Q4 2021 IDEAYA Biosciences Inc Earnings & IDE397 Preliminary Clinical Data Update Call

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Good day and welcome to the IDEA Bioscience IDE397 Preliminary Clinical Data Update Conference call. Today's conference is being recorded. At this time, I would like to turn the call over to Yujiro Hara, CEO , IDEA Biosciences. Please go ahead.

Good day and welcome to the idea of Bioscience I D. E 397 preliminary clinical data update conference call. Today's conference is being recorded at this time I would like to turn the call over to use your IATA CEO idea of Biopharma Sciences. Please go ahead.

Yujiro Hara: Good morning, everyone. I'll be making some forward looking statements today. And today we're absolutely thrilled to provide a program update on I-397 as well as our Q1 2022 earnings update.

Good morning, everyone I'll be making some forward looking statements today.

And today, we're absolutely thrilled to provide a program update on 39 seven.

As well as our Q1 2022, our earnings update.

Full year end 2021 has been an absolutely transformational year for the company, we've been able to advance two programs in the clinic as well as make significant progress across two additional late stage preclinical programs.

Yujiro Hara: A full year in 2021 has been an absolutely transformational year for the company. We've been able to advance two programs in the clinic as well as make significant progress across two additional late-stage preclinical programs in PARG and Pall Theta.

And part and Paul data is.

Yujiro Hara: As part of this key advancement across our portfolio, today we'll be giving an additional update on the IE397 phase one dose escalation program.

As part of this she advancement across our portfolio today, we will be giving an additional update on the IAA 397 phase one dose escalation program.

Yujiro Hara: Before we begin, I wanted to thank all of the employees of IDEA and our partner GSK for its contributions to the ID397 program, both through our IDEA-GSK-MAT-SUED joint development committee, as well as the broader joint steering committee.

Before we begin I wanted to thank all the employees at my dad, and our partner GSK for its contributions to the <unk> 97 program, but also our idea of GSK bought to a joint development Committee as well as the broader joint steering Committee.

Yujiro Hara: GSK has been a phenomenal partner and invaluable in advancing our thinking on this program from both a monotherapy and combination development perspective.

GSK has been a phenomenal partner and invaluable in advancing our thinking on this program from both a monotherapy and combination development perspective.

Yujiro Hara: We also thank GSK for its review and approval of the presentation materials that we will share today.

We also think GSK for its review and approval of the presentation materials, but we will share today.

The focus of today's <unk> hundred 97 program update will be specifically on the data required to complete the GSK option data package.

Yujiro Hara: The focus of today's ID 397 program update will be specifically on the data required to complete the GSK option data package.

Yujiro Hara: which includes key preclinical pharmacodynamic data, clinical PK,

Which includes key preclinical pharmacodynamic data.

Clinical PK.

Clinical adverse events and clinical plasma and tumor pharmacodynamic data.

Yujiro Hara: and clinical plasma and tumor pharmacodynamic data.

At the end of the session. We will have an open the Q&A session with our analysts and we do ask for the portion of <unk> hundred 97% to keep the scope of the cautions to be within the data categories and whats enclosed in this presentation.

Yujiro Hara: At the end of this session, we will have an open Q&A session with our analysts, and we do ask for the portion of ID397 to keep the scope of the questions to be within the data categories and what's enclosed in this presentation. And that is the content that has been reviewed and approved by GSK under our partnership agreement.

And that is the content that has been reviewed and approved by GSK under our partnership agreement.

Yujiro Hara: In terms of the agenda for today, I will first start with providing a high-level profile on the GSK option data package requirements and a high-level overview of the collaboration economics.

In terms of the agenda for today I will first start with providing a high level profile on the GSK option data package requirements and a high level overview of the collaboration economics.

Yujiro Hara: Next, Dr. Matt Mauer, our head of clinical oncology, will provide a walkthrough on the Phase I-II Clinical Development Plan, the protocol amendment that has been submitted to the FDA to enable both the monotherapy expansion phase as well as the clinical combination initiation for this program.

Next Dr. Mark Bauer, our head of clinical oncology will provide a walkthrough on the phase one two clinical development plan.

The protocol amendment that has been submitted to the FDA to enable both the monotherapy expansion phase as well as the clinical combination initiation for this program.

Yujiro Hara: Next, Matt will provide an overview of the clinical pharmacokinetic data, as well as the favorable clinical adverse event profile that we've observed to date.

Next Matt will provide an overview of the clinical pharmacokinetic data.

As well as the favorable clinical adverse event profile that we've observed to date.

Matt Mauer: After that, Dr. Michael White, our Chief Scientific Officer, will provide a walkthrough of the ID397 pharmacodynamic data, including a very robust data set around the preclinical tumor pharmacodynamic data, as well as the clinical plasma and tumor pharmacodynamic data. And then lastly, a PKP analysis, as well as projected clinical efficacy time, the preclinical projections to our clinical.

After that Dr. Michael White, our Chief Scientific officer will provide a walkthrough of the IV <unk> hundred 90, <unk> pharmacodynamic data, including a very robust dataset around the preclinical tumor pharmacodynamic data as well as the clinical plasma and tumor Pharmacodynamic data and then lastly, our PK PD analysis.

As well as projected clinical efficacy tying the preclinical projections to our clinical uphold farmer.

Matt Mauer: both pharmacodynamic and pulmonary data.

Pharmacodynamic a preliminary data.

And then at the end I will provide a summary of the presentation today as well as next steps for this program.

Matt Mauer: And then at the end, I will provide a summary of the presentation today as well as next steps for this program.

And then we will transition to the next phase of the presentation you can give us a summary from our Q1 2022, our earnings update which Paul Stone, our Chief Chief Financial Officer, who will walk through.

Matt Mauer: And then we will transition to the next phase of the presentation and give a summary from our Q1 2022 earnings update, which Paul Stone, our Chief Financial Officer, will walk through.

Moving on to the next slide on Slide three this is a summary of the GSK option data package, both in terms of timing and scope of the data supporting the GSK opt in decision.

Paul Stone: Moving on to the next slide on slide three, this is a summary of a GSK option data package, both in terms of timing and scope of the data supporting the GSK opt-in decision.

Paul Stone: And as noted earlier, today's clinical data update on ID397 will be focused on these key parameters and data categories that are required under our agreement for the option data package.

And as noted earlier today's clinical data update on <unk> hundred 87 will be focused on these key parameters and data categories that are required under our agreement for the option data package.

In terms of preclinical data. The contents include both non clinical safety pharmacokinetic data and Pharmacodynamic data as well as in vivo efficacy.

Paul Stone: In terms of preclinical data, the contents include both nonclinical safety, pharmacokinetic data, and pharmacodynamic data, as well as in vivo efficacy.

Paul Stone: This data package is now complete and is being uploaded currently to the online data room.

This data package is now complete and has been uploaded currently to the online data room.

Paul Stone: Next, the clinical data requirements for the MATSUI option data package or GSK is safety and tolerability data, pharmacokinetic data, and pharmacodynamic data, both including plasma as well as tumor pharmacodynamic data.

Next the clinical data requirements for battery option data packages GSK is safety and Tolerability data.

Pharmacokinetic data and Pharmacodynamic data.

<unk>, including plasma as well as tumor pharmacodynamic data.

Paul Stone: Based on where we are in the dose escalation, which we are currently enrolling cohort six, we are targeting expansion for the monotherapy expansion phase in mid-year 2022.

Based on where we are in the dose escalation, which is we are currently enrolling cohort six we are targeting expansion for the monotherapy expansion phase in mid year 2022.

Paul Stone: In addition, based on where we are on the assembly of the data package to GSK, we also anticipate that we will deliver the option data package to GSK mid-year 2022.

In addition, based on where we are on the assembly of the data package to GSK. We also anticipate that we will deliver the option data package to GSK mid year 2022.

If GSK exercises its option there would be a $50 million option exercise fee due subject to HSR clearance.

Paul Stone: If GSK exercises as option, there will be a $50 million option exercise fee due subject to HCR clearance.

Paul Stone: If GSK elects to opt in, the cost split would modify to an 80-20% cost share, with GSK responsible for 80% of the cost moving forward, and IDEA for 20%.

If GSK elects to opt in the cost split.

The modified to an 80%, 20% cost share with GSK responsible for 80% of the cost moving forward an idea for 20%.

Paul Stone: Next, there will be a set of milestone payments that could be potentially due, including $465 million in development and regulatory milestones, as well as $475 million in sales milestones.

Next there will be a set of milestone payments that could be potentially do including $460 million by $1 billion in development and regulatory milestones as well as $475 million sales milestones.

Paul Stone: In addition, we have retained 50-50 U.S. profit splits, as well as ex-U.S. high single-digit to sub-teen double-digit percentage royalties.

In addition, we have retained 50 50 U S profit splits as well as ex U S high single digit to Subteen double digit percentage royalties.

Paul Stone: We believe this partnership structure with GSK in the scenario of opt-in is highly value accretive for our shareholders and enables a very cost-efficient fashion to advance this program in the finite cost.

We believe this partnership structure with GSK in the scenario of the opt in is highly value accretive for our shareholders and enables a very cost efficient.

To advance this program in the clinic.

Speaker Change: So with that, I will now pass it along to Dr. Matt Maurer, our Vice President, Head of Clinical Oncology, to go through the next phase of the presentation. Matt, we'll pass it on to you.

