone.

Andrew Funderburke: The combination with <unk> essentially on their agenda substrate businesses.

Kelly: Sort of the actual Dcs you're treating in.

Andrew Funderburke: It's probably a good starting point, but ICD potential applications have definitively beyond that so essentially.

Kelly: The tissue.

Kelly: You're measuring cytokine secretion <unk> inhibition thereof.

Operator: This does conclude today's conference call. Thank you for participating. You may now disconnect.

Operator: This does conclude today's conference call. Thank you for participating. You may now disconnect.

Andrew Funderburke: In a way I mean, youre target might be ended up as the coverage of the same population as optimized currently cover those which is actually both calculated resistant prostate cancer.

Kelly: Congrats again, thank you.

Speaker Change: And the next question comes from Edward <unk> with Piper Sandler Your line is open.

Edward: Great. Thanks, good morning, and thanks for the very thorough.

As well as the company sensitive prostate cancer, so actually listening to your ultimate liquidation population you can target or is this is actually quite growth.

Speaker Change: Sense of update today.

Speaker Change: My question has to do with the <unk>.

Speaker Change: Cancer.

Andrew Funderburke: And would you.

Speaker Change: Focus on prostate cancer, which makes a lot of sense.

Envision combination trials in the future. Thanks.

Matt: Obviously as Matt.

Matt: Let me go through multiple cycles.

Andrew Funderburke: The combination of combination trials beyond.

Matt:

Andrew Funderburke: The owned.

Matt: Including.

Matt: Androgen deprivation therapy.

The combination of <unk>.

Matt: <unk> and abiraterone.

Andrew Funderburke: It's certainly a possibility I mean, there doesn't seem to be.

Matt: Their mutational burden exchanges.

Andrew Funderburke: It doesn't seem to be any.

Matt: Do you see.

Andrew Funderburke: Significant additional flexibility by combining these two these two drugs together. So I think it's definitely definitely combinable etsy, the first step would be.

Matt: Deal application is 42359.

Matt: What kind of combinations do you think are worth exploring thank you.

Andrew Funderburke: To develop this as a combination of on the origin.

Andrew Funderburke: <unk>.

Matt: Yes.

Andrew Funderburke: Potentially again, either intersected one or even into first line. When there is a possibility to potentially replace combination of endogenous <unk> inhibitor as chemotherapy.

Matt: It's a great question I think logically I think starting off starting the second line and the <unk>.

Matt: Combination with drugs like <unk> to essentially on their agenda subsidiary inhibited us.

Andrew Funderburke: Great. Thanks.

Matt: It's probably a good starting point, but I think the potential applications are definitely beyond that so essentially.

Marc Frahm: And our next question will come from Marc Frahm with TV Cowen Your line is open.

Matt: <unk>.

Marc Frahm: Hi, Thanks for taking my questions and I think through it.

Matt: In a way I mean, youre target might be ended up as the coverage of the same population as well.

Marc Frahm: Very comprehensive presentation, maybe on that one.

Matt: <unk> currently cover us, which is actually both calculate resistant prostate cancer.

Speaker Change: The site.

Marc Frahm: So I became changes that youre able to show in the ex vivo simulation.

Matt: As well as the complete sensitive prostate cancer, so actually listening to your ultimate preservation population you can target or is this is actually quite road.

Marc Frahm: It's in the context of maybe what's been achieved with maybe a b cell directed therapy like a PTK or.

Matt: And would you and <unk>.

Marc Frahm: Or on the T cell side with more of the T cell specific therapies.

Matt: Combination trials in the future. Thanks.

Marc Frahm: <unk> hundred 17 inhibitors and other.

Matt: The combination of combination trials beyond.

Marc Frahm: Single cytokine mechanisms just okay, but the context of.

Matt: The old.

Marc Frahm: This brought inhibition kind of what are you achieving on each side of the equation and then also with the with the dosing just the PK and the Mad dosing looks like Youre getting very sustained.

Matt: The combination of is a low watermark.

Matt: It's certainly a possibility I mean, there doesn't seem to be.

Matt: It doesn't seem to be any.

Matt: Significant additional toxicity by combining <unk> together, so I think it's definitely definitely combinable, let's see the first step would be.

Marc Frahm: Pressure to grab one should we think about extended dosing beyond once daily to maybe test a weekly or anything like that in some of these.

Matt: Develop this is a combination of.

Marc Frahm: Trials that are to come.

Matt: On the origin of that agent.

Matt: Potentially again, either intersected one or even into first line dose.

Marc Frahm: Yes, I mean I'll start with your with your second question I think.

Matt: That is a possibility to potentially replace combination of endogenous <unk> inhibitor as chemotherapy.

Marc Frahm: High level.

Short statement tiers.

Speaker Change: I think what you saw in today's presentation of course.

Matt: Great. Thanks.

Marc Frahm: Creates.

Marc Frahm: And our next question will come from Marc Frahm with TV Cowen Your line is open.

Marc Frahm: A lot of Optionality.

Marc Frahm: In regards to.

Marc Frahm: Two dose regimens.

Marc Frahm: I think that's roughly our strengths of molecular.

Marc Frahm: Hi, Thanks for taking my questions.

