Q4 2022 Atreca Inc Earnings Call
Speaker 1: You.
Speaker 2: Thank you for standing by and welcome to a trekkers fourth quarter and year and 2022 earnings call. At this time, all participants are in a listen only mode. After the speaker presentation, there will be a question and answer session.
Speaker 2: To ask a question during the session, you will need to press star 1 1 on your telephone. I would now like to hand the call over to head of investor relations, Alex Gray. Please go ahead. I'd now like to leave the phone back and continue the conversation.
Speaker 3: Thank you, operator, and thank you to those joining us today. We are pleased to host our year-end 2022 conference call and webcast, including updated data from our ongoing Phase 1B trial of ATRC 101. Joining me for the prepared remarks are John Orwin, CEO , Dr. Tito Serafini, Chief Strategy Officer, and a Traeger founder. And I'm John Orwin, CEO , Traeger founder.
Speaker 3: Dr. Felipe Bishop, Chief Medical Officer, and Dr. Steven Gould, Chief Scientific Officer. Also on the line is Herb Cross, Chief Financial Officer, who will be available during the Q&A session. For those joining by phone, I'd note that we are presenting slides as part of today's program, which can be viewed via the webcast link included in our earnings release and posted to the events and presentations section.
Speaker 3: of significant risks and uncertainties and our actual results may differ materially. For a description of risks and factors that could affect our future financial results in business, please refer to the disclosure in the accompanying slides, our most recent forms 10-K and 10-Q, and the reports that we may file on form 8-K with the Securities and Exchange Commission.
Speaker 3: All our statements are made as of today, March 29, 2023, based on information currently available to us. We can give no assurance that these statements will prove to be correct. We undertake no duty to update these statements except as required by law. I'll now turn it over to John Orwin. John ?
Speaker 3: Thank you Alex on today's call Tito will provide an update on Our discovery platform and its evolution Sheila Philippe will present data from the ATRC 101 monotherapy and pemberlizmab combination cohort in our ongoing phase 1b trial
Speaker 3: And Stephen will then provide an overview of our preclinical pipeline.
Speaker 3: I will then discuss our financials and upcoming milestones before opening the line for Q&A.
Speaker 3: Shown on slide four is a broad overview of our platform and pipeline. As a reminder, Matryika has a proprietary platform that enables us to access novel antibodies binding to novel tumor targets that would unlikely be found via traditional discovery approaches. As Tito will discuss in more detail.
Speaker 3: We have continued to invest in the development of the platform, which has enabled us to find promising antibodies and identify their targets more efficiently.
Speaker 3: we've generated a robust pipeline led by ATRC 101, which as we'll discuss later has demonstrated durable anti-tumor activity in the ongoing phase 1b trial in which we believe validates the ability of our platform to identify active tumor targeting antibodies with therapeutic potential.
Speaker 3: We plan to provide an update on our clinical strategy for ATRC 101, including a go-no-go decision for phase 2 development by the end of this year.
Speaker 3: We're also advancing multiple promising preclinical programs including APN 497444, which targets a novel tumor-specific bicam and is advancing as an antibody drug conjugate, as well as APN 346958.
Speaker 3: which recognizes the self-surfaced RNA binding protein target and is advancing as a T cell engager in partnership with NCORP.
Speaker 3: We expect to nominate clinical candidates from both programs later this year and begin clinical studies for additional oncology programs in 2025. I will now turn it over to Tito to briefly discuss our discovery platform and its evolution before we review the updated ATRC 101 data and preclinical pipeline.
Speaker 4: Thanks, John . On slide five, our pipeline is generated by an approach in which the active immune response guides us to novel antibodies finding novel targets. On the top half of the slide, starting on the left, our approach begins with blood samples from patients whose adaptive immune system is attacking tumor tissue.
Speaker 4: Moving to the right, via those samples, we access that immune response, and importantly, the active immune response by analyzing single B cells of a defined type to generate at high fidelity the natively paired heavy and light chains of the antibodies that are being generated in that patient at that point in time.
Speaker 4: Moving again to the right, we then analyze and select those antibody sequences in silico for synthesis and further evaluation in the laboratory.
Speaker 4: By screening these synthesized antibodies in vitro, we ask a simple question.
Speaker 4: Does this antibody, which comes from the immune response of one patient, bind to tumor tissue of other patients, that is non-autologous tumor tissue, and does it do so preferentially over normal tissue?
Speaker 4: If the answer is yes, and the antibody also binds to the surface of a tumor cell line is measured by flow cytometry, we have a HIT antibody.
Speaker 4: On the bottom half of the slide, we then further evaluate and develop our HIT antibodies in order to turn them into clinical candidates, as I'll describe in a moment in more detail.
