Q3 2023 Exscientia PLC Earnings Call
Speaker 1: Hello everyone, my name is Sarah and I will be your conference operator today. At this time, I would like to welcome everyone to Accentia's Business Update Call for the third quarter of 2023.
Hello, everyone. My name is Sarah and I will be your conference operator today at this time I would like to welcome everyone to <unk> business update call for the third quarter.
<unk> of 2023.
Speaker 1: After the prepared remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star 1.
After the prepared remarks, there will be a question and answer session. If you would like to ask a question. During this time simply press star one.
Speaker 1: At this time, I would like to introduce Sarah Sherman, Vice President of Investor Relations. Sarah, you may begin.
At this time I would like to introduce Sara Sherman Vice President of Investor Relations, Sir you may begin.
Thank you operator, our press release and 6K were issued this morning, with our third quarter 2023 financial results and business update.
Speaker 2: Thank you, operator. A press release in 6K where it should this morning with our third quarter, 2023 financial results and business update.
Speaker 2: These documents can be found on our website at investors.extension.ai along with the presentation for today's web.
These documents can be found on our website at investors that extent, yet dot AI along with the presentation for today's webcast before we begin I'd like to remind you that we may make forward looking statements on our call. These may include statements about the initiation timing and progress of and data collected during and reported from the Companys clinical trial <unk>.
Speaker 2: Before we begin, I'd like to remind you that we may make forward-looking statements on our call. These may include statements about the initiation, timing, and progress of, and data collected during and reported from, the company's clinical trials, expectations regarding the growth of the company's capabilities and the performance of its technology platform, and the company's projected cash runway. Actual results may differ materially from those indicated by these statements.
<unk> regarding the growth of the company's capabilities and the performance of its technology platform and the company's projected cash runway.
Actual results may differ materially from those indicated by these statements unless required by law Accenture does not undertake any obligation to update these statements regarding the future or to confirm these statements in relation to actual results on.
Speaker 2: Unless required by law, extension does not undertake any application to update these statements regarding the future or to confirm these statements in relation to actual results.
Speaker 2: On today's call, I'm joined by Professor Andrew Hopkins, Chief Executive Officer, Dr. Dave Hallett, Chief Scientific Officer, and Ben Taylor, CFO and Chief Strategy Officer. Dr. Mike Krems, Chief Quantitative Medicine Officer, will also be available for the Q&A session. And with that, I will now turn the call over to you.
On today's call I'm joined by Professor Andrew Hopkins, Chief Executive Officer, After Dave Hallett, Chief Scientific Officer, and then Taylor CFO and Chief Strategy Officer, Dr. Micron's, Chief Quantitative Medicine Officer will also be available for the Q&A session.
And with that I will now turn the call over to Andrew.
Thank you Sarah.
Speaker 3: Thank you, Thera. In the food quarter of 2023, we meet great striates across our internal and partners.
In the food quarter of 2020 free we made great strides across all internal.
A lot of their programs.
Speaker 3: We are executing on a focused development pipeline and prioritizing our most differentiated, highest value oncology programs, including GTA, EXS617, our CDK7 inhibitor in partnership with GTA Peron, which is enrolling patients in a phase 1, 2 clinical trial.
<unk> executed on a focused development pipeline and prioritizing our most differentiated highest value oncology programs, including GTA Exs 617, our CDK <unk> inhibitor in partnership with GTA, Poland, which is enrolling patients in our phase one two clinical trial.
Speaker 3: and E-XS 74539, our LSD-1 inhibitor, for which we anticipated an IND in the first quarter of 2024.
<unk> 740, <unk> hundred nine our L. A C. One inhibitor for which we anticipate submitting an IND in the first quarter of 2024.
Speaker 3: We also advanced partner programs, achieving a first milestone in our Sonoffie collaboration and inked a new partnership with Mirk KGAA that bolstered our financial strengths and expanded our...
We also advanced partner programs, achieving our first milestone how sanofi collaboration and inked a new partnership with Luke Keiichi AA.
That bolstered our financial strength and expanded our reach we continue to push forward with clinical validation, our precision medicine platform X sight. One is a multicenter observational trial evaluation of a predictive power of a functional precision medicine platform in a very cancer. We also have a similar program with charity and Hematological cancers.
Speaker 3: We continue to push forward with clinical validation, our precision meant.
Speaker 3: ExCite 1 is a multi-center observational trial evaluating the predictive power of a functional precision medicine platform in ovarian cancer. We also have a similar program with
Speaker 3: As a learning company, we're always looking for ways to advance and develop new
As a learning company, we're always looking for ways to advance and develop new tech.
Speaker 3: Accent here's automation facility, Reacing the Open, and we have begun screening biological
<unk> automation facility recently opened and we've begun screening biological assay.
Speaker 3: We plan to migrate all the primary assays we can from our CROs to our automated...
We plan to migrate all the primary assays, we come from a CLO so automated labs we.
Speaker 3: We synthesized our first compound, other automation labs, and through 2024 plan to bring you more information of how we integrate in AI to automate chemical synthesis at the facility.
We synthesize the first compound out of automation labs and through 2024 plants. We bring you more information on how we integrated AI to automate chemical synthesis Axa facility.
Speaker 3: Productivity in the automated laboratory will ramp up through 2025.
Productivity can be automated laboratory will ramp up through 2024.
Speaker 3: We're expecting a meaningful impact on the quantitative data we generate as well as vital times from the new labs. We are committed to the integration of AI and automation to improve the way you've drugged.
We are expecting a meaningful impact on the quantity of data, we generate as well as cycle times will believe labs, we are committed to be integration of AI and automation to improve the way drugs are designed.
Speaker 3: We also recently presented data on an automated, denover design tool that is able to deliver potent, kindness hits from the alpha force.
We also recently presented data on an automated dean overdesigned to about is able to deliver potent kinase hits from BL fulfill structures we.
Speaker 3: We developed this capability based on learning from prior successful projects. The
We developed this capability based on learnings from prior successful projects.
First exemplification of its design effort was to show how novel potent selective <unk> inhibitors can be generated to de novo from the alpha fold kind of models.
Speaker 3: was to show how novel potent and selective kinds inhibitors can be generated denover from the alpha-fold kind of models. The method can potentially
The method can potentially be applied across the proteome.