I will now pass it along to Dr. Mike Bauer, our vice President head of clinical oncology to go through the next phase of the presentation.

Pass it onto you.

Thank you Dear.

So on this slide you can see the the schedule. The 397 development plans from your comprehensive approach to proof of concept evaluation of both monotherapy and combinations.

Matt Maurer: So, on this slide, you can see the sketch of the 397 development plan showing a comprehensive approach to proof of concept evaluation of both monotherapy and combinations, which are supported by our preclinical evaluation.

Supported by our preclinical evaluations.

Matt Maurer: A parallel mono and combo strategy provides multiple shots on goal and optimizes our probability of uncovering transformational opportunities that can be rapidly brought to registrational follow-up studies.

Hello, Mono and combo strategy provides multiple shots on goal and optimize their probability of recovering transformational opportunities that can be rapidly brought two registrational follow up studies.

Matt Maurer: The tumor types of main interest include non-small cell lung cancer and esophagogastric carcinomas.

The tumor types of main interests include non small cell lung cancer and esophageal gastric carcinomas for.

Matt Maurer: for both monotherapy testing, as well as in combination with taxing. These choices were based upon our preclinical monotherapy activity, as well as the high-end medical need, and largely addressable MTAP-deleted populations.

For both monetary testing as well as in combination with vaccines. These choices were based upon our preclinical monotherapy activity as well as the high unmet medical need and larger addressable tap deleted populations.

Matt Maurer: It should be noted that MTAB-deleted cancers have a relatively poor prognosis and do not respond well to immunotherapy, given that they're generally cold tumors and thus require novel therapies.

It should be noted that <unk> deleted cancers have a relatively poor prognosis and do not respond well do immunotherapy given that there are generally cold tumors.

Require novel therapies.

Matt Maurer: You can see that for each tumor type, we were combining with a standard of care taxane, docetaxel for lung, and paplitaxel for esophageal gastric. We and others have validated preclinical combinatorial activity with MAT2A inhibition and taxanes, and thus are excited about the prospect of clinical benefit.

You can see that for each tumor type we were combining with the standard of care Taxane Docetaxel for lung and Paclitaxel group cyclical gastric, we and others have validated preclinical combinatorial activity with <unk> inhibition and Taxane.

So we're excited about the prospects of clinical benefit.

Matt Maurer: In addition, we have monofavory basket cohorts for exploration across other tumor types.

In addition, we have monotherapy basket cohorts for exploration across other tumor types and.

Matt Maurer: and an opportunistic evaluation of another combination partner in which we have demonstrated preclinical synergy.

In an opportunistic evaluation of another combination partner in which we have demonstrated preclinical synergy.

We are targeting launch of expansion in combination testing in the middle of this year.

Matt Maurer: We are targeting launch of expansion and combination testing in the middle of this year.

Excellent.

Yeah.

Shown on this slide our representations of our preclinical pharmacokinetic data key.

Matt Maurer: Shown on this slide are representations of our preclinical pharmacokinetic data.

Matt Maurer: Key points to highlight are the well-behaved steady-state concentrations over time curves.

Key points to highlight are the well behaved steady state concentrations over time curves and.

Matt Maurer: in the left panel, and dose proportional increase in exposure shown as fold increases on the right panel. We are most excited about the ability to deliver dosing that has reached our target efficacious exposures based on preclinical data.

In the left panel and dose proportional increase in exposure shown as fold increases on the right panel. We are most excited about the ability to deliver dosing that has reached your target efficacious exposures based on preclinical data.

Dose cohort five.

Matt Maurer: which is our in our target range has been cleared and preliminary tolerability. And we are currently enrolling into core six where the first patient has cleared the DLT period.

Which is in our target range has been cleared and preliminary tolerability and.

And we are currently enrolling into core six where the first patient has cleared the DLT period.

Matt Maurer: You can see the normalized relative fold increase in exposures across a 20-fold range.

You can see the normalized rolling some fold increase in exposure to across a 24 range.

Matt Maurer: ID397 shows flat and consistent temporal PK profiles across doses with a low Cmax to Cmin ratios.

307 shows flat and consistent temporal PK profiles across doses with a low <unk> ratios and.

Matt Maurer: In short, the favorable PK profile supports an acceptable clinical dosing regimen.

In short the favorable PK profile supports an acceptable clinical dosing regimen.

Okay.

Excellent.

And this slide provides a bit more detail on the safety experience, thus far among the patients treated through cohort five the pen.

Matt Maurer: And this slide provides a bit more detail on the safety experience thus far among the patients treated through cohort five.

Matt Maurer: The panel on the right shows the number of patients that have experienced drug-related adverse events per investigator broken out by grade.

On the ratios the number of patients that have experienced drug related adverse events per investigator broken out by grade.

The side effect profile, so far has been manageable with low grade <unk> thrombocytopenia that have not affected dosing, specifically dose related aes occurring in greater than 10% of patients include low grade nausea decreased appetite diarrhea dehydration.

Matt Maurer: The side effect profile so far has been manageable with low-grade GI events and mild thrombocytopenia that have not affected those.

Matt Maurer: Specifically, dose-related AEs occurring in greater than 10% of patients include low-grade nausea, decreased appetite, diarrhea, dehydration, and thrombocytopenia.

Thrombocytopenia.

There has been only been only one grade related grade three event of Athenian there had been no drug related aes or dose limiting toxicities to date.

Matt Maurer: There has been only been only one drug-related grade 3 event of isthenia. There have been no drug-related SAEs or dose-living toxicities to date.

Matt Maurer: We believe these data set the drug up for appropriate monotherapy testing, as well as a therapeutic window useful for combination testing.

We believe these data set the drug up for appropriate monotherapy testing as well as a therapeutic window useful for combination testing.

This emerging safety profile also compares favorably to prior drugs targeting <unk> five and <unk>.

Matt Maurer: This emerging safety profile also compares favorably to prior drugs targeting PRMT5 and MAT2A, which were limited by either hematologic or limited or type 6 disease.

Which were limited by either hematologic <unk>.

So with that I'll pass it over to Mike to walk through some preclinical data as well as our clinical PD data.

Speaker Change: So with that, I'll pass it over to Mike to walk through some preclinical data as well as our clinical PD data.

Thank you Matt Good morning, everyone I'll take a few minutes to walk you through our preclinical and clinical Pharmacodynamic biomarker data the key pharmacodynamic markers for the E. 397 program are directly related to the mechanism of action underpinning the maturation clinic lethal interaction with them Felicia.

Mike: Thank you, Matt. Good morning, everyone. I'll take a few minutes to walk you through our preclinical and clinical pharmacodynamic biomarker data. The key pharmacodynamic markers for the IDE397 program are directly related to the mechanism of action underpinning the MAT2A synthetic lethal interaction with MTAP deletion. As illustrated in the schematic on the left, upon MTAP deletion, which happens in 15% to follow tumors.

Illustrating the schematic on the left upon and tap deletion, which happens in 15% of solid tumors. The cellular <unk> substrate MTA accumulates and partially inhibits the essential enzyme <unk> five in tumor cells, which is hit one of this <unk> synthetic lethal opportunity <unk> inhibitor <unk>.

Mike: The cellular MCAP substrate, MTA, accumulates and partially inhibits.

Mike: the essential enzyme PRMT5 in tumor cells, which is HIT1 of this parawise synthetic lethal opportunity. The MAT2A inhibitor, IDE397, reduces the availability of cellular SAM, which PRMT5 needs to activate splicing factors via symmetric dimethyl arginine modification, STMA.

<unk> hundred 97 reduces the availability of cellular Sam which <unk> five needs to activate splicing factors via symmetric di Michael RJ modification SMA.

Mike: That's hit two. So this one-two punch selectively disrupts essential pre-mRNA splicing in mTAP-deleted tumors. You can see that in action on the right.

So this one two punch selectively disrupts essential pre mrna splicing in and calculated tumors you can see that in action on the right no inhibition of SG&A accumulation in <unk> cells, even with high doses of either <unk> hundred 97, and strong suppression of S. GMA accumulation in <unk> cells.

Mike: No inhibition of SDMA accumulation in MTAP wild type cells, even with high doses of IDE397.

Mike: and strong suppression of SDMA accumulation in MTAP-deleted cells, even at low dose.

Even at low doses, notably as shown on the far right the disruption of essential splicing in and tap deleted cancer cells by <unk> hundred southern is equivalent to that observed with direct Sam competitive peer NP five inhibitor and.

Mike: Notably, as shown on the far right, the disruption of essential splicing in mTAP-deleted cancer cells by IDE397 is equivalent to that observed with direct SAM-competitive PRMP5 inhibitor. In contrast, IDE397 has very limited activity in mTAP wild-type cells consistent with the synthetic lethal mechanism. The same can't be said for the PRMP5 inhibitor, which strongly perturbs mRNA splicing in all cells.

In contrast, <unk> hundred 87 has very limited activity in <unk> wild type cells consistent with the synthetic lethal mechanism. The same can't be said for the <unk> inhibitor, which strongly <unk> mrna splicing in all cells.

Mike: So given this mechanism of action in patients on trial, we follow drug-dependent MAT2A inhibition by measuring the concentration of samin plasma, that's our peripheral PD, and we follow the extent of inhibition of PRMT5 by measuring the abundance of SDMA in cancer cells from tumor biopsies, that's our tumor PD. So on.