Speaker 4: Moving to slide six, this slide illustrates the biology behind why our approach works. The key point of this slide is that we generate antibodies from plasmablasts, those four B cells in the middle of the figure. Plasmablasts uniquely provide information on the antigens being processed.
Speaker 4: and the antibodies being generated during an active immune response.
Speaker 4: In the blow up, we're showing as dots antibodies generated at two time points from one patient before treatment in purple and after treatment in green and we've circled groups of dots. These groups of plasmablasts antibodies are clonal families derived from a single progenitor B cell and these particular families colored green
Speaker 4: were generated in this case as the patient was successfully attacking his tumor tissue to yield a partial response.
Speaker 4: By analyzing clonal families such as these, their appearance, persistence, disappearance, size, all of that enabled by our approach, as well as by analyzing antibody sequences more directly, we focus on and select particular antibodies for further evaluation in the laboratory.
Speaker 4: Our in silical analysis delivers synthesized antibodies binding non-ophologous tumor tissue approximately 50% of the time in our primary screens.
Speaker 4: And as noted at the bottom of the slide, our proprietary approach is protected by composition of matter claims in multiple jurisdictions worldwide, which goes beyond the more typical method of use claims often granted around processes.
Speaker 4: Moving to slide seven, this is the discovery platform that we have built in over a decade to execute on our approach. I'll focus on a few key points.
Speaker 4: Starting on the left, we run our own non-interventional studies in order to acquire samples from cancer patients and we have generated a valuable sample repository now with over 1,700 clinically annotated samples from over 500 donors representing nearly 40 tumor types.
Speaker 4: Moving right, I've briefly described that we use these samples to generate, analyze, and select plasmablast antibodies for analysis by histology and polycytometry to generate antibodies.
Speaker 4: And then moving further right, turning these hit antibodies into leads requires their evaluation in vitro for tumoricidal activity, but in a manner that provides information about which weaponization would be most suitable. And then with the active antibody in hand that also has positive histology data, we work to identify the target found by the antibody and then to the twenty-Fourth trend.
Speaker 4: biomarkers suitable for use during clinical development.
Speaker 4: Moving to slide 8, as we promised to do, we've evolved the platform over time to achieve greater efficiency in delivering pipeline assets. On this slide, I'm highlighting a few of the more salient advances that we've made.
Speaker 4: Starting in the top left, we've expanded our sample collection to new sites and indications. Moving down, we're operating our flow cytometry now at an industrial scale and speed. And below that, our histological analysis has now incorporated more automation to enable earlier evaluation of tumor and normal tissue expression of our antibody targets.
Speaker 4: Moving to the top right, we've implemented proprietary high throughput assays to measure in vitro the activity relevant to weaponization. Next down, whole genome functional genomic screens were added to existing biochemical methods to remove a bottleneck that target identification had represented in our platform. And finally, but again not exclusively, we've implemented structure-based and unbiased Melan GG streaming on the system.
Speaker 4: which Philippe will discuss in detail. You'll then hear from Steve about the other currently preclinical pipeline assets. Turning it over to Philippe. Thanks, Tito, and thank you, everyone, for joining the call today. On slide 12 is a top-line summary of ATRC-101 Phase 1B study update I am presenting today, which includes information from 71 patients treated.
Speaker 5: in the ongoing trial, 21 of whom were enrolled since March 2022 update.
Speaker 5: The primary objective of the study is to evaluate safety, and we're pleased to share that ATRC 101 continues to be well tolerated in the monotherapy and combination arms, including at the highest dose level of 30 milligrams per kilogram. We continue to see anti-tumor activity in patients that express target.
Speaker 5: Furthermore, we're excited to report that in this heterogeneous and heavily pretreated participant group, we are seeing durable responses and stable diseases across several cancer types in participants treated with model therapy and combination therapy.
Speaker 5: Before we discuss the data, I will briefly review the trial design, the baseline characteristics of participants treated, and the analysis set in the next three slides.
Speaker 5: As a reminder, and as shown on slide 13, this is a basket trial enrolling patients across multiple tumor types. The primary objective of the trial is to determine the safety and tolerability of ATRC-101 when administered as monotherapy or in combination.
Speaker 5: with key additional objectives, including measuring clinical activity, analyzing target expression, and determining indications for expansion.
Speaker 5: The trial began with ATRC 101 administered as monotherapy every three or two weeks, followed by studying the combination with pembrolizumab every three weeks in patients who had progressed or, in the opinion of the treating physician, achieved an unsatisfactory response following an anti-PD-1 or PD-L1 therapy. The initial dose escalation cohort included patients regardless of target expression.
Speaker 5: Last year, when early data suggested a targeted expression appeared to discriminate patients likely to respond, we amended the protocol and started to enrich based on targeted expression. To date, we have treated participants at five dose levels, ranging from 0.3 to 30 milligrams per kilogram. Having completed the dose escalation phases of the trial, we have also completed the first dose escalation phase of the trial.