Speaker 3: This tool is a continuation of our philosophy of encoding and automating drug discovery wherever possible and we look forward to applying this at scale across future
This tool is a continuation of our philosophy of encoding and automated drug discovery wherever possible and we look forward to apply invest at scale across future projects.
Speaker 3: We believe we remain well capitalized with $447.8 million in cash at the end of a quarter, providing us with a runway well into 2020.
We believe we remain well capitalized with $448 million in cash at the end of the quarter provides us with a runway well into 2026 to advance our near term programs as well as grow our capabilities driven by recent investments in automation as well as a lead in technological.
Speaker 3: to advance our near-term programs, as well as grow our capabilities, driven by recent investments in automation, as well as other leading technological and scientific advances.
Scientific advances, which allow us to reach key inflection points that will drive the value of our platform.
Speaker 3: which allow us to reach key inflection points that will drive the value of up.
Speaker 3: We've recently prioritized our pipeline to focus internally on the programs we believe will have the greatest clinical impact for patients and which have the highest probability.
We've recently prioritized our pipeline to focus internally on our programs. We believe we will have the greatest clinical impact for patients.
And which has the highest probability of success.
Speaker 3: As previously mentioned, our partnership business continues to mature.
As previously mentioned our partnership business continues to mature. This is highlighted by the new collaboration we announced in September with Merck Keiichi AI based in Darmstadt, Germany.
Speaker 3: This is highlighted by the new collaboration we announced in September with Merck KGAA based in Darmstadt, Germany.
Speaker 3: Prior to finding the agreement, we identified three potential first in class or best in class targets in oncology and immense.
Prior to signing the agreement we identified three potential first in class or best in class targets in oncology and immunology.
Under the terms of the agreement, we will receive an upfront cash payment of $20 million from Merck if all milestones for all three initial programs have achieved will be eligible for discovery development regulatory and sales based milestone payments of up to $674 million.
Speaker 3: Under the terms of the agreement, we will receive an upfront cash payment of $20 million from Merck. If all milestones for all three initial programmes are achieved, we will be eligible for discovery, development, regulatory and sales-based milestone payments of up to $674 million.
Speaker 3: We are excited to announce this partnership, as we believe our integrated technology platform will complement MOOC's scientific prowess as we partner to address drug discovery challenges in cancer and immunos.
We are excited to announce this partnership as we believe our integrated technology platform will complement merck's scientific prowess as we partner to address drug discovery challenges in cancer and immunology.
Speaker 3: We focus our internal pipeline on oncology targets, where our technology can help improve the probability of success through precision design and precision medicine. Two highly differentiated molecules that demonstrate a strategy, a GTA.
We focus our internal pipeline on oncology targets, where our technology can help improve the probability of success through precision design and precision medicine.
Highly differentiated molecules have demonstrated strategy of GTA, exs 617 or 617.
Speaker 3: our CDK7 inhibitor, and EXS74539 or 539, our LSD1 inhibitor.
CDK <unk> inhibitor and Exs 745 hundred 39, or <unk> 49, our LSD one inhibitor.
Speaker 3: Fix-1-7 has potential as a besting class reversible CD case.
607 has potential as a best in class reversible CDK <unk> inhibitor.
Speaker 3: It was designed for improved potency, selectivity and farm co-kinetics compared to other molecules and...
Was designed for improved potency selectivity and pharmacokinetics compared to other molecules in development.
Speaker 3: Enrollment is ongoing in the phase one due and lucidative adaptive clinical trial with advanced solitumas included head and neck cancer, pancreatic cancer, non-smolfer lung-
Beaumont is ongoing in the phase one to elucidate adaptive clinical trial with advanced solid tumors, including head and neck cancer pancreatic cancer non small cell lung cancer hormone receptor positive <unk> negative breast cancer.
Speaker 3: hormone receptor positive, her two negative breast cancer, Cholorectal cancer and of various...
Lola rectal cancer and ovarian cancer.
Speaker 3: The model-driven adaptive trial is study in 6 or 7 as both a monoferope and in combination with standard of care, where we expect our precision-meds and platform to play a critical role in determining the optimal combination.
The model driven adaptive trial is studying 617 as both a monotherapy.
<unk> in combination with standard of care, where we expect a precision medicine platform to play a critical role in determining the optimal combinations.
Speaker 3: 539, our LSD1 inhibitor also has best in class but
<unk> hundred nine our LSD. One inhibitor also has best in class potential 59 is a high level of differentiation due to its reversible mechanism of action CNS penetration preclinical safety profile and anticipated flexibility of dosing that should help maximize therapeutic index. This year.
Speaker 3: 539 is a high level of differentiation due to its reversible mechanism of action.
Speaker 3: CNS penetration, pre-clinical safety profile, and anticipated flexibility of dosing that should help maximize therapeutic.
Speaker 3: This unique set of properties provides both first-in-class and best-in-class potential for small cell lung cancer and acute myeloid leukemia.
Unique set of properties provides both first in class.
<unk> best in class potential for small cell lung cancer and acute myeloid leukemia.
Speaker 3: GLC Talk Studies with Compo.com. I'll expect to submit an IND in the first quarter of 2020.
<unk> Tox studies with compound are complete and we expect to submit an IND in the first quarter of 2024.
Speaker 3: Just behind 539 is our MOLT1 inhibitor, EXS73565.
Just behind 549 is a bolt one inhibitor exs seven free 565, all 565 Vishal.
Speaker 3: We believe that 565 is highly differentiated due to reduced UGT-1A1 inhibition combined with portency and celcius.
We believe at 56 five is highly differentiated due to reduced UGG one a one inhibition combined reportedly and sensitivity 50.
Speaker 3: 565 is progressing through IND and CTN Able to studies, and we look forward to sharing more information on this with you in the first half of 2020.
565 is progressing through <unk> and Cta, enabling studies and we look forward to sharing more information on this with you in the first half of 2024.
Speaker 3: As for our partner programs, we currently have free nucleic. EXS 4318 or 4318, a PKC FETA inhibitor designed by Accentia and inlicensed by Bristol-WireSquib is in phase one. And two programs designed by Accentia for Sumitomo Pharma, DSP0038, a bi-specific 5HT1A agonist, and 5HT2A antagonist.