Marc Frahm: <expletive> readers in general I've received the catalytic mechanism.

Marc Frahm: Thanks for that.

Marc Frahm: Very comprehensive presentation, maybe on that one.

Of course, depending a little bit on sort of what the DB synthesis reader for protein munis.

Marc Frahm: The cytokine.

Marc Frahm: Cytokine changes that Youre able to show in the ex vivo simulation.

Marc Frahm: And the daily dosing is not the only option you have and I think that can create interesting.

Marc Frahm: In the context of maybe what's been achieved with maybe a b cell directed therapy that could PTK or.

Marc Frahm: Opportunities.

Marc Frahm: <unk>.

Marc Frahm: Yeah.

Marc Frahm: Or on the T cell side with more of the T cell specific therapies.

Marc Frahm: How we compare to two other molecules.

Marc Frahm: I would say really very right.

Marc Frahm: <unk> hundred 17 inhibitor is another single.

Marc Frahm: Single cytokines.

Marc Frahm: Sure I mean, we looked at what does a PTK inhibitor too.

Marc Frahm: Just to put the cart.

Marc Frahm: Text of this.

Marc Frahm: This brought inhibition kind of what are you achieving on each side of the equation and then.

Marc Frahm: Clinical doses.

Marc Frahm: What are the IL 17.

Marc Frahm: With the.

Marc Frahm: The dosing just the PK.

Marc Frahm: And.

Marc Frahm: <unk> three antagonist stewing.

Marc Frahm: <unk> dosing it looks like Youre getting very sustained suppression of Avalon should we think about extended dosing.

No I think we compete very favorably here obviously.

Marc Frahm: <unk> once daily to maybe test that weekly or anything like that in some of these.

Marc Frahm: Not every healthy volunteer trial and that space has been reported out in.

Marc Frahm: As trials that are to come.

Marc Frahm: And we actually project called <unk> used interferon gamma law, because that seems to be the one everyone looks at.

Yes.

Marc Frahm: Stock with your with your second question I think.

Marc Frahm: And I would say clearly hit the mark here.

Marc Frahm: High level.

Marc Frahm: Short statement tiers.

Marc Frahm: Up to 99% inhibition it doesn't mean that we need to get some 99% but.

I think what you saw in today's presentation of course.

Marc Frahm: Creates.

Marc Frahm: A lot of Optionality in regards to two dose regimens I think that's certainly a strength of molecular.

Marc Frahm: I think it's great.

Marc Frahm: So happy to see that and then obviously adjust the dose as you want to get to whatever level. You think is best for your indication.

Marc Frahm: <expletive> readers in general I've received the catalytic mechanism.

Marc Frahm: Of course, depending a little bit on sort of what the DB synthesis reader for protein. This.

Marc Frahm: Okay. That's very helpful. Maybe just on the prostate cancer expansion cohort.

Marc Frahm: And the daily dosing is not the only option you have and I think that can create interesting.

Marc Frahm: Recognize it's up to 20 to 30 or are there kind of.

Marc Frahm: Any interim gating factors, we should think about in terms of enrollment through the rest of the year.

Marc Frahm: Opportunities.

Marc Frahm: <unk>.

Marc Frahm: How we compare to two other molecules.

Marc Frahm: Yes.

Marc Frahm: Yes, I mean, its assignment states showed signs of this in interim.

Marc Frahm: Although I would say really value item.

Marc Frahm: Sure I mean, we looked at what does a PTK inhibitor to.

Marc Frahm: Efficacy Readouts again.

Marc Frahm: Admittedly this is early.

Marc Frahm: At clinical doses.

Marc Frahm: But as we said Super Super encouraging.

Marc Frahm: What are the IL 17.

Marc Frahm: And.

Marc Frahm: With that.

Marc Frahm: <unk> three antagonist stewing.

Marc Frahm: Im response.

Marc Frahm: Steve would you seizes and.

Marc Frahm: Again, I think we compare very favorably here obviously.

Marc Frahm: It's clearly helped us obviously to gain excitement and momentum on an enrollment and so it is an interim efficacy.

Marc Frahm: Not every healthy volunteer trial and that space has been reported out in.

Marc Frahm: Criteria.

Marc Frahm: Not every assay project quality to same used interferon gamma allot across that seems to be the one everyone looks at.

Marc Frahm: Ed.

Marc Frahm: We look at for full expansion to 20 to 30, but of course.

Marc Frahm: I would say, we clearly hit the Mark here.

Marc Frahm: Not as simple as looking at a response rate bar because I think you also need to look at how heavily are these.

Marc Frahm: Up to 99% inhibition it doesn't mean that we need to get some 99%.

Marc Frahm: Being pretreated.

Marc Frahm: Needless to say we've been looking at.

Marc Frahm: I think it's great.

Marc Frahm: Early data not the recently released speeds in the early phase one data from.

Marc Frahm: To have that to see that and then obviously adjust the dose as you want them to to get to whatever whatever you think is best for your indication.

Marc Frahm: From Pfizer.

Marc Frahm: And the combination with <unk>.

Marc Frahm: <unk> two inhibitor.

Marc Frahm: Sorted out I think are our patient population here is more heavily pretreated.