So given this mechanism of action and patients on trial, we follow drug dependent <unk> inhibition by measuring the concentration of salmon plasma thats, our peripheral PD and we met that we follow the extent of inhibition of <unk> five by measuring the abundance of SD MMA in cancer cells from tumor biopsies tumor PD.

So on the next slide please euro.

Mike: In slide eight, you can see in preclinical tumor models and inpatient biopsies, we measure tumor SDMA by immunohistochemistry with an anti-SDMA antibody. In our workhorse, preclinical MTAP-deleted lung cancer model on the left, we validated dose-dependent reduction of tumor SDMA by IDE397 with complete inhibition of tumor SDMA and tumor growth by 30 milligrams per kilogram.

In slide eight you can see in preclinical tumor models and in patient biopsies, we measure tumor <unk> by immunohistochemistry with an anti <unk> antibody and our workforce preclinical and tap deleted lung cancer model on the left we validated dose dependent reduction of tumor SG&A by <unk> hundred 90.

Seven with complete inhibition of tumor SG&A and tumor growth.

At 30 milligrams per kilogram that same dose extinguished tumor CMA across a subset of <unk> patient derived xenograft models as shown on the right demonstrating that <unk> inhibition is sufficient to block <unk> five activity in <unk> deleted tumors in vivo 912 and calculated.

Mike: That same dose extinguished tumor SDMA across a subset of mTAP-deleted patient-derived xenograft models, as shown on the right, demonstrating that MAT2A inhibition is sufficient to block PRMT5 activity in mTAP-deleted tumors in vivo. 9 of 12 mTAP-deleted models evaluated had 80 to 100% reduction of tumor SDMA as compared to time-matched vehicle control.

<unk> evaluated had 80% to 100% reduction of tumor SG&A as compared to time matched vehicle controls will give you two vignettes from one of our key indications of interest on the next couple of slides.

Mike: We'll give you two vignettes from one of our key indications of interest on the next couple of slides.

On slide nine.

Mike: Non-small-cell lung cancer is a patient population of high interest for the IDE397 program, and in this mTAP-deleted lung squamous cell carcinoma PDX model, we achieved 92% tumor growth inhibition by end of study.

Non small cell lung cancer is a patient population of high interest for the <unk> hundred 97 program in English and tap deleted lung squamous cell carcinoma Pdx model, we achieved 92% tumor growth inhibition by in the study.

With respect to the PD the vehicle arm Middle panel showed extensive SG&A staining with an H score of 85, the tumor SG&A H score was reduced to zero by <unk> hundred 97 treatment as shown on the right, indicating 100% suppression of the production of S. DMA in the tumor.

Mike: The vehicle arm, middle panel, showed extensive SDMA staining with an age score of 85.

Mike: The tumor STMH score was reduced to zero by IDE397 treatment as shown on the right, indicating 100% suppression of the production of STMH in the tumor.

On slide 10.

Here's another example in the same disease indication, where we saw tumor regression by end of study. This tumor had an SD MAA score of 250 and control animals quite high the Max is 300 as you can see in the middle panel, 95% of that baseline signal is gone and residual I'd <unk> hundred 97.

Mike: Here's another example in the same disease indication, where we saw tumor regression by end of study. This tumor had an SDMAH score of 250 in control animals, quite high, the max is 300, as you can see in the middle panel. Ninety-five percent of that baseline signal is gone in residual IDE397-treated tumors, as you can see on the far right.

Treated tumors as you can see on the far right.

On slide 11.

As I mentioned earlier in the clinical phase one dose escalation study, where following plasma Sam as a peripheral PD biomarker in tissues DMA as the tumor PD biomarker, we've observed significant plasma Sam reduction on treatments across cohorts one through cohort by to date as an example, you can see the deep and.

Mike: As I mentioned earlier, in the clinical phase 1 dose escalation study, we're following plasma SAM as a peripheral PD biomarker and tissue SDMA as the tumor PD biomarker.

Mike: We've observed significant plasma SAM reduction on treatment across cohorts one through cohort five to date. As an example, you can see the deep and consistent post-treatment plasma SAM reduction among the valuable patients in our recently cleared cohort, cohort five on the left, with a mean reduction of 77% after three weeks of therapy.

<unk> post treatment plasma Sam reduction among evaluable patients in our recently cleared cohort cohort five on the left with a mean reduction of 77% after three weeks of therapy.

On the right you can see that across all evaluable patients on trial to date the percent plasma Sam inhibition is associated with increasing drug exposure, indicating exposure dependent target modulation.

Mike: On the right, you can see that across all evaluable patients on trial to date, the percent plasma SAM inhibition is associated with increasing drug exposure, indicating exposure-dependent target modulation.

Mike: On the next slide, we'll move to the tumor PD from the trial.

On the next slide we will move to the tumor PD from the trial.

So here on slide 12, we were very pleased to see exposure associated tumor S. DMA reduction in target tumor types are.

Mike: So here on slide 12, we were very pleased to see exposure associated tumor SDMA reduction in target tumor types.

Mike: Our first pre-dose and on-treatment paired biopsies came from a pancreas cancer patient from cohort three, shown on the far left, and displayed little detectable modulation of tumor SDMA on treatment.

Our first pre dose and on treatment paired biopsies came from a pancreas cancer patient from cohort three shown on the far left and displayed little detectable modulation of tumor SG&A on treatment.

Mike: The cohort four pancreas cancer patient, middle panel, showed both nuclear and cytoplasmic SDMA staining in the pre-dose tumor biopsy. Those dark brown ovals are SDMA positive nuclei, which are surrounded by lighter brown cytoplasmic SDMA staining in the pre-treatment biopsy shown in the top panel. This patient's AUC plasma drug exposure is about 2.5 fold higher than the pancreas cancer patient in cohort three.

The cohort four pancreas cancer patient Middle panel showed both nuclear and cytoplasmic S. GMA staining in the pre dose tumor biopsy. Those dark brown ovals are <unk> positive nuclei, which was surrounded by lighter brown cytoplasmic S. TMA staining in the pre treatment biopsy shown in the top panel.

This patients AUC plasma drug exposure was about two five fold higher than the pancreas cancer patient in cohort three.

Mike: Notably, the cytoplasmic staining is absent on treatment with also a detectable, although modest reduction in nuclear SDMA staining, middle bottom panel, indicating an emerging pharmacological response to IDE397 in the tumor.

Notably the cytoplasmic expanding his absence on treatment with also a detectable although modest reduction in nuclear SG&A staining middle bottom panel, indicating an emerging pharmacological response to <unk> hundred 97 in the tumor.

Mike: Finally, on the right panel at the higher IDE397 exposures, you can see almost complete loss of STMA standing in the post-treatment biopsy from this lung cancer patient in cohort five.

Finally on the right panel at the higher <unk> hundred 97 exposures you can see almost complete loss of S. TMA standing in the post treatment biopsy from this lung cancer patient in cohort five.

Mike: The plasma drug exposure in this patient is almost six-fold higher than what we saw in that cohort three patient. We'll go in a deeper dive on the next slide.

The plasma drug exposure and this patient is almost six fold higher than what we saw in cohort three patients will go into a deeper dive.

On the next slide.

Slide 13 first.

Mike: It's worth noting that the steady-state exposures for patients in Cohort 5 are getting within the predicted efficacious concentration range based on preclinical in vivo efficacy studies using a representative mTAP-deleted lung cancer model.

Worth, noting that the steady state exposures or patients in cohort five are getting within the predicted efficacious concentration range based on preclinical in vivo efficacy studies, using a representative and calculated lung cancer model.

Mike: This patient was on the high side of exposures observed in Cohort 5 and the plasma SAM reduction is also on the high end at 79%.

This patient was on the high side of exposures observed in cohort five in the plasma Sam reduction is also on the high end at 79%.

Mike: The central lab pathologist tumor SDMA score for the pre-dose biopsy was 280. As shown in the bar graph on the right, the vast majority of tumor cells in the pre-dose biopsy had the maximum SDMA staining intensity receiving scores of three plus.

The Central lab pathologists tumor stm's score for the pre dose biopsy was 280.

As shown in the bar graph on the right. The vast majority of tumor cells in the pre dose biopsy had the maximum <unk> staining intensity receiving scores of three plus.

Mike: In contrast, the H-score for the on-treatment biopsy was only 13. And in the bar graph shown on the right, the vast majority of tumor cells in this sample were completely negative for SDMA, receiving scores of zero. I'll sum up on

In contrast, the H score for the on treatment biopsy was only 13 and in the bar graph shown on the right. The vast majority of tumor cells. In this sample will completely negative for CMA receiving scores of zero.

I will sum up on the next slide.

The slide 14 pre clinically.

Mike: The slide 14, preclinically, we see strong tumor growth control as well as tumor regressions in multiple mTAP-deleted CDX and PDX tumor models using once-daily oral IDE397 doses from 10 milligrams per kilogram and above.

We see strong tumor growth control as well as tumor regressions in multiple end calculated CTX and pdx tumor models using once daily oral <unk> hundred 97 doses from 10 milligrams per kilogram and above significant.

Mike: Significant reduction of tumor SDMA is detectable at three milligrams per kilogram and is maximally suppressed by 30 milligrams per kilogram. We've plotted those exposure response details for the MTAP null lung cancer model H838 on the right.