As for our partner programs. We currently have free in the clinic Exs for free one <unk> or four <unk>, a pique see FIFA inhibitor designed by <unk> and in licensed by Bristol Myers Squibb is in phase one and two programs designed break Cynthia for Sumitomo pharma DSP zebras Eagle free H E bike specific.
<unk>, five <unk> agonist and <unk> antagonist and.
Speaker 3: And DSP 2342, a dual 5HT2A 5HT7 antagonist also are in phase 1s.
And DSP $23 four to a dual five <unk> seven antagonist also are in phase one studies.
Speaker 3: We also achieved our first milestone fund, Immunology and Information Target, with NL Collaboration with SIN.
We also achieved our first milestone for immunology and inflammation target within our collaboration with Sanofi.
As a reminder, the Sanofi collaboration is for up to 15 oncology and immunology targets.
Speaker 3: As a reminder, the Sanofi collaboration is for up to 15 oncology and immunological targets.
Speaker 3: And potential milestone payments, love to 343 million per prog-
And potential milestone payments of up to 343 million per program.
Speaker 3: Beyond the programs highlighted, we believe we have a well-balanced blend of internal and partner programs. This means that we're able to de-risk some programs with the help of our partners and fully maximize the value of a program that we solely own.
Beyond the programs highlighted we believe we have a well balanced blend of internal and partnered programs. This means our able to derisk some programs with the help of our partners and fully maximize the value of our programs that we solely owed.
I'll now hand over to Dave <unk>, our Chief Scientific officer to walk us through an update of our LSD, one and multiple programs, including data presented last month at ESMO, The European Society for medical oncology.
Speaker 3: I'll now hand over to Dave Hallett, I'll achieve scientific officer to walk us through an update of our LSD1 and Malt1 programs, including data presented last month at ESMO, the European Society for Medical Uncology.
Dave.
Thank you Andrew.
Speaker 4: I'll start by spending some time on why we are so excited by our LSD1 inhibitor, including the recent data we presented at the ESMO Congress last month.
I'll start by spending some time on why we're so excited by our LSD one inhibitor, including the recent data we presented at ESMO Congress last month.
Speaker 4: As Andrew mentioned, we believe our LSD1 inhibitor 539 has best-in-class potential, as its reversible mechanism of action and its predicted human half-life is expected to translate to an improved therapeutic index through more flexible dosing options.
Andrew mentioned, we believe our LSD one inhibitor <unk> hundred nine as best in class potential reversible mechanism of action and its predicted human half life is expected to translate to an improved therapeutic index through more flexible dosing options.
Speaker 4: We also believe it could be of benefit to patients with brain metastases due to its brain penetrant design.
We also believe it could be a benefit to patients with brain metastases due to its brain penetrant design.
Speaker 4: We have completed GLP toxicity studies, and we intend to file an IND for 539 in the first quarter of 2024.
We have completed DLP toxicity studies, and we intend to file an IND for <unk> hundred 39 in the first quarter of 2024.
Speaker 4: If the IND is cleared, this will enable us to go into a healthy volunteer study also in 2024.
If the IND is cleared this will enable us to go into a healthy volunteer study also in 2024.
Speaker 4: Understanding the impact of LSD1 inhibition on cells of myeloid lineage, such as platelets, is critical.
Understanding the impact of LSD, one inhibition on sales of myeloid lineage such as platelets is critical.
This is likely to be highly valuable in heavily pretreated oncology patients.
Speaker 4: This is likely to be highly variable in heavily pre-treated on-call-de-patient.
Speaker 4: Hence why we believe starting with healthy volunteers is the best strategy.
Hence why we believe starting with healthy volunteers is the best strategy.
Like all things, we do at Accenture, we will incorporate this trial data into our simulations as part of our modeling formed drug development approach.
Speaker 4: Like all things we do at Accenture, we will incorporate this trial data into our simulations as part of our modeling formed drug development approach.
Speaker 4: In turn, this will then allow us to establish a therapeutic dose and enable combinations studies in acute myeloid leukemia and small cell lung cancer at the outset.
In turn this will then allow us to establish a therapeutic dose and enable combination studies in acute myeloid leukemia, and small cell lung cancer at the outset.
Speaker 4: As combination therapy is the ultimate goal, we believe a pathway via healthy volunteers is the fastest route to achieve.
As combination therapy is the ultimate goal, we believe a pathway by a healthy volunteers is the fastest route to achieve this.
Speaker 4: We are currently running translational studies which will inform the combination strategies we prioritize when we start studies in patients.
We are currently running translational studies, which will inform the combination strategy as we prioritize when we start studies in patients.
Speaker 4: The literature has shown the potential benefit of LSD1 inhibition in a variety of indications, including neuroendocrine pancreatic and prostate cancer.
The literature has shown the potential benefit of LSD, one inhibition in a variety of indications, including neuroendocrine pancreatic and prostate cancers. We believe that 539 has the highest potential benefit for patients with AML and small cell lung cancer.
Speaker 4: We believe that 539 has the highest potential benefit for patients with AML and small cell lung cancer.
Speaker 4: Highlighted here is the U.S. incidence for these two indications.
Highlighted here is the U S incidence for these two indications.
Speaker 4: In the U.S. alone, there are 45,000 patients each year impacted by these diseases.
In the U S alone there are 45000 patients each year impacted by these diseases.
As a brain penetrant molecule <unk> hundred nine should help address that population of small cell lung cancer patients that will develop brain metastases, which is roughly 50%.
Speaker 4: As a brain penetra molecule, 539 should help address that population of small cell lung cancer patients that will develop brain metastasis, which is roughly 50%.
Through our precision medicine platform work, we will be aiming to identify those that are most likely to respond and factor this into our clinical development strategies.
Speaker 4: Through our precision medicine platform work, we will be aiming to identify those that are most likely to respond and factor this into our clinical development strategy.
Our goal when designing $5 39 was to combine CNS penetration with an appropriate predicted human half life and a reversible mechanism.
Speaker 4: Our goal when designing 539 was to combine CNS penetration with an appropriate predicted human half-life and a reversible mechanism.
Speaker 4: It refers to deactivating this enzyme can contribute to poor control of playlet level.
Irreversibly Deactivating this enzyme can contribute to pope controlled of platelet levels.