Speaker 5: we're not expanding enrollment at the 30 milligrams per kilogram every three week dose level for both monotherapy and combination cohorts.
Speaker 5: 514 is an overview of the baseline characteristics of participants enrolled onto study. As of the data cutoff of February 17, 2023, 71 participants had enrolled overall, with 48 on the three-week monotherapy schedule, 14 on the two-week monotherapy schedule, and 9 in the combination R.
Speaker 5: The median age of participants was 62 years, with most having an e-code performance status of 1. You can see how patients enrolled in the study are distributed across cancer types. It is very important to note that the majority of participants enrolled in the study have metastatic disease and were heavily pre-treated.
Speaker 5: with a median of five prior lines of therapy. Nearly half of the patients had prior exposure to one or more checkpoint inhibitors, and for those enrolled onto the combination arm, as per protocol, all patients had to have received prior therapy with a PD-1 or PD-1 agent and experienced an unsatisfactory response or disease progression following treatment.
Speaker 5: On slide 15, I would like to describe the pertinent data sets used in today's presentation. Beginning with the safety, today's results will include all 71 participants enrolled on to study who received at least one dose of ATRC-101. Although we studied five dose levels, we consider pharmacologically relevant doses to be not identified yet.
Speaker 5: the 3, 10, and 30 milligrams per kilogram, either as a model therapy or in combination with Pambrolizumab.
Speaker 5: Participants treated at these doses will be the focus of the interim analysis for activity presented today. For these analyses, there are 62 patients with a large number enrolled at the 30 milligram per kilogram dose. For more information visit our website 1999.avored. uploadedWantA
Speaker 5: Of the 62 subjects, 50 were evaluable for each score. That is defined as a composite score comprised of target expression intensity by immunohistochemistry and the proportion of cells positive for target expression. When examining target expression correlations to clinical activity and editing into Aaroncedes
Speaker 5: we will focus on the 45 who were valuable for RESIST and H-score, and the 49 who were valuable for BEST overall response and target expression. For these results, we will present the monotherapy results separately from the overall population that include nine individuals.
Speaker 5: who receive combination therapy. Presented on slide 16 is the distribution of participants accessible for overall response in HCOR by cancer type. As you can see, the number of subjects enrolled with specific tumor types range from 18 to zero. As such, the small numbers make it difficult for conclusive inferences about ATRC 101 activity.
Speaker 5: for a specific cancer type or indication. And although we are getting close to sufficient numbers in some of the tumor types, we believe it is important to continue enrollment of the study to provide additional insights and inform future development decisions.
Speaker 5: Moving to slide 17, ATRC continues to be well tolerated. With the 71 participants enrolled and who received at least one dose of ATRC 101, most of the reported adverse events were grade one or two, as shown by the dark and blue bars. For more information, visit www.atrc.gov.
Speaker 5: for the treatment emergent adverse events on the left and the treatment related adverse events on the right. Of these adverse events observed, there remains no pattern to suggest a particular toxicity profile, nor were there a relationship between incidence of severity of adverse events with those.
Speaker 5: or incidence of adverse events with targeted expression. The most common treatment-related adverse events were pain, fatigue, and nausea, with no serious adverse events determined to be related to treatment with ATRC-101. Only two grade 3 AEs were reported as potentially treatment-related, including one instance of heart failure associated with a stroke and loss of memory. Many Room Matters after flight because of a
Speaker 5: each of a headache and a small intestinal obstruction.
Speaker 5: Six patients experienced an AAE leading to dose interruptions. These included patients who had a grade two infusion reaction on cycle one, day one. The infusion was interrupted temporarily, and the AAE managed as per protocol. The dosing was restarted without complication. Others...
Speaker 5: included liver function laboratory abnormalities, a grade one tachycardia, a grade two nausea, a grade two fatigue, and the grade three small intestinal obstruction that was noted earlier in my comments. No participant has had to come off study due to drug related toxicity.
Speaker 5: Moving to slide 18, the interim assessment for activity once again supports the use of an H-score cutoff to predict the probability of observing disease control or tumor response to ATRC-101. As noted previously, the H-score is obtained using a CAP-CLIA immunohistochemistry-based assay.
Speaker 5: An H-score can range from zero at the negative end to a maximum target expression score of 300. Based on prior analysis showing a correlation of H-score to response for disease control, the target positive H-score cutoff implies an H-score.
Speaker 5: greater to or equal to 50.
Speaker 5: On the left bar graph, for patients who receive monotherapy, 59% achieved disease control if their tumor expressed the target. This is in contrast to 25% of patients whose tumor has an age score below 50.
Speaker 5: The bar graph on the right includes patients treated with combination therapy and yielded a similar result.