Marc Frahm: Okay. That's very helpful. Maybe just on the prostate cancer expansion cohort.

Marc Frahm: Everyone not just the one.

Marc Frahm: Recognize it's up to 20 to 30 or are there any.

Marc Frahm: Wherever you have accurate assessment they once it has been enrolling since.

Marc Frahm: The interim gating factors, we should think about in terms of enrollment through the rest of the year.

Marc Frahm: Some form of a mutation in the androgen receptor pathway and so obviously, we have to put that into the equation.

Marc Frahm: Yes.

Marc Frahm: Yes, I mean, its assignment states showed signs of this as an interim efficacy readouts again.

Speaker Change: Thanks, Rob Im sure there was a lengthy answer to a relatively short question. The short answer is yes. There is an interim efficacy assessments to then go to the floor in 'twenty two thirds.

Marc Frahm: Admittedly this is early.

Marc Frahm: But as we said Super Super encouraging.

Marc Frahm: Okay.

Marc Frahm: Yeah.

Marc Frahm: With that.

Robert Driscoll: And our next question comes from Robert Driscoll with Wedbush. Your line is open.

Marc Frahm: In response to.

Marc Frahm: Steve will diseases.

Marc Frahm: Enter.

Marc Frahm: It's clearly helped us obviously to gain excitement and momentum on an enrollment and so it is an interim efficacy.

Robert Driscoll: Thanks, Good morning, guys. Congrats on all the progress here just a couple of questions.

Marc Frahm: Criteria.

Speaker Change: $23 59 for the breast.

Speaker Change: Breast cancer cohort, how are you thinking about the make buy them off there and I guess the potential patient population.

Marc Frahm: We look at for full expansion to 20 to 30, but of course, it's not as simple as looking at a response rate trial, because I think you also need to look at how heavily are these.

Speaker Change: And then second question just just any extended thoughts on why there appears to be this discrepancy between the preclinical data.

Speaker Change: Hum.

Marc Frahm: Being pretreat and of course, needless to say we've been looking at.

Speaker Change: Clinical data.

Speaker Change: Biomarker.

Speaker Change: Commscope loss.

Marc Frahm: Early data not beat the recently released speeds in the early phase one data from from Pfizer.

Speaker Change: Yeah, So let's start with restaurants or you look at breast Gary.

Marc Frahm: And the combination with <unk>.

Marc Frahm: <unk> two inhibitor.

Speaker Change: In a very similar way as we look across your product our pre clinical data immediately and SATA lines in PD axis.

Marc Frahm: <unk> started out I think are our patient population here is more heavily pretreated.

Marc Frahm: Everyone not just the one.

Speaker Change: Suggested semic high expression is very widespread.

Marc Frahm: Wherever you have accurate assessment once it has been enrolling since <unk>.

Speaker Change: We don't think we need to home in on a particular sub population just like foresee RPC.

Marc Frahm: Some form of a mutation in the androgen receptor pathway and so obviously, we have to put that into the equation.

Speaker Change: No need to have a companion diagnostic.

Speaker Change: Thanks, Rob Im sure there was a lengthy answer to relatively short question and the short answer is yes. There is an interim efficacy assessments to then go to the $4 20 to 30.

Speaker Change: <unk> sensing and trust like you alluded to this interplay between <unk> and <unk>.

Speaker Change: We see this score.

<unk> and <unk>.

Speaker Change: As well.

Marc Frahm: Okay.

Speaker Change: But again.

Marc Frahm: Thank you.

Speaker Change: And our next question comes from Robert Driscoll with Wedbush. Your line is open.

Speaker Change: This quarter lacks a little bit behind and so you don't really have.

Speaker Change: Any detail yet.

From from that cohort two shea.

Robert Driscoll: Thanks, Good morning, guys. Congrats on all the progress here just a couple of questions.

Speaker Change: In regards to biomarker positivity.

Speaker Change: $23 59 for the breast cancer cohort how are you thinking about the mix by market Theyre in.

Speaker Change: Sure.

Speaker Change: You'll have to scratch your head right. When you see then re.

Speaker Change: We spent a lot of time.

Robert Driscoll: Central patient population.

Looking at.

Robert Driscoll: And then second question just just any extended thoughts on why there appears to be this discrepancy between the preclinical data.

Speaker Change: The overall data sets.

Speaker Change: Not just cell line or pdx data even.

Speaker Change: <unk> sure.

Robert Driscoll: Okay.

Robert Driscoll: Clinical data.

Speaker Change: I think youre, probably looking at a situation where.

Robert Driscoll: Biomarker.

Robert Driscoll: Thanks.

Speaker Change: Our clinical trial population is more heavily pretreated than what you typically get industrial growth data sets not mentioning the companies regarding data from them, but definitely more heavily pretreated.

Speaker Change: Yes, so let's start with breast right. So if you look at breast vary.

Speaker Change: In a very similar way as we look at prostate biotech our preclinical data immediately and SATA lines in PD axis.

Speaker Change: And we're using a different assay and again sure.

Speaker Change: We try to make sure that these assays somehow met shopping.

Speaker Change: Suggested <unk> high expression is very widespread.

Speaker Change: It's not completely off by about <unk> seven.