Speaker 4: We believe that having a reversible mechanism and combining this with a shorter half-life should result in a better therapeutic index.
We believe that having a reversible mechanism and combining this with a shorter half life should result in a better therapeutic index.
CNS penetration is important because it helps address brain metastases, which is prevalent in advanced disease.
Speaker 4: CNS penetration is important because it helps address brain metathesis, which is prevalent in advanced disease.
Speaker 4: We believe that we have designed the first molecule that combines these three key criteria.
We believe that we have designed the first molecule that combines these three key criteria.
Speaker 4: LSD1 is an epigenetic modifier, but also forms a variety of complexes with transcription factors, promoters, activators, co-repressors, and non-coding RNAs.
LSD one is an epigenetic modifiers, but also forms a variety of complexes with transcription factors promoters oxy basis co represses on non coding Rnas.
Speaker 4: As a result, the key mechanisms of action are different in AML and small cell lung cancer.
As a result, the key mechanisms of action are different in AML and small cell lung cancer.
Speaker 4: though LSD-1 inhibition leaves tumor cells vulnerable to cytotoxic agents in both indications.
So LST one inhibition leaves tumor cells vulnerable to cytotoxic agents in both indications.
Speaker 4: In AML, LSD1 inhibition promotes cell differentiation by blocking the growth factor independent repressor complex leading to a circulation of key promotes.
In AML LSD, one inhibition promote cell differentiation by blocking the growth factor independent repressor complex, leading to a saturation of key promoters.
Speaker 4: This results in the induction of leukemic blast cell differentiation, which slows or stops the expansion of tumor cells.
This result in the reduction of leukemic blood cell differentiation, which slows or stops the expansion of tumor cells.
<unk> mechanism of action is different in small cell lung cancer.
Speaker 4: LSD1's mechanism of action is different in small cell lung
Speaker 4: Here, in addition of LSD1, suppresses neuroendocrine features through up-regulation of not stigling. We can turn promotes differentiation into quiescent cancer cells.
Here inhibition of LSD, one suppresses neuroendocrine features through upregulation of not signaling, which in turn promotes differentiation into quiescent cancer cells.
Speaker 4: These quiescent cells are sensitized to combinations with cytotoxic agents or checkpoint inhibition.
These crest itself are sensitized to combinations with cytotoxic agents or checkpoint inhibition.
Here, we showcase the potential safety benefits of having a reversible mechanism coupled with a shorter half life.
Speaker 4: Here we showcase the potential safety benefits of having a reversible mechanism coupled with a shorter half-life.
Speaker 4: This additional in vivo data highlights the activity of 539 compared to an irreversible LSD-1 inhibitor currently in clinical development.
This additional in vivo data highlights the activity of $5 39, compared to an irreversible <unk> inhibitor currently in clinical development.
In the left panel you see the outcome of a 20 day study in a mouse model.
Speaker 4: In the left panel, you see the outcome of a 20-day study in a mouse model.
Speaker 4: 539 was dosed on a twice per day schedule at 6.6 milligrams per kilogram.
<unk> nine was dosed on a twice per day schedule at six six milligrams per kilogram.
Speaker 4: 16 hours after the final dose on day 20, play the levels with a famous control. This is in stark contrast.
16 hours after the final dose on day 20, platelet levels were the same as control.
This is in Stark contrast to the irreversible inhibitor.
Despite only administering this compound once per week optimal 0.4 milligrams per kilogram.
Speaker 4: only administering this compound once per week at 0.4mg per kilogram. Mouse platelets remain substantially depleted on day 20.
Platelets remain substantially depleted on day 20.
On the right panel you see the outcome of a 15 day rat non GOP study, where we looked up platelet levels as a function of both time and dose.
Speaker 4: On the right panel, you see the outcome of a 15-day RAT non-GLP study, where we looked at platelet levels as a function of both time and dose.
Speaker 4: Note the higher doses of 539 compared to the efficacy study and the dosing schedule studied here, 3 days on, 4 days off.
Note the higher doses of $5 three 9% compared to the efficacy study on the dosing schedule studied here three days on four days off.
Whilst we initially saw a reduction in rat platelets, followed by a rebound of drug by day 15, platelets with packet control levels.
Speaker 4: Whilst we initially saw a reduction in rap platelets followed by a rebound of drug, by day 15 platelets were back at control level.
539, as a reversible LSD one inhibitor when coupled with intermittent dosing is expected to reduce on target toxicity.
Speaker 4: 539 as a reversible LSD1 inhibitor when coupled with intermittent dosing is expected to reduce on target tops.
Speaker 4: Irreversible inhibitors, regardless of dosing frequency, require re-synthesis of the LSD1 protein before its normal functions resume, and are predicted to have an inferior therapeutic endotry.
Irreversible inhibitors, regardless of dosing frequency required re synthesis of the LSD one protein before its normal functions resume on a predictor to hop on inferior therapeutic index.
Turning to efficacy here, we highlight dose dependent oral efficacy observed with 539, and a small cell lung cancer xenograft model.
Speaker 4: Turning to efficacy, here we highlight dose-dependent oral efficacy observed with 539 in a small cell lung cancer xenograft.
And the same study we also evaluated a well described blood based neuroendocrine small cell lung cancer biomarker pro gastrin releasing peptide.
Speaker 4: In the same study, we also evaluated a well-described blood-based neuro-edit crime small cell lung cancer biomarker, progastrin-releasing peptide or pro-GRP for short.
GOP for short.
On the left we can see dose dependent monotherapy activity and a small cell lung cancer xenograft, when dosed up to $3 three milligrams per kilogram on a twice a day schedule.
Speaker 4: On the left, we can see dose-dependent monotherapy activity in a small cell lung cancer zener graft when dosed up to 3.3 milligrams per kilogram on a twice a day schedule.
Speaker 4: On the right you can see the corresponding effect on Plasma ProGRP level.
On the right you can see the corresponding effect on plasma <unk> levels.
Speaker 4: At 3.3 milligrams per kilogram, pro-GRP levels are below the limit of detection in our assay, and this tracks beautifully with maximal effect on tumour volume.
At $3 three milligrams per kilogram pro GOP levels below the limit of detection and our assay and this trucks beautifully with maximal effect on tumor volume.