A reduction in tumor S. DMA is detectable at three milligrams per kilogram and is maximally suppressed by 30 milligrams per kilogram. We've plotted those exposure response details for the <unk> lung cancer model H 838 on the right.

Mike: Clinically, IDE397 achieved plasma SAM reduction of 60% or more across cohort one through five in the phase one. We've plotted the steady state exposures for the patients discussed in this presentation on the right, benchmarked against the preclinical observations.

Politically <unk> hundred 97 achieved.

<unk>, Sam reduction of 60% or more across cohorts one through five in the phase one we've plotted the steady state exposures for the patients discussed in this presentation on the right benchmark against the preclinical observations.

Mike: Clinical tumor STMA is showing an exposure-dependent relationship with 95% reduction of tumor STMA in cohort 5. Based on these observations, cohort 5 is in the target exposure range for efficacy, and we are currently exploring a higher dose in cohort 6. So with that, I'll hand the presentation back to you, Jerome.

Clinical tumor S. GMA is showing in exposure dependent relationship with 95% reduction of tumor S. TMA in cohort five.

Based on these observations cohort five is in the target exposure range for efficacy and we are currently exploring a higher dosing cohort six so with that I'll hand, the presentation back to usual.

Jerome: Great, Mike. Thank you so much for that walkthrough. And thank you, Matt, for the walkthrough of the clinical data as well.

Great Mike. Thank you so much for that Walter and thank you Matt for the walk through.

Clinical data as well.

In terms of key next milestones for <unk> 907.

Jerome: In terms of key next milestones for ID397, first is to deliver the GSK option package mid-year 2022. And then second, to initiate both the monotherapy expansion and combination studies in mid-year 2022.

First is to deliver the GSK option package mid year 2014, and then second to initiate both the monotherapy expansion and combination studies in mid year 2022.

Jerome: And as noted earlier, the protocol amendment to the FDA has been submitted to enable this next phase of the clinical program.

And then as noted earlier the protocol amendment to the FDA has been submitted to enable this next phase of the <unk>.

Michael program.

In terms of a summary of the presentation. Today, we believe we've demonstrated <unk> seven shows robust suppression of tumor pharmacodynamics across multiple end tap deleted pdx models, including a 100% reduction of tumor <unk> we.

Jerome: In terms of a summary of the presentation today, we believe we've demonstrated IDA397 shows robust suppression of tumor pharmacodynamics across multiple MTOP-deleted PDX models, including 100% reduction of tumor SDMA.

Jerome: We have completed the preclinical package for the option data package, and the data has been uploaded to the option data package data room.

We have completed the preclinical package for the option data package and the data has been uploaded to the option that data package data room.

Jerome: Next, ID397 has demonstrated a favorable human PK profile that we believe supports once-failed dosing as noted on clinicaltrials.gov.

Next I'd 397 has demonstrated a favorable human PK profile that we believe supports once daily dosing as noted on clinical trials Dot Gov.

I think 297 has demonstrated robust clinical pharmacology of plasma pharmacodynamics across all cohorts in exposure dependent tumor pharmacodynamics.

Jerome: ID397 has demonstrated robust clinical plasma pharmacodynamics across all cohorts and exposure-dependent tumor pharmacodynamics.

Today, we have also observed a very favorable human AE profile, including no serious adverse events and the maximum tolerated dose has not yet been reached.

Jerome: To date, we've also observed a very favorable human AE profile, including no serious adverse events, and the maximum tolerated dose has not yet been reached.

Jerome: Importantly, the summary of this data, we believe we are seeing an emerging preliminary risk-benefit profile versus historical.

Importantly, the summary of this data we believe we are seeing an emerging.

Pulmonary risk benefit profile versus historical.

On the benefit side.

Jerome: On the benefits side, as noted earlier, we have seen clinical activity, including robust plasma and tumor pharmacodynamics, and as reported earlier, tumor shrinkage in multiple patients.

Earlier, we have seen clinical activity, including robust plasma and tumor pharmacodynamics and a reported earlier tumor shrinkage in multiple patients.

Jerome: From a risk profile side, we believe we have observed a favorable AE profile, including, again, no SAEs and an MTD that has not yet been achieved.

From a risk profile side, we believe we have observed a favorable AE profile, including again no Smes.

MTGE that has not yet been achieved.

Jerome: To contextualize this risk-benefit profile, we wanted to highlight two additional molecules in this pathway, including GSK's PRM25 inhibitor, who had an expansion dose selected at 400 mg once a day. And as noted here, at that expansion dose, you saw approximately 26% SAEs and 53% grade 3-4 AEs.

To contextualize this risk benefit profile, we wanted to highlight too.

Additional molecules on this pathway, including Gsk's <unk> inhibitor, who had an expansion dose selected at 400 <unk> once a day and as noted here at that expansion that you saw approximately 26% Smes and 53% Greentree for Aes.

For <unk> hundred 70 at the 200, Meg QD expansion dose they observe just under 20% grade three or higher aes and at the next dose level ops of 200, Megs PID are 67% grade three or higher AE.

Jerome: For AD270, at the 200 mg QD expansion dose, they observed just under 20% grade 3 or higher AEs. And at the next dose level ups of 200 mg BID, a 67% grade 3 or higher AE.

Jerome: At the outset of this program, IDEA's belief has been generating a molecule that has sufficient exposure.

At the outset of this program ideas believes it has been generating a molecule that has sufficient exposure.

That can deliver a robust pharmacodynamic modulation.

Jerome: that can deliver robust pharmacodynamic modulation.

Jerome: with an AE profile that is superior from previous compounds would provide a unique profile to interrogate this opportunity within MTAP deletion.

With an AE profile that is superior from previous compounds would provide a unique profile to interrogate this opportunity within <unk> deletion.

Jerome: We believe this interim clinical data positions the molecule well to enter into the next phase of development.

We believe this interim clinical data positions the molecule well to enter into the next phase of development.

Jerome: And we believe this favorable risk-benefit profile will position ID397 to potentially evaluate unique combinations.

And we believe this favorable risk benefit profile will position <unk> hundred 97.

To potentially evaluate unique combinations.

Jerome: as well as to explore potentially earlier lines of treatment as monotherapy agents.

As well as to explore potentially earlier lines of treatment as a monotherapy agent.

Jerome: With that, this is the conclusion of the prepared remarks for the ID397 Phase 1 Clinical Program Update, and with that, I will pass it along to Paul Stone, our Chief Financial Officer, to provide an update across the portfolio as well as our financials as it relates to our Q1 2022 Earnings Release Update.

With that this is the conclusion of the prepared remarks for the IV <unk> hundred 97 phase one clinical program update.

That I will pass it along to Paul Stone, our Chief financial Officer to provide an update across the portfolio as well as our financials as it relates to our Q1 2022 earnings release date.

Jerome: Hi, good morning, everyone. I'm Paul Stone, Chief Financial Officer of Idea.

Hi, Good morning, everyone I'm, Paul Stone, Chief Financial Officer of idea.

Paul Stone: I'm going to report on our financial results for the full year 2021 as well as a corporate update.

I'm going to report on our financial results for the full year 2021, as well as the corporate update.

Paul Stone: In 2021, for the full year, we had operating expenses of $78 million. This left us with a cash balance of $368 million, which provides us with a runway for planned operations into 2025.

In 2021 for the full year, we had operating expenses of $78 million.

This left us with a cash balance of $368 million.

It provides us with the runway for planned operations into 2025.

From a program perspective.

Paul Stone: From a program perspective, the robo-assertive phase 2 clinical and our pre-clinical programs are each maturing.

Our <unk> phase III clinical and preclinical programs are each maturing.

Paul Stone: Starting with Jaroma Sirtib, we are currently enrolling patients in a phase two.

Starting with Jerome assertive, we are currently enrolling patients in our phase two.

Paul Stone: clinical evaluation of dorovasertib in combination with cozotinib in collaboration with Pfizer under clinical collaboration and supply arrangements.

Clinical evaluation of Jerome assertive in combination with <unk>.

In collaboration with Pfizer.

Collaboration and supply arrangement.

We are evaluating.

Paul Stone: We are evaluating that combination in both metastatic uveal melanoma as well as GNAQ11 mutated.

That combination in both metastatic uveal melanoma as well as G&A accumulation.

Mutated skin melanoma.

Paul Stone: We also opened recently a monotherapy evaluation of drovacertib in primary uveal melanoma.

We also opened recently a monotherapy evaluation of drove assertive in primary Uveal melanoma.

Paul Stone: And we are considering and evaluating expansion opportunities preclinically, both with KRAS inhibitors and KRAS-driven tumors, and in combination with crizotinib and potentially other CMAT inhibitors in CMAT-driven tumors.

And we are considering and evaluating expansion opportunities pre clinically.

Both with <unk> inhibitors in key rest driven tumors and in combination with <unk> and potentially other C met inhibitors.

C met driven tumors.

Paul Stone: In terms of key updates and catalysts, we announced yesterday that we've expanded our relationship with Pfizer on our clinical collaboration and supply arrangement to support a potential registrational trial in metastatic Euglen melanoma, as well as to support a phase one clinical evaluation of the combination in CMET-driven tumors subject to preclinical validation.

In terms of key updates in catalysts.

We announced yesterday that we've expanded our relationship with Pfizer.

On our clinical collaboration and supply arrangement to support a potential registrational trial in metastatic uveal melanoma as well as to support a phase one.