Speaker Change: We don't think we need to come in on a particular sub population just like foresee RPC.

Speaker Change: 70% to 80% as predicted versus 30% that is a huge difference and honestly made small cell lung cancer for us.

Speaker Change: No need to have a companion diagnostic.

Speaker Change: In that setting and trust like beef alluded to this interplay between <unk> and <unk>.

Speaker Change: A lot more less attractive one top of perspective again sure standard of cares that population has changed and certainly.

Speaker Change: We see this for.

Speaker Change: Semic and ER as well.

Speaker Change: You are now current study population isn't any easier to treat I think thats all our best explanation.

Speaker Change: But again.

Speaker Change: This cohort lacks a little bit behind and so you don't really have.

Speaker Change: Any detail yet.

Speaker Change: Im sure part of for now.

Speaker Change: From from that cohort two shea.

Speaker Change: Now focusing we saw the data we have the totality of the data that we have on prostate cancer makes a ton of sense.

In regards to biomarker positivity.

Speaker Change: Sure.

Speaker Change: You all just scratch your head right. When you see you then.

Speaker Change: Perfect. Thank you.

Speaker Change: Spent a lot of time.

Michael Schmidt: And the next question will come from Michael Schmidt with Guggenheim. Your line is open.

Speaker Change: Looking at Rio.

Speaker Change: Real World data sets.

Speaker Change: Not just cell line or pdx data even.

Speaker Change: <unk> I'm sure.

Michael Schmidt: Michael Your line is now open.

Speaker Change: I think youre, probably looking at a situation where.

Michael Schmidt: Thanks for taking my questions.

Speaker Change: Our clinical trial population is more heavily pretreated than what you typically get industrial growth data sets not mentioning the companies, we got the data from but definitely more heavily pretreated.

Michael Schmidt: Question on.

Michael Schmidt: On <unk>, obviously, the safety profile looks very clean.

Michael Schmidt: As you described it.

Michael Schmidt: Are there any expected on target side effects that you're paying attention to for example infections or.

Speaker Change: And we're using a different assay and again sure.

Speaker Change: Try to make sure that these assays somehow met sharpen.

Michael Schmidt: Thanks.

Michael Schmidt: Very interesting.

Speaker Change: It's not completely off fiber true like small cell.

Speaker Change: 70% to 80% as predicted versus 30% that is a huge difference and honestly made small cell lung cancer for us.

Michael Schmidt: So you were breaking up a bit.

Michael Schmidt: <unk> based on what I thought I understood so on target potential on target toxicities.

Speaker Change: A lot more less attractive on top of the expected again sure standard of cares that population has changed and certainly.

Michael Schmidt: I would say.

Michael Schmidt: Really non based on the preclinical data we have.

Michael Schmidt: Obviously.

Speaker Change: You are now current study population doesn't any easier to treat and I think that's our best explanation and again <unk>.

Michael Schmidt: <unk>.

Michael Schmidt: <unk> Tox study.

Michael Schmidt: So nothing no test article related findings and be dose extremely high you talked about the states a while ago and we have margins here for 500 food.

Speaker Change: Now focusing resulted data behalf.

Speaker Change: <unk> of the data we have on prostate cancer makes a ton of sense.

Speaker Change: Our boss.

Michael Schmidt: Based on.

Speaker Change: Perfect. Thank you.

Michael Schmidt: Isolating this off either red or where sandoz.

Michael Schmidt: And the next question will come from Michael Schmidt with Guggenheim. Your line is open.

Michael Schmidt: All the information we have I mean, you did immune phenotyping and Cmos on such as this immune modulators.

Speaker Change: Yeah.

Michael Schmidt: England suppressor.

Speaker Change: Michael Your line is now open.

Michael Schmidt:

Michael Schmidt: Can you absolutely excludes.

Speaker Change: Thanks for taking my questions.

Michael Schmidt: Excludes infection risk.

Speaker Change: Question on.

Speaker Change: I would say no I think no one in this field nobody in ini.

Speaker Change: One obviously the safety profile is very clean.

Ken: Ken actually quite a few vantage Melissa I think it's August the year as a risk.

Speaker Change: As you described it.

Speaker Change: Are there any expected on target side effects that you're paying attention to for example infections or other things.

Speaker Change: Again based on everything we've seen so far.

Speaker Change: We're not concerned at all obviously the square.

Speaker Change: Interesting.

Speaker Change: Longer term Tox studies.

Speaker Change: And then this route and we haven't disclosed any details there, but I think we did make a statement in today's presentation that.

Speaker Change: So you were breaking up a bit.

Speaker Change: <unk> based on what I thought I understood so on target potential on target toxicities.

Speaker Change: Clinical data combined received the long term talks.

Speaker Change: I would say.

Speaker Change: We now have gives us a lot of confidence index a clear path.

Speaker Change: Really non based on the preclinical data we have.

Speaker Change: Okay, great. Thanks, and then.

Speaker Change: Obviously.

On the PD one program just sort of reconciling some of the data that was presented today.

Speaker Change: <unk>.

Speaker Change: <unk> Tox study.

Speaker Change: So nothing no test article related findings can be dosed extremely high you talked about the states are by logo and we have margins here for 500 food.