It is important to note that 559 was well tolerated throughout this 28 day mouth city.
Speaker 4: It is important to note that 539 was well tolerated throughout this 28 day mouse study.
As a reminder, LSD one inhibition is predicted to leave tumor cells vulnerable to combination approaches and we demonstrated in vitro combination activity later in this presentation.
Speaker 4: As a reminder, LSD1 inhibition is predicted to leave tumour cells vulnerable to combination
Speaker 4: And we demonstrate in vitro combination activity later in this presentation.
Speaker 4: Further in vivo combination studies are planned and we expect to share the data with you in 2024.
Further in vivo combination studies are planned and we expect to share the data with you in 2024.
At ESMO, we presented new preclinical data demonstrating that <unk> hundred nine in juices AML cell differentiation market expression when used on primary AML samples ex vivo.
Speaker 4: At ESMO, we presented new preclinical data demonstrating that 539 induces AML cell differentiation marker expression when used on primary AML samples ex vivo, confirming 539's general activity.
Affirming <unk> general activity.
As shown in the poster healthy non transformed bone marrow blast differentiation was unaffected in our setup.
Using <unk> six as a biomarker for blood cell differentiation, we were able to compare <unk> to some irreversible LSD one inhibitors currently in the clinic.
Speaker 4: Using CD86 as a biomarker for blast cell differentiation, we were able to compare 539 to some irreversible LSD1 inhibitors currently in the clinic.
The top graph shows that the level of differentiation on the Y axis was comparable at different concentrations on the X axis for different LSD one inhibitors.
Speaker 4: The top graph shows that the level of differentiation on the y-axis was comparable at different concentrations on the x-axis for different LSD weights.
Speaker 4: This highlights that 539, a reversible inhibitor, has comparable ex vivo activity to clinical stage irreversible inhibitors at the concentrations tested.
This highlights that 539, a reversible inhibitor has comparable ex vivo activity to clinical stage irreversible inhibitors other concentrations tested.
Speaker 4: In the bottom graph, we observe a high level of variability across patient samples in the differentiation response post-LSD1 inhibition across 539 and the two irreversible compounds.
In the bottom graph, we observe a high level of variability across patient samples and the differentiation response post LSD, one inhibition across 539 and the two irreversible compounds.
Speaker 4: There are samples representing high, medium, and low levels of differentiation.
There are samples representing high medium and low levels of differentiation.
Speaker 4: And this level of heterogeneity supports further exploration of patient selection strategies in the clinic.
And this level of heterogeneity support further exploration of patient selection strategies in the clinic.
Speaker 4: Our precision medicine platform can also potentially help us identify the best combination therapies for a patient before entering the clinic.
Our precision medicine platform can also potentially help us identify the best combination therapies, but a patient before entering the clinic.
We also presented ex vivo data, where we quantified the activity of 539 on AML cancer cells viability.
Speaker 4: We also presented ex vivo data, where we quantify the activity of 539 on AML cancer cells viability.
The bar plot on the left highlights the variability of single agent response within a cohort showing in juice loss of cell viability in decreasing order.
Speaker 4: The bar plot on the left highlights the variability of single agent response within our cohort, showing induced loss of cell viability in decreasing order.
This produced a baseline to subsequently compare monotherapy response versus 539, plus standard of care combinations as seen on the panel on the right.
Speaker 4: This produced a baseline to subsequently compare monetary response versus 539 plus standard of care combinations as seen on the panel on the right.
Each column on the panel to the right represents a standard of care treatment option.
Speaker 4: Each column on the panel to the right represents a standard of care treatment option.
Speaker 4: Each row is a patient sample corresponding to the list on the left.
Each row is a patient sample corresponding to the list on the left.
Speaker 4: The grid displays whether synergistic effects were seen using the HSA method for 539 in combination with each standard of care ops.
The grid displays whether synergistic effects were seen using the HSA method for $5 39 in combination with each standard of care option.
This data demonstrates that <unk> nine has general combination potential with common AML standard of care treatments.
Speaker 4: This data demonstrates that 539 has general combination potential with common AML standard of care treatment.
Even though samples with low single agent activity to 539 could demonstrate a synergistic effect with the current standard of care treatment.
Speaker 4: Even though samples with low single-agents as activity to 539 could demonstrate a synagetic effect with a current standard of care treatment.
Okay.
Speaker 4: We believe it may be beneficial to identify AML patients more likely to respond to 539 as a single agent in the clinic as well as rational combination.
We believe it may be beneficial to identify AML patients more likely to respond to 539 as a single agent in the clinic as well as rational combinations.
Speaker 4: We are currently generating patient and richment hypotheses leveraging our single cell omits capabilities to detail 539 induced gene expression on AML cell subpopulation.
We are currently generating patient enrichment hypotheses leveraging a single cell <unk> capabilities to detail <unk> induced gene expression on AML cell subpopulations.
Speaker 4: We look forward to sharing more data on this and testing our hypotheses retrospectively in AML patients.
We look forward to sharing more data on this and testing our hypotheses retrospectively in AML patients.
Speaker 4: In addition to our ESMO poster, we have also generated additional preclinical data for LSD1 in small cell lung cancer.
So asthma poster we have also generated additional preclinical data for LSD, one in small cell lung cancer.
Speaker 4: The graph on the left shows the level of synergy in cell-line models.
The graph on the left shows the level of synergy and sell Lai models.
Speaker 4: This synergy, assessed using the BLIS independence model, is measured across the different small cell lung cancer subtypes on the y-axis.
The synergy assessed using the Bliss independents model is measured across the different small cell lung cancer subtypes on the Y axis are measured between 539 and various small cell lung cancer standard of care treatments and targeted therapies on the X axis.
Speaker 4: measured between 539 and various small cell lung cancer standard of care treatments and targeted therapies on the exact
Speaker 4: As displayed by the color coding, synergistic effects were most frequently obtained in the two most prevalent molecular subtypes, A and P, which account for more than 80% of small cell lung cancer patients.
As displayed by the color coding synergistic effects were most frequently obtained in the two most prevalent molecular subtypes.
And the P, which account for more than 80% of small cell lung cancer patients.
Speaker 4: The right-hand side highlights data that we have produced in cell lines known to be unresponsive to LSD1 inhibitors.