Clinical evaluation of the combination in C met driven tumors subject to preclinical validation.

Paul Stone: Finally, for this program, we are targeting FDA guidance as well as a clinical data update in mid-year 2020.

Finally for this program, we are targeting FDA guidance as well as the clinical data update mid year 2022.

Our next most advanced program is <unk> 161, which is a wholly owned program targeting park for patients that have HRD or BRCA mutations.

Paul Stone: Our next most advanced program is ID161, which is a whole new program targeting PARC for patients that have HRD or BRCA mutations.

Paul Stone: In this program, we've observed in vivo efficacy with enhanced tumor growth inhibition and or tumor regressions in multiple NREPRIB-resistant models, which is a part.

This program, we've observed in vivo efficacy with enhanced tumor growth inhibition and or.

Tumor regressions in multiple <unk> resistant models, which is a PARP inhibitor.

Paul Stone: We are targeting IND in Q4 of this year.

We're targeting an IND in Q4 of this year.

And our Pulsator program also partnered with GSK.

Paul Stone: In our Pulse Data Program, also partnered with GSK, we've demonstrated in vivo efficacy in combination with Nurapirib, which is GSK's partner.

Demonstrated in vivo efficacy in combination with Niraparib, which as just Keith PARP inhibitor and we are in R&D enables settings.

Paul Stone: And we are in IND-enabled settings first half of this year.

Half of this year.

Paul Stone: Importantly, for this program with GSK, we have the potential for up to 20 million in aggregate additional milestones from preclinical.

Partially for this program with GSK, we have the potential for up to $20 million in aggregate.

<unk>.

Milestones from preclinical through early phase one.

Paul Stone: Finally, on Werner Helike's, we are targeting a development candidate with GSK in collaboration with them in 2023.

Finally on the Warner Hela case.

We are targeting a development candidate with GSK in collaboration with them in 2023.

Paul Stone: And similarly, for this program, we have the potential for up to $20 million in aggregate milestone.

And similarly for this program, we have the potential for up to $20 million in aggregate milestone payments from preclinical to early phase one we're excited to see these programs mature.

Paul Stone: from preclinical to early phase one. We're excited to see these programs mature.

Great.

Speaker Change: And Paul, anything additional for the financial results or is that the conclusion? No, I think we covered the financial results. As I said, $78 million of operating expenses for 2021, cash into 2025 with $360 million on the balance sheet for this year.

And Paul anything additional for the financial results.

I think I think we've covered the financial results as I said $7 million to $8 million of operating expenses for 2021 cash into 2025% to $360 million on the balance sheet for this year.

Great.

Speaker Change: Thank you, Paul, for that summary. And this will be the end of our prepared remarks. And with that, the operator will open it up for the analyst Q&A session.

Thank you Paul for that summary.

This is will be the end of our prepared remarks and with that the operator will open it up for the analyst Q&A session.

Speaker Change: If you would like to ask a question, please signal by pressing star 1 on your telephone keypad. If you're using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment.

If you would like to ask a question. Please signal by pressing star one on your telephone keypad, if you're using a speaker phone. Please make sure. Your mute function is turned off to allow your signal to reach our equipment.

Again, Please press star one to ask a question.

Speaker Change: Again, please press star one to ask a question.

Speaker Change: We will take our first question from Anupam Rama with J.P. Morgan. Please go ahead.

And we'll take our first question from <unk> Rama with JP Morgan. Please go ahead.

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

Anupam Rama: Hey, guys. Thanks so much for taking the question. Just a logistical question from me. Can you remind us once the data upload is complete and to GSK by mid-year, how long GSK has to make a formal opt-in decision? And will you be disclosing when the package is delivered or just ultimately the GSK decision? Thanks so much.

Just a logistical question for me can you remind us once sort of the data upload is complete and to GSK by mid year, how long GSK has to make a formal opt in decision and will you be disclosing when the packages delivered or just ultimately the GSK decision. Thanks, so much.

Speaker Change: Yeah, so the timeframe for GSK's review period has not been disclosed, but I would say that, you know, we've been in very close communication with GSK. Towards the end of last year, you know, based on that communication, we've begun building the data room early.

Yeah, Bob So the timeframe for Gsk's review period has not been disclosed but.

But I would say that we've been in very close communication with GSK.

Towards the end of last year.

Based on that communication, we've begun building the data room early.

Speaker Change: And a lot of the data room has already been occupied, including preclinical data, as well as several key pieces of the clinical data. So, our view is that when the dose is selected for the expansion phase of this trial, it will be an incremental review, which we would hope would enable an efficient, time-efficient decision by GSK on the opt-in.

And a lot of the data room has already been occupied including preclinical data as well as several key pieces of the clinical data is our view is that one the the dose is selected for the expansion phase of this trial it will be incremental review, which we would hope with enable.

Inefficient time efficient decision by GSK on the opt in.

Speaker Change: In terms of would we provide guidance on when the option package is delivered relative to the decision by GSK, we have not made a decision on that at this point, but I think our hope is that those two events may be in fairly close proximity, and based on that, I think it may not be a bad baseline assumption that we would make an announcement as part of an actual GSK decision on the option.

In terms of.

When we provide guidance on when the option packages that delivered.

Relative to the decision by GSK, we have not made the decision made a decision on that at this point, but I think our hope is that those two events may be in fairly close proximity.

And based on that I think it may not be a bad baseline assumption that we would make an announcement as part of <unk>.

Actual GSK decision on option.

Thanks, so much for taking the question sure.

Speaker Change: Thanks so much for taking our question. Sure.

Speaker Change: And our next question comes from Maury Raycroft with Jeffries. Please go ahead.

And our next question comes from Maury Raycroft with Jefferies. Please go ahead.

Maury Raycroft: Hi, good morning, and thanks for taking my questions as well. I was just wondering if you can talk more about what exactly is going to be submitted to GSK. It sounds like it's subject to initiation of expansion cohorts or MTD, and you're starting dosing with dose level 6. And so I just wanted to see if you can talk more about what else can still impact or be included in the GSK data package. And will you include any data from cohort 6 in the package?

Hi, good morning, and thanks for taking my questions as well.

I was just wondering if you can talk more about.

What exactly is going to be submitted to GSK. It sounds like it's subject to initiation of expansion cohorts or MTV and youre, starting dosing with dose level six and so I just wanted to see if we can talk more about what else can still impact or be included in the GSK data package and will you include any data from cohort six and the <unk>.

Package.

Speaker Change: Yeah, so I think in terms of data categories that will be provided in the option package that's noted in the schedule and our agreement was as outlined.

Yes, so I think in terms of data categories that will be provided in the option package. That's noted in the schedule in our agreement was as outlined.

Speaker Change: in one of the earlier slides of the presentation. In terms of cohort, Maury here, I would say it depends on how cohorts it goes. So we are currently in that cohort, as I believe was noted in the print materials. We have cleared the first patient on the DLT window. My understanding is that second patient will likely clear sometime next week, if they get through next week.

One of the earlier slides of the presentation.

Terms of cohort Mowry here I would say it depends on how cohort chico's. So we are currently in that cohort.

I believe as noted in.

The print materials, we have cleared the first patient in the DLT window.

My understanding is that second patient will likely sometime next week, if they get through next week.

Speaker Change: And so it depends on if six is a possible dose for expansion. If it's up to five and we end up selecting five in the expansion dose, I would say the data that what was presented today will be largely the data they see. If it's a scenario that we decide to escalate into cohort seven and we clear that cohort, obviously that cohort would be included as well.

And so it depends on it.

<unk> as a possible dose for expansion.

That's up to five and we ended up selecting five and expansion dose I would say the data.

What was presented today will be will be largely the same.

Thats a scenario that we decide to escalate into cohort seven and we clear that cohort, obviously that cohort will be included as well.

Speaker Change: I would say at this point, the baseline working assumption that we are internally utilizing for planning for this next phase of development is that the potential to expand this current cohort rolling, which is cohort.

I would say at this point the baseline working assumption that we are internally utilizing for planning for this next phase of development.

The potential to extend at this current cohort, we're rolling which is <unk> six.

Speaker Change: Got it. That's very helpful. And also just wanted to check to see if you're seeing anything additional on impact on Billy Rubin. And you've mentioned the UGT1A1 biomarker in the past. I'm just wondering if you can remind me if you've assessed that in the clinic and if you're seeing any differences versus AG270 on on those measures.

Got it that's very helpful. And also just wanted to check to see if youre seeing anything additional on impact on bilirubin and you've mentioned the <unk> 101 biomarker in the past and just wondering if you can remind me if you if thats that in the clinic and if youre seeing.

Any differences versus AG 270 on on those measures.

Sure Matt do you want to answer that in terms of liver safety profile today versus agency SMT and our clinical experience there yes.

Speaker Change: Sure. Matt, do you want to answer that in terms of liver safety profile to date versus HG2-370 and our clinical experience there?

Matt: Yeah, so we don't have the liability on the liver enzyme, so, you know, and we have not seen any significant liver toxicity to date. So, you know, we're encouraged by that.

Yes, so we don't have the reliability and the liver enzymes so and.

And we have not seen any significant liver toxicity to date so.

We're encouraged by that.

Got it okay. Thanks for taking my questions.

Great. Thanks Marty.

And we will take our next question from Charles <unk> with Guggenheim Securities.