Speaker Change: If you looked at correlating.

Speaker Change: BT, one degradation with clinical activity in patients.

Speaker Change: So far and.

Speaker Change: Our boss.

Speaker Change: I don't know if you disclose that.

Speaker Change: Based on.

Speaker Change: Tumor type that that one responder in the biomarker positive patients was the lung cancer patient or neuroendocrine and then thanks for the.

Speaker Change: Isolating this off either red or worse, who knows.

Speaker Change: Sure.

Speaker Change: All the information we have I mean, you did in UN phenotyping and Sandoz on such as this immune modulators.

Speaker Change: Spots.

Speaker Change: Sure.

Speaker Change: Yes.

Speaker Change: Yes, so the.

Speaker Change: <unk> suppressive.

Speaker Change: The PR that we saw in the.

Speaker Change: Can you absolutely excludes.

Speaker Change: The biomarker positive.

Speaker Change: Excludes infection risk.

Speaker Change: Patient.

Speaker Change: I would say no I think no one in dispute nobody in ini.

Speaker Change: During dose escalation Deb wasser, neuroendocrine bladder characterized by extremely high expression of offer and Nick.

Speaker Change: Ken actually quite a few dented Louis I think it's August the year as a risk.

Speaker Change: Again based on everything we've seen so far.

Speaker Change: Almost.

Speaker Change: It's quality of signature.

Speaker Change: We're not concerned at all obviously this graph.

Speaker Change: Patient for the setting, but again fair to CMV disgusted.

Speaker Change: Longer term Tox studies.

Speaker Change: That sort of high end the population on Saturday Wassa like Greer.

Speaker Change: And then as well and we haven't disclosed any details Durban I think we did make a statement in today's presentation that.

Speaker Change: Not as frequent as we had hoped even in your endocrine tool.

Speaker Change: Clinical data combined with feed the long term talks.

Speaker Change: Tumors, but again certainly.

Speaker Change: We now have gives us a lot of confidence index a clear path.

Speaker Change: Ah patient.

Speaker Change: It.

Speaker Change: It gives us confidence that the.

Speaker Change: Okay, great. Thanks, and then.

Speaker Change: The drug works.

Speaker Change: Of course.

Speaker Change: The patient we saw.

Speaker Change: On the cheese PD one program just reconciling some of the data that was presented today.

Speaker Change: The 60% degradation of the cheese Pizza you won in totality or so its not many patients as you can tell.

Speaker Change: If you looked at correlating.

Speaker Change: PT, one degradation with clinical activity in patients so.

Speaker Change: In the biomarker positive you've seen very decent level of degradation, 60% to 70% in line with.

Speaker Change: So far and.

Speaker Change: I don't know if you disclosed.

Speaker Change: Tumor type.

Speaker Change: The preclinical data and expectation.

Speaker Change: One responder in the biomarker positive patients with lung cancer patient or Noranda frame and then thanks for the responses.

Speaker Change: You have not received yet.

Any data from from prostate, mostly because not just more street simply because you were unable to get the paired biopsies.

Speaker Change: Good.

Speaker Change: Yeah. So the.

Speaker Change: The PR that we saw in the.

Speaker Change: These are not.

Speaker Change: Trivial thanks again.

Speaker Change: The biomarker positive.

Speaker Change: Happy when we get the screening biopsies.

Speaker Change: Patient.

Speaker Change: We've done really value they are getting that second biopsy again, we have a very decent success rates.

Speaker Change: During dose escalation that was.

Speaker Change: Neuroendocrine bladder characterized by extremely high expression of offer and mix.

Speaker Change: So about a third application spun we're not getting that on everyone and uncertainty for our prostate be having a cup of tea at the San Francisco.

Speaker Change: Almost a year.

Speaker Change: It's quality of signature.

Speaker Change: Yeah.

Speaker Change: Patient for the setting, but again fair to say and we've discussed it.

Speaker Change: Thank you.

Speaker Change: The next question comes from Eric Joseph with Jpmorgan. Your line is open.

Speaker Change: That's sort of high end Mitt population Saturday was.

Eric Joseph: Thanks for taking my questions good morning, maybe.

Speaker Change: Greer.

Speaker Change: Not as frequent as we had hoped even in euro endocrine.

Speaker Change: Maybe just.

Eric Joseph: One question on the VAT one program.

Speaker Change: Tumors, but again certainly.

Eric Joseph: Anything you can share at this point in terms of how novartis might be thinking about duration.

Speaker Change: Ah patient.

Speaker Change: It gives us confidence that the two.

Eric Joseph: The initial phase II trial.

Speaker Change: The drug works.

Speaker Change: Of course.

Eric Joseph: And I Wonder if you are just given the.

Speaker Change: Their patient we saw.

Speaker Change: The 60, some percent degradation of the cheese pizza one in totality, although its not many patients and as you can tell.

Eric Joseph: The seven day, Matt.

Eric Joseph: And that portion of the study is there any chance of.

Eric Joseph: Uh huh.

Eric Joseph: I guess I'm asking around comfort on the safety side, whether you expect any sort of intermediate.

Speaker Change: In the biomarker positives, you've seen very decent leverage degradation, 60% to 70% in line with.

Eric Joseph: Link.