The right hand side highlights data that we have produced in cell lines known to be unresponsive to LSD one inhibitors.
Speaker 4: As expected, 5,3,9 as a monotherapy has limited effect on proliferation in these cell lines.
As expected 539, as a monotherapy has limited effect on proliferation in the cell lines.
Speaker 4: However, the interesting thing that we observe is that 539 has synergistic effects with suboptimal concentrations of the standard of care or targeted therapy.
However, the interesting thing that we observe is that $5 39, a synergistic effects with suboptimal concentrations of the standard of care or targeted therapies.
Speaker 4: This further highlights the need for selecting the right combinations for the right patient.
This further highlights the need for selecting the right combinations for the right patients.
Speaker 4: I'll now spend a few moments on our MOLT1 inhibitor in IND-enabling studies.
I'll now spend a few moments on our <unk> inhibitor in IND, enabling studies.
Yeah.
Speaker 4: Alongside 539, we also presented data on 565, our MOLT1 inhibitor as.
Alongside <unk> 39, we also presented data on 565 <unk>.
One inhibitor asthma.
This highlights 565 precision design characteristics and its potential follow drug drug interactions.
Speaker 4: This highlights 565's precision design characteristics and its potential for low drug-drug interaction.
As we have shown previously we believe we have designed a high quality allosteric <unk> inhibitor with a potential key safety differentiator.
Speaker 4: As we have shown previously, we believe we have designed a high quality, Alastairic, Malt-1 inhibitor with a potential key safety differential.
Once daily administration of 565 is supported by human pharmacokinetic predictions with low predicted human clearance and high oral bioavailability.
Speaker 4: Once daily administration of 565 is supported by human pharmacokinetic predictions, with low predicted human clearance and high oral biodevelopability.
Importantly, even for the highest predicted human dose of 565, the risk of inhibiting that UGG, one a one enzyme as well as several transporters involved in bilirubin disposition is low.
Speaker 4: Importantly, even for the highest predicted human dose of 565, the risk of inhibiting the UGT1A1 enzyme, as well as several transporters involved in bilirubin disposition is low, resulting in a lower burden on the liver. This is something I
Resulting in a lower burden on the liver this.
This is something I will expand on later.
Here, we highlight in vivo activity of 56 5 million to xenograft models.
Speaker 4: Here we highlight in Vivo activity of 565 in 2 Zenergoth model.
One of which we newly published at ESMO is a b cell non Hodgkin lymphoma model called OCI L. Y 10 shown here on the left hand side.
Speaker 4: One of which we newly published at ESMO is a B-cell non-Hodgkin lymphoma model called OCI-LY10, shown here on the left-hand side.
In vitro the OCI <unk> model is sensitive to both <unk>, one inhibitors and PTK inhibitors, such as it breaching it.
Speaker 4: In VITRO, the OCI-LY-10 model is sensitive to both MOT1 inhibitors and BTK inhibitors, such as Ibrutonis.
Speaker 4: At EZMO, we highlighted data which showed that tumor growth regression was achievable with 565 as a monotherapy, other high dose evaluated, which was 60 milligrams per kilogram twice a day.
At ESMO, we highlighted data, which showed that tumor growth regression was achievable with 565 as a monotherapy at the highest dose evaluated which was 60 milligrams per kilogram twice a day.
Speaker 4: This compares very favorably to data previously published from a clinical stage MOLT1 compound.
This compares very favorably to data previously published from a clinical stage one compounds.
And the same model this competitor compound did not show monotherapy progression.
Monotherapy administration of either 565, and 10 milligrams per kilogram, a twice a day or a bruton at 25 milligrams per kilogram once daily.
Inhibiting tumor cell growth did not meet thresholds to demonstrate tumor growth regression.
However, with 565 on Ibrutinib were given at the same doses in combination that wasn't apparent synergistic effects, leading to tumor growth regression.
565 is well tolerated during the dosing period with no effects on body weight compared to the vehicle group.
Data from a diffuse large b cell lymphoma model T. M. D. H is on the right hand side.
In vitro the cell line is sensitive to both <unk> and BT can emission.
However, historically this has been a really challenging model to show efficacy in vivo for either mechanism.
The cell line is our model, reflecting a more recalcitrant lymphoma that way and allow me to also observe in the clinic and which may benefit from a combination approach.
As can be seen from the graph 565 in combination with Ibrutinib are synergistic effects display meaningful antitumor effects.
Yeah.
We also presented data in primary human chronic lymphocytic leukemia or CML cells for the first time at ESMO.
These CLO samples were taken from patients that were either treatment naive or had been exposed to previous lines of therapies.
Importantly, we observed limited impact to T cell viability in the experimental setup.
This data showed that 565 selectively inhibited the proliferation of human primary cell cells.
This points to a broadening of target patients beyond just diffuse large b cell lymphoma.
You may have seen the recent disclosure from the first <unk> inhibitor that went into patients validating the potential of this mechanism by demonstrating clinical activity in lymphomas.
As we've highlighted before we believe there is a risk of hyperbilirubinemia linked to inhibition of UGG won a wan from somewhat one inhibitors.
Inhibiting <unk> mediates bilirubin glueck renovation, which in turn can lead to jaundice our hyperbilirubinemia.
As a result selectivity over <unk>, one was a key feature of our target product profile for 565.
And the published peer data as shown on this slide hyperbilirubinemia was observed in more than 40% of patients treated.
We have shown pre clinically that 565 has a lower predicted risk of hyperbilirubinemia compared to this clinical compound.
Notably our predicted efficacious doses.
The potential to also inhibit UGG one Avon has a margin approximately 14 fold greater 4565 compared to a clinical stage compounds.
The predictions for this pharma clinical asset are consistent with the published phase one results.
Based on this data we believe 565 has a lower risk of drug drug interactions potentially allowing a wider range of combination use.
This could also facilitate dose escalation in the clinic.
Overall 565 profile offers potential for further exploration of <unk> inhibition as a monotherapy and in combination with other targeted agents in Hematological malignancies, and we look forward to providing further updates of 565 in the first half of 2024.
I'll now hand, it over to Ben Taylor, our Chief Financial Officer to walk us through the financials.
Thank you Dave.