Speaker Change: And we will take our next question from Charles Zhu with Guggenheim Securities.

Good morning, everyone. Thanks for hosting this event and thanks for taking my questions.

Charles Zhu: Good morning, everyone. Thanks for hosting this event and thanks for taking my questions.

Charles Zhu: My first one, I want to ask on the tumor SDMA down modulation signals that you've disclosed so far. I guess in addition to potentially looking at it from the perspective of percent tumor SDMA reduction, how should we also think about these tumor SDMA levels?

My first one I wanted to ask on the tumor stm's down modulations signals that you've disclosed so far I.

I guess in addition to potentially looking at it from the perspective of percent tumor S. DMA reduction how should we also think about these tumor SG&A levels.

Charles Zhu: not only as a percent reduction, but also on an absolute level. For example, the cohort for pancreatic cancer patients you have showed some...

Not only as a percent reduction, but also on an absolute level of for example, the cohort for pancreatic cancer patients you have showed some.

Charles Zhu: level of knockdown, but post-treatment, it looks like the absolute amount could still be, you know, perhaps comparable to what some other tumors may be on the pre-treatment perspective. So I guess, could you provide some thoughts on that front as well, you know, not only on the percent knockdown, but also on absolute amounts post-treatment, thanks.

<unk> knockdown, but post <unk> treatment and it looks like the absolute amount could still be.

Perhaps comparable to what some other tumors may be on the pre treatment perspective, So I guess could you provide some thoughts on that front as well not only on the percent knockdown, but also on absolute amounts post treatment. Thanks.

Mike do you want to take that.

Speaker Change: Yeah, absolutely. Thank you for that question. With respect to the absolute SDMA signal, when we look at that signal, we are really looking at the proteins that have been modified by that symmetric dimethyl arginine. And our therapeutic mechanism of action requires that dimethylation to occur in order to support the pre-mRNA splicing that will allow the tumor to thrive.

Yes, absolutely. Thank you for that question with respect to the Absolutes S. DMA signal when we look at that signal. We are really looking at the proteins that have been modified by that symmetric dimethyl arginine and our therapeutic mechanism of action requires that dime escalation to occur in order.

To support the pre mrna splicing that will allow the tumor to thrive. So in terms of absolutes concentrations of SG&A in a tumor pre clinically we find that the better you suppress those absolute values of SMA. The better response, you have with respect to tumor shrinkage.

Speaker Change: So in terms of absolute concentrations of SDMA in the tumor, pre-clinically, we find that the better you suppress those absolute values of SDMA, the better response you have with respect to tumor shrinkage. So in terms of what the absolute values are in the clinical arena and whether or not there's going to be indication-specific thresholds.

In terms of what the absolute values are in the clinical arena and whether or not there is going to be indication specific thresholds for efficacy remains to be seen but from the preclinical studies, we do know that the more we can suppress tumor CMA the better efficacy we see in those preclinical models, both the CTX on the PD.

Speaker Change: for efficacy remains to be seen, but from the preclinical studies, we do know that the more we can suppress tumor SDMA, the better efficacy we see in those preclinical models, both the CDX and the PDX.

Yes.

Got it understood and I guess.

Speaker Change: got it understood and i guess excuse me

Excuse me.

Speaker Change: Well, I'm also curious, then, you know, what are the potential implications on a pre-treatment H-score impact, and, you know, could we still potentially expect to see efficacy in low-baseline H-score tumors? You want me to take that, Eudreo? Sure. Yeah. Yeah.

Also curious what are the potential implications on pre treatment H score impact and would we could we still potentially expect to see efficacy and a low baseline <unk> score two tumors.

Okay got you Joe sure, yes from what we have seen on the preclinical side.

Speaker Change: When we have a response to the MAT2A inhibitor, we have a suppression of the tumor SDMA. We have found tumors that have age scores.

When we have a response to the <unk> inhibitor, we have a suppression of the tumor S. DMA. We have found tumors that have H scores of 80 to 100 that grow well and become suppressed and we have tumor control with us with the match way inhibitor treatment I showed you an example of that.

Speaker Change: of 80 to 100 that grow well and become suppressed. And we have tumor control with the MAT2A inhibitor treatment. I showed you an example of that with one of those lung cancer, squamous cell lung cancer samples. We also have tumors that have age scores close to 300, which is the maximum age score that you can have. And we find that we can suppress that.

That was one of those lung cancer squamous cell lung cancer samples. We also have tumors that have aged scores.

Close to 300, which is the maximum H score that you can have and we find that we can suppress that all the way down to single or low double digits and that corresponds to efficacy.

Speaker Change: All the way down to two single or low double digits and that corresponds to efficacy

Speaker Change: So the absolute concentration of SDMA in any given sample we think is going to be variable. It's going to be based on the snapshot in time with respect to the turnover rate of the proteins that are methylated, as well as the activity of the enzymes involved. It's going to be related to the speed of the growth of the tumor. But we do find that we see efficacy irrespective of the starting point of the SDMA signal, as long as we are able to suppress that with sufficient exposure to IDE397.

So the absolute concentration of SMA in any given sample, we think is going to be variable.

It's going to be based on a snapshot in time with respect to the turnover rate of the proteins that are methylated as well as the activity of the enzymes involved thats going to be related to the speed of the growth of the tumor but.

But we do find that we see efficacy irrespective of the starting point of the CMA signal as long as we are able to suppress that with a sufficient exposure to <unk> hundred 97.

Got it thanks for providing that level of color and detail and maybe just one last one if I could squeeze it in I may have missed it but what's the potential significance of observing what appears to be 100% knockdown of cytoplasmic SDN may.

Speaker Change: Got it. Thanks for providing that level of color and detail. And maybe just one last one, if I could squeeze it in. I may have missed it, but what's the potential significance of observing what appears to be 100% knockdown of cytoplasmic SDMA while also knocking down 12% of the nuclear SDMA in that cohort for a patient? Thanks.

While also knocking down 12% of the new nuclear S. DMA in that cohort four patient. Thanks.

Speaker Change: Mike, do you want to take that again? Sure, I'll take that one too. What we're seeing in that patient is signs of activity of IDE397 in the tumor that is indicated by a reduction in the signal of the cytosol and a little bit in the nucleus. We don't understand the mechanistic relationship there with respect to whether a tumor has a cytosolic signal or not.

Sure I'll take that one too well.

Is seeing in that in that patient.

As signs of activity of <unk> hundred nine <unk> in the tumor that is indicated by a reduction in the signal of the cytosol and a little bit in the nucleus. We don't understand the mechanistic relationship there with respect to whether a tumor hazardous side of solid signal or not.

Mike: So what we can say at this point is, in that cohort for patients, we are seeing emerging signs of productive pharmacology vis-a-vis the drug is getting to the site of action for the intended therapeutic mechanism, is engaging the target, and is having a consequence on the pharmacology. That's the extent of the conclusion that we wish to draw.

So what we can say at this point is in that cohort four patients. We are seeing emerging signs of productive pharmacology vis vis the drug is getting to the site of action for the intended therapeutic mechanism is engaging the target and is having a consequence on the pharmacology, that's the extent of the <unk>.

<unk> that we wish to draw.

Got it thanks for taking all my questions.

Great. Thanks for the question Charles.

Speaker Change: And our next question comes from Joel Beattie with RW Baird. Please go ahead.

And our next question comes from Joel Beatty with R. W. Baird. Please go ahead.

Joel Beattie: Hi, thanks for the presentation. First question is for the five SAEs and the grade three AE. Can you share what doses they occurred at?

Hi, Thanks for the presentation first question is for the five ftes in the grade three AE.

Are you sure doses they occurred.

Sure, Matt do you want to take that.

Yes, so the all cause let's say use occurred across doses and are generally related to complications of.

Speaker Change: Yeah, so the all-cause SAEs occur at across doses and are generally related to complications of their malignancies and progression of their malignancies.

They are malignancies and progression of the malignancies.

Speaker Change: And I think the one was also the one grade three. I see the grade three Athena was being it was being at.

And I think the one was also the one Greg.

I see the grade III Athena was seen or we've seen that.

Okay.

The dose level four.

Got it I appreciate that and then also could you confirm whether GSK will take response data and progression that at all into consideration when they make their opt in decision.

Speaker Change: Got it. I appreciate that. And then also, could you confirm whether GSK will take response data and progression data at all into consideration when they make their opt-in decision?

Yes, I think.

Speaker Change: Yeah, I think at this point, Joel, the schedule of the option data package requirement is the data that we've provided around the categories, including pharmacodynamic data.

At this point sure. The this schedule of the option data package requirement.

Is the data that we provided around the categories, including Pharmacodynamic data.

Joel Beattie: So, at this point, those are the contents of the actual option data package. Obviously, the two organizations are in regular communication, you know, through the

At this point those are the contents of the actual option data package.

Really the two organizations are in regular communication through the bulk.

Joel Beattie: both the Joint Development Committee of MAT-2A as well as the Joint Steering Committee. But just to be clear, the actual schedule for the option decision

Both the joint Development Committee about two way as well as the joint steering committee, but just just to be clear that the actual schedule for the option decision.

Joel Beattie: the data requirements ends with the tumor pharmacodynamic data.

The data requirements.

With the Pharmacodynamic tumor pharmacodynamic data.

Great. Thank you.

Sure.