Eric Joseph: Phase <unk> trial before moving into a longer randomized phase III program and then.

Speaker Change: The preclinical data and expectation.

Speaker Change: You have not received yet.

Eric Joseph: The <unk> one program.

Speaker Change: Any data from from prostate, mostly because not just mostly simply because you were unable to get the paired biopsies.

Eric Joseph: Just having focused in prostate cancer going forward.

Eric Joseph: And can you just talk a little bit about your sense of how.

Eric Joseph: Mick expression trucks with mine of treatment.

Speaker Change: Is a lot.

Speaker Change: Trivial thanks again.

Speaker Change: Yes, happy when we get the screening biopsies.

Eric Joseph: Whether there is any.

Eric Joseph: I guess the variation.

Speaker Change: We've done really value they are getting that second biopsy again, we have a very decent success rates.

Eric Joseph: <unk>.

Eric Joseph: Patients are more heavily pretreated.

Eric Joseph: Thanks.

Speaker Change: So about a third application spun we're not getting that on everyone and uncertainty for our prostate be having company be it the <unk> samples yet.

Eric Joseph: Yes, so I'll start on the.

Eric Joseph: You have asked one question.

Eric Joseph: I think again best answer I can give you is.

Speaker Change: Thank you.

Speaker Change: The next question comes from Eric Joseph with Jpmorgan. Your line is open.

Eric Joseph: Broken progress.

Eric Joseph: Try designs are being worked on.

Eric Joseph: Thanks for taking my questions good morning, maybe.

Eric Joseph: No details to disclose.

Speaker Change: Maybe just.

Speaker Change: One question on the <unk> program.

Eric Joseph: The best assumption hears.

Eric Joseph: Pretty much going to be standard designs.

Speaker Change: Anything you can share at this point in terms of how novartis might be thinking about duration.

Eric Joseph: I think with regards to the <unk> software.

Speaker Change: The initial phase III trial.

Eric Joseph: The treatment in that yes, it's seven doses, but of course the upside here.

Speaker Change: And I Wonder here just given the.

Speaker Change: The seven day Mad portion of this study is there any chance of.

Eric Joseph: We were able to see in the presentation.

Speaker Change: Yes.

Eric Joseph: Raekwon leveraged down for an additional seven days so from a safety assessment.

Speaker Change: Asking around comfort on the safety side, whether you expect any sort of intermediate.

Eric Joseph: We see additional one week of collecting safety observations Rod we've essentially recorded.

Speaker Change: Link.

Speaker Change: <unk> type trial before moving into a longer randomized phase III program.

Speaker Change: And then on.

Eric Joseph: Two weeks off low back on with a total of <unk> observation on them and so I think.

Speaker Change: The <unk> one program.

Speaker Change: Just having focused in prostate cancer going forward.

Eric Joseph: Yeah.

Speaker Change: Can you just talk a little bit about your sense of how.

Eric Joseph: But whatever the lengths of these are phase III as our brand reasonably quick <unk> P M.

Speaker Change: <unk> expression tracks with line of treatment.

Eric Joseph: And so again.

Eric Joseph: I've said it multiple times.

Speaker Change: Whether there is any.

Eric Joseph: Sounds like a broken record, but this really gives us a clear path introduced.

Speaker Change: I guess some variation.

Speaker Change: <unk>.

Speaker Change: Ah patients that are more heavily pretreated.

Eric Joseph: Phase III trials.

Eric Joseph: Yeah.

Speaker Change: Thanks.

Eric Joseph: On the $23 59 in Semic again, and Thats why why we are so excited about it.

Speaker Change: Yes, so I'll start on the.

Speaker Change: Youre back one Christian.

Eric Joseph: <unk> seen.

Eric Joseph: <unk> op and correlating to arm.

Speaker Change: I think again best answer I can give furious.

Speaker Change: Broken progress.

Eric Joseph: Throughout.

Eric Joseph: C.

Speaker Change: Try designs are being worked on.

Eric Joseph: The lifecycle of prostate cancer is kind of a weird name.

Speaker Change: No details to disclose.

Eric Joseph: And so I think that makes it a lot easier said as some of these smaller Ellen and Mick indications sorry, because.

Speaker Change: The best assumption years.

Pretty much going to be standard designs.

Speaker Change: I think with regards to the lengths offer.

Eric Joseph: As soon as you have an AI driven cancers hemic seems to be.

Speaker Change: The treatment in that yes, it's seven doses, but of course the upside here.

Eric Joseph: Quite relevant and almost the year so no needs to go in and to define the expression levels upfront.

Speaker Change: We were able to see in the presentation.

Speaker Change: <unk> leverage stay down for an additional seven days so from a safety assessment.

Eric Joseph: Again early right, but so far.

Eric Joseph: The data we're seeing.

Speaker Change: With the additional one week of collecting safety observations right, we've essentially recorded.

Eric Joseph: And many of you sort of confirm spin.

Eric Joseph: Okay.

Speaker Change: Two weeks off low vast one.

Eric Joseph: Okay. Thanks for taking the questions.

Speaker Change: <unk> observation on them and so I think.

Speaker Change: The next question comes from Ellie Merle with UBS. Your line is open.