We announced last month that we are prioritizing development of a focused number of internal programs that are highly differentiated across oncology target with clear market need.
This will enhance the operational efficiency and allow us to maintain our cash runway well into 2026, while delivering on multiple important milestones in our key programs.
We have also been applying the same discipline to our partnered discovery programs and I am going to provide you with a brief update across the portfolio.
We want all of our programs, whether internal or partnered to have meaningful competitive differentiation and market potential.
And our existing partnerships. We have ended our collaboration with <unk> following the announced acquisition by Revolution medicines, and we retain ownership to all intellectual property developed during that collaboration.
With BMS, we have mutually decided to prioritize certain programs and not proceeded with others. Some of the initial programs are still running but we are also evaluating multiple ways to work together on newer targets or technologies.
Our portfolio prioritization exercise has had no impact on our Sanofi or Merck NGA collaborations as Andrew mentioned this quarter. We also achieved our first Sanofi collaboration milestone for in immunology and inflammation target. We have also initiated the three programs with Merck PGA.
The combination of prioritization and our internal and partnered pipeline maintains a broad portfolio of over 20 programs, but focuses our activities on those projects that we believe have the most potential for differentiation and patient impact.
Looking forward most macroeconomic forecast now projected conservative environment into 2024.
We are also seeing large pharma go through dramatic strategic shifts and leadership changes that will also continue into 2024.
This means that we need to be highly nimble as an organization to respond to the changes in the external environment quickly.
We have and will continue to do this through our operational efficiency initiatives, but we are also evaluating how we can evolve the partnership business to be more nimble in the future.
Our existing partnerships with Sanofi, BMS and Merck give us primary operational control, but require us to maintain substantial infrastructure to execute this was initially necessary. So that we could redefine the process of AI based strike discovery.
Over the last few years, we have demonstrated how that process can lead to better outcomes and we have also learned and what ways, we add the most value.
In order to become more efficient and reduce unnecessary infrastructure, we are focusing our conversations with potential partners on the areas, where we have the highest impact primarily design and novel technologies.
This should retain high value downstream economics, while increasing the profitability and flexibility of our partnerships.
We also want to find structures that allow our partners to change their strategic focus without transferring that risk onto us.
This will likely have an impact on timing of our ongoing discussions.
While it is still possible we may sign a second partnership this year, our expectation is that it will be in 2024, given external uncertainties, we will maximize value creation over speed.
I'll now take a minute to close with highlights from our financial results full results are detailed in our press release and form 6K.
I'll review the results in U S dollar using the September 32023 constant currency rate of one two to one four.
We ended the quarter with $448 million in cash cash equivalents and bank deposits.
Note that this excludes the upfront payment from Merck and the first milestone from Sanofi, which will be reflected as cash inflows in the fourth quarter of 2023 financials.
We now expect to save over $55 million in 2023 versus our original budget based on ongoing efficiency programs combining efficiency with our portfolio prioritization has put us in a strong financial position with a cash runway well into 2026.
This will allow us to advance our differentiated clinical programs deliver on our partnerships and invest in new platform technologies.
Yeah.
Our net operating cash burn has decreased every quarter of this year for the first nine months of the year. Our net operating cash burn was $145 million and we expect operating expenses for the fourth quarter to be largely offset by payments for Merck, a GAA Sanofi and R&D tax.
<unk>.
While we are not providing specific guidance for 2024, we expect cash outflows to be largely flat year over year with increased inflows from the partnership business.
With that I will turn the call back to Andrew.
Thank you Ed so.
So as you've heard today at extent yet.
Laser focused on continuing to build an engine that designs and develops high impact medicines that have the potential to transform patients' lives. We are continuing to build out a highly differentiated internal oncology pipeline, particularly our clinical and <unk> enabled and stage programs targeting <unk>.
Seven and LSD one.
In addition, our partnerships are steadily progressing in Cleveland, <unk> recently announced a small stone with Sanofi and.
And the new collaborations with Merck K GAA.
These developments paired with our technological advancements solidified <unk> leadership in AI enabled drug design and development.
With that we'll open up the call for questions and answers.
Thank you if you would like to ask a question. Please press star one on your telephone keypad to withdraw your question simply press Star one again.
Your first question comes from the line of Alec Stranahan with Bank of America. Your line is open.
Hey, guys. Congrats on the progress this is Jon and Mark just a quick question for me.
On the bi.
Goodbye.
Not one inhibitor asset.
So are you guiding to update in the first half of next year. So can you just give more color on what extent of data can we be expecting.
And what can we expect going into the second half of.
Next year.
Some data readout.
Thanks.
Sure.
Hi, Alex.
Good to hear from you.
We are certainly ex excited by the data we showed on multiple today to give you a little.
On the preclinical and into development program I wanted to introduce microns actually too.
To the party.
Yes, hi, thanks for the question. So we're currently working through our R&D, perhaps studies and.
Are anticipating that we can provide you with an update early next year.
But.
Our thinking is that.
We will move into a clinical development strategy that proved very efficiently demonstrate our ambition to have a better therapeutic index building on what Dave discussed earlier relative differentiation on the liver tox issues.
<unk>.
Got it thanks for color.
Your next question comes from the line of Peter Lawson with Barclays. Your line is open.
Great. Thanks for taking my question.
And then just the commentary you made around the changes within pharma.
Any way you can kind of.
Sure.
Some color around how pharma kind of thinking about AI and become more interested in something they want.
Dan you want to do through collaborations or if it's something they want to build internally.
Yes, great question Peter.
So we still see a lot of interest in large firm I'd say, each one has a slightly different strategy.
Almost all of them I would say our.
Building significant AI capabilities.
And what we see is really a variation some of which are looking more for during multiple partnerships externally some of them want to complement their own internal efforts.
But.
What we have.
Seen come across most clearly is they're really interested in our differentiated technologies.
I think there will be many aspects of AI that just become standardized in the industry.
So, it's really where does our proprietary data our combination of technology is our ability to put the technologies together make a difference.
That's where a large firm are really come to us and want to see how we can solve some of the problems that.
They can't traditionally do where they can't do with their internal operations.
Okay. Thank you and then.
As we think of that kind of large data sets of patients I know there was there's across the wire. This morning.
The player in the space.
Is that something you need to kind of secure yourself to get access to.