Speaker Change: Once again, if you would like to ask a question, please press star 1. Our next question comes from Ben Burnett with Stiefel. Hey, thank you very much for taking our question. I guess based on what you're seeing thus far, what's your current expectation for how long STMA and how long SAM levels need to be reduced before seeing a clinical response?

Once again, if you would like to ask a question. Please press star one.

Our next question comes from Ben Burnett with Stifel. Please go ahead.

Alright, Thank you very much for taking our question.

I guess based on what Youre seeing thus far what's your current expectation for how long S TMA and how long Sam levels need to be reduced before seeing a clinical response.

Speaker Change: Yeah, great, great question, Joel. Mike, do you want to take a stab at that one?

Yes, great Great question, Joel Mike do you want to take a stab at that one.

Hi, Jan.

Mike: One of the things that is an important mechanism of action for us.

One of the things that.

Is an important mechanism of action for US is perturbation of splicing, which then has a consequence on the protein milieu within the tumor that is supporting the disease state. So our mechanism of action requires inhibiting the enzyme that modulates displacing factors that causes displacing <unk>.

Mike: is perturbation of splicing, which then has a consequence on the protein milieu within the tumor that is supporting the disease state.

Mike: So our mechanism of action requires inhibiting the enzyme that modulates the splicing factors that causes the splicing perturbation.

Bashan.

Mike: that interferes with protein function. So it's a multi-step process, and will create a situation where some time is required in order to be able to have sufficient suppression of tumor-selective proteins that are supporting tumorigenesis. When we look at the preclinical...

Interferes with protein function. So it's a multi step process and we will create a situation where some time as required in order to be able to have sufficient suppression of.

Tumor selective proteins that are supporting tumor agenesis, when we look at the preclinical models, sometimes we see situations where upon dosing. The tumor continues to grow and then turns over and as control and other models, we see control from the beginning so there may be indication specific differences in the timing there.

Mike: Sometimes we see situations where upon dosing, the tumor continues to grow and then turns over and is controlled. In other models, we see control from the beginning. So there may be indication-specific differences in the timing. There may be indication-specific, rather, differences with respect to how fast we see a consequence of these effects based on the turnover rate of the splicing factors that are methylated.

<unk> indication significant indication specific rather differences with respect to how.

How fast we see a consequence of these effects based on the turnover rate of the splicing factors that are methylated. So there are a lot of factors at play here that could affect the timing at which the therapeutic mechanism is engaged from our preclinical studies. What we do know is that we need to stay on the target in order to be able to maintain <unk>.

Mike: So there are a lot of factors at play here that could affect the timing at which the therapeutic mechanism is engaged.

Mike: From our preclinical studies, what we do know is that we need to stay on the target in order to be able to maintain control of the tumor. And we need to be able to suppress the target strongly to be able to evoke a productive pharmacological response continuously over time.

Troll of tumor.

And we need to be able to suppress the target strongly to be able to invoke a productive pharmacological response continuously over time.

Yes, and maybe just.

Speaker Change: And maybe just, Ben there, I just would add to Mike's, I think really, you know, in addition to duration to your question, as Mike noted, I think here at the importance of continuous dosing.

I just would add to mikes been relayed in our nation to duration to your question as Mike noted I think here at the importance of continuous dosing.

Speaker Change: without having dose holidays, dose reductions. And that's why we did the comparative at the end of the presentation versus some of the historical, because as we've seen some of that pharmacodynamic data, but based on the AAP profiles, obviously I think the continuous dosing, lack of dose holidays and dose reductions obviously have been challenging for some of these past molecules.

Without having dose holidays dose reductions and Thats why we did the comparative at the end of the presentation versus some of the historical because as we've seen some of that pharmacodynamic data, but based on.

The AE profiles, obviously I think.

The continuous dosing.

Lack of dose holidays and dose reductions obviously have been challenging for some of these past molecules.

Speaker Change: Understood. Okay. That's super helpful. And just one quick kind of clarification question. You mentioned some higher dose cohorts. Is there a goal or is there an appetite to go up until you hit an MTD? Or do you plan on stopping?

Understood. Okay. That's super helpful and just one quick clarification question you mentioned.

Some higher dose cohorts is the is it.

Is there a goal or is there an appetite to go up until you hit an MPD.

Do you plan on shopping at a certain dose.

Speaker Change: Yeah, that's a great, great question. But, you know, I think we are having that discussion internally and we'll be continuing the communication with GSK. You know, we do think now in cohort six, you know, based on the PK PD data that Mike and the human PK data that that Matt walked through, you know, we do think we're at that dose range where, you know, we believe we're in the efficacious range.

Yes, that's correct.

Great question.

I think we are having that discussion internally, we'll be continuing the communication with GSK.

We do the same now in cohort six based on the PK PD data that Mike and the human PK data that that might walk through.

We do think we're at that dose range, where we believe we are in the efficacious range.

Speaker Change: So, I think there is a very likely scenario that if we clear this cohort six.

So I think there is a very likely scenario that if we clear this cohort checks that we would initiate the monotherapy expansion at that dose.

Speaker Change: that we would initiate the monotherapy expansion at that dose.

Speaker Change: And then, for example, start the combination at dose minus 1. And while we do that, we could, in parallel, continue the dose escalation to cohort 7.

And then for example start the combination at dose minus one.

And while we do that we could in parallel continue the dose escalation cohort setup.

Speaker Change: So, but I think these are all discussions that are occurring real time, but I think that's a potential scenario.

But I think these are all discussions that are occurring real time, but I think thats it.

In a potential scenario.

Speaker Change: Okay, okay, that makes sense. Thanks very much. Sure. Thanks for the question.

Okay. Okay that makes sense. Thanks, very much sure. Thanks for the question Doug.

Speaker Change: And the next question comes from Tim Shang with Northland Securities. Please go ahead.

And the next question comes from Tim Chiang with Northland Securities. Please go ahead.

Tim Shang: Hi, thanks. Eugero, just going back to the GSK opt-in decision, is there any requirement for them, actually for you, to show a maximum tolerated dose before they opt in? I'm just sort of wondering, you know, do you have enough data to show to GSK such that, you know, GSK would opt in? You know, what do you think the likelihood of that is at this point?

Hi, Thanks.

Just going back to the GSK opt in decision.

Is there any requirement for them.

For you to show.

A maximum tolerated dose.

Before they opt in I'm, just sort of wondering.

Do you have enough data.

To show to GSK.

Such that GSK would opt in.

What do you think the likelihood of that is at this point.

Speaker Change: Yeah, so, Tim, the way the schedule is written for the option, it's the expansion dose selected.

Yes, so Tim the way the schedule is written for the option.

It's the expansion dose selection dead.

Speaker Change: for this next phase of development or MTD.

For this next phase of development or MTBE.

Tim Shang: So, and so really it's based on the decision we make for initiating the monotherapy.

And so it really it's based on the decision we make for initiating the monotherapy.

Tim Shang: expansion. I think separately to the question that Ben asked earlier, you know, I think there is a scenario that we would pick a dose, for example, cohort six, as the expansion does as we continue to dose escalate to define MTD.

Expansion.

I think separately to the question that Matt asked earlier I think there is a scenario that we would pick a dose for example cohort six as the expansion does as we continue to dose escalate to define MTBE.

Tim Shang: Um, but that you know, that's not that's not a requirement for

But that that's not that's not a requirement for.

Tim Shang: Uh, the option package delivery, uh, it's really more based on the dose selection for the next phase and that could be either a lower dose or or an empty.

The option package delivery, it's really more based on the dose selection for the next phase and that could be either a lower dose or an MTT dose.

Speaker Change: I see, OK, and maybe just one follow up and it's.

I see okay, and maybe just one follow up.

Speaker Change: Really on Dara-Ovassertiv, I mean, I guess you just announced an expansion of that collaboration with Pfizer. Could you just talk a little bit about what that entails? You know, is Pfizer going to supply you more product, more active product? Or are they, you know, also going to devote some resources to this study?

Really on.

None of US are too I mean, I guess, you just announced.

Pension of that collaboration with Pfizer, just talk a little bit about what that entails.

Going to supply more product more active product.

Or are they.

So we're going to devote some resources.

Two the studies going forward.

Speaker Change: Yeah, no, you know, we were very excited to be able to make that announcement yesterday on derovus seratib with Pfizer. And there were two agreements, or two new agreements that were put into place. And so first for metastatic uveal melanoma, you know, in our earlier agreement with Pfizer, it was very specific that it would not include work for a registrational trial.

Yes.

Very excited to be able to make that announcement yesterday on.

<unk> with Pfizer and there were two agreements.

Two new agreements that were put into place and so first for metastatic uveal melanoma.

In our earlier agreement with Pfizer.

Very specific but it would not include work or a registrational trial.

Speaker Change: So the new agreement that was put in place was specifically to enable a potential registration enabling trial. And I think part of that is because, you know, it does require more just engagement, interaction with Pfizer, both from a regulatory perspective, and Tim, as you can appreciate, you know, if approved, obviously would be, you know, would be a label changing event as well. In terms

So the new agreement that was put in place with specific lead to enable a potential registration, enabling trial and I think part of that is because it does require more just engagement interaction with Pfizer both from a regulatory perspective and Timna as you can appreciate if approved obviously.

B.

Would be a label changing of that as well.

In terms of the setup.