Speaker Change: Sure.

Speaker Change: But whatever the lengths of these phase III as our brand reasonably good shape here.

Speaker Change: Hi, This is Jasmine Entre Ali thanks for the update and a question a couple on next.

Speaker Change: And so again.

Speaker Change: I've said it multiple times.

Speaker Change: It sounds like a broken record, but this really gives us a clear path introduced.

Speaker Change: Can you remind us.

Speaker Change: The level of degradation that you'd like to see here in Q b potentially supportive of efficacy and then.

Speaker Change: Phase III trials.

Speaker Change: On on $23 59 in Semic again, and Thats why we are so excited about it.

Speaker Change: Can you elaborate a bit on the decision to play out in the phase one proof of concept in the pericarditis population versus some other options. Thank you.

Speaker Change: You've seen.

Speaker Change: <unk> op and correlating to arm.

Speaker Change: Really throughout.

Speaker Change: I start with fee.

Speaker Change: The.

Speaker Change: Expected.

Speaker Change: The lifecycle of our prostate cancer is kind of a weird name.

Speaker Change: Degradation and I know Thats always a favorite question.

Speaker Change: And so I think that makes it a lot easier asset as some of these smaller Ellen and Mick indication so I because.

Speaker Change: From folks and I'd say again, if you just look at the data we have in the stack in previous decks at 2% degradation.

Speaker Change: As soon as you have an AI driven cancers hemic seems to be.

Speaker Change: At least in the ex vivo stimulation assay.

Speaker Change: Quite relevant and almost the year, so no needs to go in and to define expression levels up.

Speaker Change: <unk> can.

Speaker Change: Can give us pretty much 100% inhibition of secretion of IL, one beta and so I would say.

Speaker Change: Again early right, but so far.

Speaker Change: 80% is probably what we're aiming for.

Speaker Change: Data receding.

Speaker Change: The single and multiple ascending dose studies.

Speaker Change: Many of these sort of confirm spin.

Speaker Change: As Orbis I throw out sort of the precautionary distribute also depend a little bit on <unk>.

Speaker Change: Okay.

Speaker Change: Okay. Thanks for taking the questions.

Speaker Change: Yeah.

Speaker Change: The next question comes from Ellie Merle with UBS. Your line is open.

Speaker Change: What we have in this presentation is based on best firms.

Speaker Change: As we go into the clinic, obviously, BVO switchover to flow cytometry, because that has proven.

Jasmine: Hi, This is Jasmine for Ali Thanks for the update and our question a couple on next.

Speaker Change: Very robust in our back one trial definitely less noise scared and especially on the work you've been targeted mass spec, which we had actually used for RMC SPT one enough students using.

Speaker Change: First can you remind us.

Speaker Change: The level of degradation that you'd like to see here in Q b potentially supportive of efficacy.

Speaker Change: Can you elaborate a bit on the decision to play out in the phase one proof of concept in the pericarditis population versus some other options. Thank you.

Speaker Change: Or do you want to address the pericarditis question.

Speaker Change: Yes.

Speaker Change: So let me start guidance is obviously like one of the indications both I mean, the next seven indication even into cardio immunologist base is actually much much broader much broader than that.

Speaker Change: I'll start briefly.

Speaker Change: Expected.

Speaker Change: Segregation and I know, that's obviously a favorite question.

Speaker Change: Both of those actually nice about pericarditis.

Speaker Change: The development pathway is actually relatively well defined.

Speaker Change: From folks and I'd say again, if you just look at the data we have in this tag in previous decks, 80% degradation.

Speaker Change: And.

Speaker Change: Definitely scalable does that answer your question or the date leave something out.

Speaker Change: At least in the ex vivo stimulation assay.

Speaker Change: Yeah No that's helpful. Thank you.

Speaker Change: <unk>.

Speaker Change: Okay.

Speaker Change: Can give us pretty much 100% inhibition of secretion of IL, one beta and so I would say.

Speaker Change: Hi.

The next question will come from Derek <unk> with Wells Fargo. Your line is open.

Speaker Change: 80% is probably what we're aiming for.

Speaker Change: Good morning. This is <unk> on for Derik, Thanks for taking our question.

Speaker Change: The single and multiple ascending dose studies.

Speaker Change: Sure.

Speaker Change: A couple from us so first on the <unk> one program kind of like what are the gate keeping steps remaining to initiate the phase two study have you Sherry there any specific milestone triggered by the initiation of this study.

Speaker Change: As rvs I throw out sort of the precautionary distribute also depend a little bit on <unk>.

Speaker Change: What we have in this presentation is based on best firms.

Speaker Change: As we go into the clinic, obviously vivo switchover to flow cytometry, because that has proven.

Speaker Change: And on the <unk> program, just how much data should we expect in the second half of the year update for the prostate cancer cohort. Thanks.

Speaker Change: We are very robust and our back one try and definitely less noise scared in restaurant or even targeted mass spec, which we had actually used for RMC SPT wanted us to using.

Speaker Change: So on that one.

Speaker Change: I mean, you saw the year.

Speaker Change: Do you want to address the pericarditis Christian.

Speaker Change: The clinical data are absolutely everything we need to know from the Fad Matt.

Yes.