Large patient datasets in oncology.
I mentioned Blake.
20, Petabytes of data is that an important component to have something.
Something you build really really important thing to remember is we're learning company more than a screening company. So if we were focused on target identification. For example, there's a lot of screening involved in that it's a big data problem.
We are most often doing is solving design problems in understanding specific patient enrichment strategies and those aspects are really how do you learn your way into something where you don't have existing data.
And so most of the data that we use actually on our design projects and for our precision medicine is actually proprietary internally generated data.
Because the data doesn't exist either in the form or at all.
That would be useful for doing a a complex analysis of it so.
We don't believe that we need.
Petabytes worth of data to be able to solve a problem.
In fact, we will look to find the most efficient way to learn.
Very specific data, how we can solve that problem.
Thank you and then just left to go back on that one.
Program.
Understand when would we see.
Would it be preclinical data update plus you had kind of flush out developmental plan.
In the first half.
Yes precisely that's the plan yes.
Perfect. Thank you so much.
Your next question comes from the line of Vikram <unk>.
With Morgan Stanley Your line is open.
Hi, This is Steve will take that will.
Taking a question.
Any update on the largest effort. Thank you.
Yes, hi, Steve good to speak to you actually saw athene will be presenting at tanks next Wednesday.
On the results we've already generators on a proof of concept work.
We are excited actually by but the data, which actually explores multiple different methodologies. So I recommend actually lookout for Shoals presentation next week.
Thank you.
Once again, ladies and gentlemen, if you have a question it is star one.
Next question comes from the line of Chris <unk> with Goldman Sachs. Your line is open.
Thank you very much good morning, good afternoon.
Grind.
Looking at how the partnership business can be more nimble in the future.
Perhaps it suggests that the arrangements that you have enable you to be less exposed to risk can you describe a little bit further about how the programs and the partnerships are evolving.
Just a little bit more visibility into.
How that could shift would be helpful.
Hi, Chris Great to speak to you.
Yes, so if you actually looked at history ex MTA actually has a history of how we learn from every partnership and how those partnerships with.
Reflect the state of the art to the technology platform at the time as well and what capabilities, we can bring to our offering.
Very much if you look at the <unk>.
Sanofi deal, which really is a.
Full end to end.
Program identifying the drug targets designed in the molecules also thinking about patient selection strategies.
We then actually with the new Merck program, we set up actually was not a nimble focused on drug design, but actually also ex MTM is bringing two of the policy. The three projects that have already.
Been initiated as part of the collaboration so this actually as an example, now all of US moving away from initially where maybe with more reliance on our partners to bring projects to the table on <unk> actually been much when control of initiation and the selection of the projects and what's been said on this.
Our prepared remarks, the importance of ascent is that so we can control risk a lot more so we can really understand.
We are best in areas, where we truly believe also we created differentiated molecules. One thing that's important for us to think about <unk> partnership work.
Is that we take as much care and understanding the target product profile and how are we going to differentiate <unk>.
Commercially as we do with our internal programs AUC, such as how SD Wan Cdk's bolt one other.
Others, which will be announced.
So this is an important element of it actually we really do with every policy that we work on with someone to have that potential at <unk> to be the <unk>.
Best differentiated molecule and its cost.
Both of them.
Others, which will be announced.
So this is an important element of it actually we really do with every policy that we work on with someone to have that potential at <unk> to be the best differentiated molecule and its cost.
And then can I ask as well I think a foundational aspect of your entire philosophy or approach artificial intelligence machine learning is that it hurt us and I would imagine through both successes and progress as well as setbacks. There is learning can.
You, perhaps summarize what the decision to discontinue <unk> candidate what were the net learnings from that I believe that there was some aspect of peer data, but as you put that together how did that decision, which was probably difficult but necessary given how difficult drug development is.
How does that inform what you're doing.
With your core capabilities going forward.
Yeah, Hey, Chris This is Ben I'll take that one so I think when we look back. So <unk> originally started as a project at accent here about six years ago.
When the company was just really doing chemistry design and partnered with <unk> for a lot of the other aspects I think if you look at what we do now.
We really run for biological and commercial analyses on all of our targets.
We put a lot of.
Analysis into that TPP that target product profile that.
That Andrew was talking about and so I think to some extent there was.
A lot of learnings coming out of a two way that formed those operations that we now have and led to a lot of the target selection that we've done on more recent programs as well as our internal pipeline.
And then I think there is also been aspects that have contributed to how do we.
Analyzing the programs as they go through that being said there is a number of commercial and competitive changes that have happened to the markets that <unk> would look at over the last six years.
And.
Maybe some of those could have predicted but many werent able to be predicted that didn't have the appropriate data out.
So that's where I think being a learning company also comes in to being nimble.
You know what there is new data out I need to reevaluate the fundamental decisions I made before.
And rather than carry them through to completion, because I'm on a path I'm going to make the better decision.
As early as I can based on the new data. So I'd say, there's two aspects to it one is our operational one and the other is really the decision making process and Chris just to underline what Ben just said.
Thing is looking at new data and that new data is also looking at it in the round of cross sell pipeline across our portfolio New data. We've seen is also what you saw today from LSD one multiple of the CDK <unk> work and actually when we then rank.
All of our programs together, that's why strategically we see actually that we have very defined questions to ask them, but I think actually with CDK.
Alex do you want to move to one and with HOA. We found actually that was actually quite a number of multiple questions of risks therefore to be onset within our trial.
And actually where we want to really consider if we want to play to win in areas is if we were to increase our <unk> success is to really understand that.
Limiting the number of parameters and dimensions of risks that we sort of.
<unk> studied within our trials that was important elements not only looking at the data within the HOA sort of message, but also look at of course, we compete in data that we have actually.
We prioritize across our whole pipeline.
Got it thank you Tony and thanks.
There are no further questions at this time I will turn the call over to Andrew Hopkins for closing remarks.
Thank you operator.
Everyone on the call today for your continued support of <unk>.
As we seek to fundamentally change the way, we design and develop drugs with a laser focus on design and the development programs that address complex drug design challenges with clear impact on broad patient populations. The continued advancement of our pipeline is testament to the power of our platform and the strength of our business model position us.
Well as we work to deliver truly personalized medicines.
And with that operator, you may now disconnect.