Speaker Change: For that, it is similar in terms of supply, there is a joint steering committee, the two organizations do meet fairly regularly. In addition, obviously, their involvement both in terms of certain specific regulatory documents and communication with FDA.

For that it is similar in terms of supply.

There is a joint steering committee.

The two organizations do meet fairly regularly in addition, obviously their involvement both in terms of certain specific regulatory documents and communication with the FDA.

Speaker Change: Obviously, the development of the clinical protocol, there are also specific provisions around joint intellectual property, of which.

Obviously the development of the clinical protocol. There are also specific provisions around joint intellectual property of which.

Speaker Change: Joint IP has been filed here already, as well as joint publication rights.

Joint IP has been filed here.

Already as well as joint publication rights.

Speaker Change: The second agreement is separate, and that is to explore this combination of darobosteratib with crizotinib and additional CMET-driven tumors.

The second agreement is separate and that is to explore this combination of dorobo share Ted with Chris Op, Ned and additional C met driven tumors.

Speaker Change: including, as was noted, hepatocellular carcinoma, and we believe another indication, non-small cell lung cancer, which it appears Pfizer has interest to explore this combination.

Including as was noted that Sam.

Cellular carcinoma, and we believe another indication non small cell lung cancer, which.

Appears Pfizer has interest to explore this combination.

Speaker Change: So, that as well, the design, the protocol, in conjunction with Pfizer has been developed. And in parallel, we are also doing some preclinical validation work, as was noted in our earnings update today.

So that as well the design the protocol in conjunction with Pfizer has has been developed and in parallel.

We are also doing some preclinical validation work as was noted in our earnings update today.

And that setup is basically mirrors, what I noted for the Registrational mom as well except that it is not for a registrational supply that would be our next step pending this.

Speaker Change: And that setup is basically MERS, what I noted for the registrational one as well, except that it's not for a registrational supply. That would be a next step pending this initial signal seeking study.

This initial signal seeking study.

Speaker Change: OK, yeah, that's that's good details. Thanks, thanks you do. Yep, absolutely 10. Thanks for the question.

Okay.

Yes, that's good details thanks, Thanks, Joe.

Absolutely Tim Thanks for the question.

And we will now take our last question in queue today coming from Zach <unk> with Roth Capital Partners. Please go ahead.

Speaker Change: And we will now take our last question in queue today coming from Zegbe Jella with Roth Capital Partners.

Zegbe Jella: Good morning. Thanks for the update. I think I just have 2 quick ones. The 1st 1 is a follow up to the question. I was asked earlier about and the absolute versus percentage change. And so I just kind of want to get us into.

Good morning, Thanks for the update I think I just have two quick ones. The first one.

Back to the question that was asked earlier.

And the absolute pricing percentage teams.

Got it thank you.

Zegbe Jella: You know, how strong the correlation is between that and tumor reduction and based on the data that you have so far. And then, I guess, another thing I wanted to ask was, you know, perhaps some variability that you may be seeing and what might be driving that is just the tumor type. You know, what are some of the variabilities that you're seeing and how do you plan to tackle that?

Hi, John the correlation between that and tumor reductions and based on that data that you have so far and then I guess another thing I wanted to ask with perhaps and some bad already that you may be seen in what might be driving that if the tumor type.

Letting some of the Vanguard is that Youre seeing and how do you plan to tackle that.

Speaker Change: Yeah, so I think first on the just, I would say clinical side, you know, we've already shown earlier, as you know, you know, CT scans, human CT scans with tumor shrinkage, and we have several of those patients. And then I also know we commented on a thymic patient, I believe was on study.

Yes, So I think first on the just I would say quite a outside we've already shown earlier.

No.

<unk> scans and Cte scans of tumor shrinkage and we have.

Several of those patients in iOS that we commented on that dynamic patient I believe was off study.

Speaker Change: at that point of the disclosure, about six months earlier in the cohort, this escalation. And we did not have tumor biopsies for those patients, so I would say we're somewhat dealing with a limited number.

At that point of the disclosure about six months earlier than the cohort dose escalation and we did not have.

Tumor biopsies for those patients decide let's say, we're somewhat dealing with a limited number.

Speaker Change: in terms of the, at least currently, of the phase one dose escalation on that specific question. But I think we have a lot of data preclinically on that association between SDMA reduction.

In terms of the lease.

Currently the phase one dose escalation on that specific question.

I think we have a lot of data pre clinically on that association between <unk> reduction.

Speaker Change: and tumor growth inhibition or regression pre-clinically. But Mike, any additional comments there you want to make?

And tumor growth inhibition of refresh and pre clinically about bike any additional comments there you want to make yes.

Mike: Yeah, thanks, Drew. Thanks for the question. Yeah, that was great. Just as a little bit of a follow up from a preclinical standpoint.

Yeah. Thanks, Joe Thanks for the question.

Yes that was great just as a little bit of a follow up from a preclinical standpoint.

Mike: But what we're really looking at here is not the delta so much as getting below a threshold. So everything that we've seen so far suggests that you need to get below a threshold of SDMA to have a response.

But what we're really looking at here is not the delta so much as getting below a threshold. So everything that we've seen so far suggests that you need to get below a threshold of CMA to have response.

Mike: you're not always necessarily going to get a response. There is in some models required, but not sufficient in the preclinical setting. But we're looking at a situation where we want to get below a threshold of SDMA in the tumor to be able to have efficacy.

Not always necessarily going to get a response there is in some models required but not sufficient in the preclinical setting, but we're looking at a situation, where we want to get below a threshold of SMA in the tumor to be able to have efficacy.

Thank you in terms of availability of gas.

Speaker Change: Thank you. In terms of the variability, I guess, in patients getting below that threshold versus those that are not, are you seeing anything there in terms of nuances and baseline characteristics?

So getting below that threshold.

Yes.

And then kind of stabilizes and baseline characteristics.

Speaker Change: Yeah, I would say, Zagpa, in terms of our clinical data, you know, I think the, at this point, the pharmacodynamic data that we have on every patient is plasma, and there it's a fairly consistent and robust reduction of the pharmacodynamic marker. In terms of tumor PD, you know, it's in a smaller subset of patients.

Yes, I would say <unk> and <unk>.

Terms of our cleanup call data I think the at this point the Pharmacodynamic data that we have on every patient is plasma.

They're fairly consistent from robust reduction of the Pharmacodynamic marker.

Tim's or tumor PD.

It's in a smaller subset of patients.

Speaker Change: So I think it's a bit hard to say in the at least at this point right now We did show pancreatic as well as lung cancer You know at least in the figures today So, you know, I think we just need a larger data set to comment on that specific question clinically this time

So I think it gets a bit hard to say in the at least at this point right now we did show pancreatic as well as lung cancer.

At least in the figures today so.

I think we just need a larger dataset to comment on that specific question clinically at this point.

Speaker Change: Thanks. And then the last 1 year is I know that the combo data is not required for the package that will be submitted to GSK. but I was just wondering in terms of when GSK has to make the decision.

Thanks Cynthia.

When you guys narrowed that the combo data is not required for a package that will be submitted to you.

Okay.

And Ken.

When people have to make that decision.

Speaker Change: relative to when you'll have the combo data. So is it likely that you'll have the combo data before GSK has?

Relative to when you will have the combo data.

Likely that Youll have the combo data before the FDA has.

Speaker Change: to make their opt-in decisions. Just kind of wondering about how the combo data might help influence some of that decision-making.

Nick.

And just taken just kind of wondering about how the combo data might help influence that decision making.

Speaker Change: Yeah, in terms of combination data, there is no requirement for us to have clinical combination data.

Yes.

In terms of combination data is like that.

There is no requirement for us to have clinical combination data.

Speaker Change: We have been working very much in a highly collaborative fashion, and GSK is

We have been working very much in a highly collaborative fashion and GSK is.

Speaker Change: from our perspective has added a tremendous amount of value on the preclinical combination evaluation.

From our perspective has added a tremendous amount of value on the preclinical combination of evaluation.

Speaker Change: both in terms of NGSK running an agnostic screen.

Both in terms of GSK running agnostic screen.

Speaker Change: as well as helping IDEA think through, you know, really the scientific rationale and basis for a lot of these combinations. And I think there we are in very solid footing, at least from our perspective, and we do have three combination arms.

As well as helping idea think through.

Really the scientific rationale and basis for a lot of these combinations and I think there we are in various solid footing at least from our perspective, and we do have three combination arms.

Speaker Change: that have been submitted as part of this protocol amendment with the FDA.

That had been submitted as part of this protocol amendment with the FDA.

Speaker Change: But just to be clear, that is not the clinical portion, at least, is not required as part of the option package. Thanks, Yajaira. Great. Thanks so much.

But just to be clear that is not the clinical portion at least is not required as part of the option package.

Thanks.

Great. Thanks, so much <unk> questions.

Operator are there any more questions on queue.

No there are no further questions.

Speaker Change: Great. So with that, we'll conclude the ID397 Phase 1 update, as well as your Q1 2022 earnings update. And again, thank you very much for the time. And operator, thank you so much for hosting the Q&A session today.

Great. So with that we'll conclude <unk> hundred 97 phase one update as well as our Q1 'twenty two earnings update and again. Thank you very much for the time and operator. Thank you so much for.

Hosting the Q&A session.

This concludes today's call. Thank you for your participation you may now disconnect.

Speaker Change: This concludes today's call. Thank you for your participation. You may now disconnect.