Speaker Change: So let me start guidance is obviously like one of the indications both I mean, the next indication even into cardio immunologist base is actually much much broader much broader than that.

Including safety of course, which looks very favorable this year.

Speaker Change: Just a couple of reaching.

Speaker Change: Switching studies that are being done.

Speaker Change: <unk>.

Speaker Change: <unk>.

Speaker Change: Formulation so to get to.

Speaker Change: It's actually nice about pericarditis.

Speaker Change: The development pathway is actually relatively well defined.

Speaker Change: Something thats more scalable for larger trials or even four liter commercialization and then.

Speaker Change: And.

Speaker Change: Definitely scalable does that answer your question or the date leave something out.

Speaker Change: The typical things that need to be nonprofit causes me to be written.

Speaker Change: Yeah No that's helpful. Thank you.

Speaker Change: And presented to the FDA is from.

Speaker Change: Okay.

Speaker Change: Again, I think like most of the brookstone clear path into.

Speaker Change: Hi.

Speaker Change: The next question will come from Derek <unk> with Wells Fargo. Your line is open.

Speaker Change: Phase III studies, known <unk>, 23, 59 and the miles.

Speaker Change: Oh.

Speaker Change: Alright back to F. One milestones, yes, there are.

Speaker Change: Good morning. This is <unk> on for Derik, Thanks for taking our questions.

Speaker Change: Phase III initiation milestones.

Speaker Change: A couple from Ross So first on the <unk> one program kind of like what are the gating steps remaining to initiate the phase two study have you Sherry there any specific milestones trigger by the initiation of this study.

Speaker Change: Our agreement.

Speaker Change: Thanks, and then just one question was how much should we expect in the second half of the year update for the prostate cancer cohort.

Speaker Change: And on the <unk> program, just how much data should we expect in the second half of the year update for the prostate cancer cohort. Thanks.

Speaker Change: Yes, I mean again hesitant to give you a specific patient number beyond what we said why do I think we can expand here.

Speaker Change: So RAF water.

Speaker Change: I mean, you saw the.

Speaker Change: On on pre specified criteria into 20 to 30.

Speaker Change: The clinical data are so everything we need to know from the fat in that.

Speaker Change: <unk>.

Speaker Change: Including safety of course, which looks very favorability this year.

Speaker Change: I think the excitement from the investigators as theorem.

Speaker Change: Just a couple of.

Speaker Change: I think that's going to be.

Speaker Change: Switching studies that are being done.

Speaker Change: A sizable.

Speaker Change: Roland.

Upgrades by the second half of the year in regards to the number of patients we would have treated but again I'm hesitant to give you a specific patient number.

Speaker Change: Formulation so to get to.

Speaker Change: Something thats more scalable for larger trials or even four liter commercialization and then.

Speaker Change: The typical things that needs to be done protocols need to be written.

Speaker Change: Thanks.

Speaker Change: And presented to the FDA soon.

Speaker Change: I show no further questions at this time I would now like to turn the call back over to Marcus for closing remarks.

Speaker Change: Again, I think like most of the <unk> path into.

Speaker Change: Phase III studies known <unk>.

Speaker Change: <unk> 23, 59 construction milestones.

Speaker Change: That's great yeah. Thanks, our interest like we thank you to.

Speaker Change: Actually sorry back to F. One milestones, yes, there are.

Speaker Change: Everyone for <unk>.

Speaker Change: Dialing into the <unk>.

Speaker Change: Obviously look forward to.

Speaker Change: Phase III initiation milestones.

Speaker Change: Presenting more and updating you in the course of this year. Thanks, everyone.

Speaker Change: And our agreement.

Speaker Change: This does conclude today's conference call. Thank you for participating.

Speaker Change: Thanks, Andrew.

Speaker Change: Just one question was how much data should we expect in the second half of the year update for the prostate cancer cohort.

You may now disconnect.

Speaker Change: Yes, I mean again hesitant to give you a specific patient number beyond what we said why do I think we can expand here based on pre specified criteria into 'twenty 230.

Speaker Change: Patients.

Speaker Change: Okay.

Speaker Change: Thank the excitement from the investigators as theorem.

Speaker Change: So I think that's going to be.

Speaker Change: A sizable.

Speaker Change: Upgrades by the second half of the year in regards to number of patients.

Speaker Change: Half.

Speaker Change: Treated but again I'm hesitant to give you a specific patient number.

Speaker Change: Thanks.

Speaker Change: I show no further questions at this time I would now like to turn the call back over to Marcus for closing remarks.

Speaker Change: That's great yeah. Thanks, our interest like pre thank you too.

Speaker Change: Everyone for.

Speaker Change: Dialing in today.

Speaker Change: Im obviously look forward to.

Speaker Change: Presenting more and updating you in the course of this year. Thanks, everyone.

Speaker Change: This does conclude today's conference call. Thank you for participating you may now disconnect.

Speaker Change: Okay.

Speaker Change: [music].

Speaker Change: Okay.

Speaker Change: Okay.

Speaker Change: [music].

Speaker Change: Sure.

Speaker Change: Yes.

Speaker Change: Okay.

Speaker Change: [music].

Speaker Change: Yes.

Speaker Change: [music].