Speaker 5: On slide 19 is another way of assessing anti-tumor activity associated with part of expression. Here we are looking at individual patient data over time for patients whose tumor has a low H score. Those treated with monotherapy are shown on the left, and on the right, the graph also includes those treated with combination therapy.
Speaker 5: As is shown here, most patients' disease progression occurred early, soon after the first month following initiation of protocol therapy. Only four patients had stable disease going past 100 days and all experienced a disease progression at 180 days or soon thereafter.
Speaker 5: On slide 20, we compared those with low target scores in the light blue lines to those with age scores of 50 or greater in the dark blue lines. And we can see that there is a greater number of patients experiencing a durable objective response or durable disease control. Several of them are well past 180 days after having initiated protocol therapy.
Speaker 5: PFS was documented at study date 350.
Speaker 5: including those who receive combination therapy on the right, we can see the melanoma patient at the bottom that we had previously reported to have achieved this CR, and that patient had their most recent response assessment at day 418 following initiation of protocol therapy.
Speaker 5: The patient's tumor had an age score of 75 and to this day continues to remain on study.
Speaker 5: Slide 21 focuses on the durability of tumor response observed by cancer type for all patients treated with ATRC-101 as monotherapy or in combination with Bamburo and whose tumor was target positive. As shown by the different line colors depicting different cancer type, the cell is shown in
Speaker 5: Durable activity is seen across multiple tumor types including melanoma, non-small cell lung cancer, head and neck cancer, colon cancer, as well as breast cancer patients who had progression-free survival documented at study day 210.
Speaker 5: Another way of looking at the anti-tumor activity by tumor type and H-score is shown in the waterfall plot on slide 22.
Speaker 5: On the left bar graph, patients with low target expression experience increase in the size of target lesions except for one patient with ovarian cancer who had a small reduction in the size of her cancer.
Speaker 5: Patients who receive ATRC-101 alone are shown in the solid bars. Those who receive combination therapy are shown in the hash bars. This is in contrast to patients whose tumor had a higher target expression on the right bar graph. Here, we see that several patients had tumor reductions in both the monotherapy cohort and other Faster KEY
Speaker 5: the solid bars, and the combination therapy cohort, the hash bars.
Speaker 5: Slide 23 is a Kaplan-Meier analysis measuring progression-free survival for patients treated as a function of each score. On the left are the patients who receive monotherapy. On the right, the Kaplan-Meier analysis includes a patient treated with monotherapy or combination therapy.
Speaker 5: Patients with an H score of 50 or greater in a dark line have a longer progression for pre-survival than patients with H score less than 50 in the blue light lines.
Speaker 5: The curves separate early at 30 days and remain separated over time. For the monotherapy cohort, the hazard ratio is 0.47 for the difference of target positive and target negative patients. And it's similar to the hazard ratio observed for all patients treated with ATRC 101 that also includes those who receive combination therapy.
Speaker 5: Here the hazard ratio is 0.4 for the difference of target positive and target negative patients. Of interest of the small vertical-sensored line on the curve representing patients who have not experienced an event, these patients remain on study and are still receiving protocol therapy.
Speaker 5: As you can see, some patients have passed 180 days at the tail end of the dark progression 3 survival curve.
Speaker 5: Now moving to the data summary and next steps on Flight 24.
Speaker 5: This is a phase 1B trial, and it has and continues to enroll patients that have, for the most part, exhausted standard of care. With this data update, ATRC101 continues to be well tolerated. There were no DLTs up to the 30 milligrams per kilogram dose level tested. What we are learning with this data update is that longer progression-free survival....
Speaker 5: recruitment efforts will need to focus on underrepresented patients.
Speaker 5: We continue to focus enrollment based on target expression at the 30 milligrams per kilogram dose in both the monotherapy in combination with pambrolizumab cohorts.
Speaker 5: In the past several months we opened the study at five new sites and close to and we have contracted with nine additional sites in startup activities. In addition, we have seven sites undergoing feasibility.
Speaker 5: Going forward, a total of 28 centers are expected to participate and contribute to the study. In addition, we adapted the protocol eligibility criteria based on investigative feedback and in some instances worked with specific clinical centers to overcome staffing issues post-pandemic. All these activities have already and are expected to continue to help increase the risk.
Speaker 5: expectedly, screen failures due to restricting enrollment to patients whose tumor are target positive. The screen failures are in line with prior expectations to target prevalence.
Speaker 5: Finally, our recruiting efforts have already seen improvements. The additional data we expect to collect should position us well to enable a go-no-go decision for further development of ATRC 101 by year-end. Leaving the way for determining a registration path with defined commercial opportunity.
Speaker 4: for ATRC 101. I will now turn it over to Stephen to discuss our preclinical pipeline program. Thank you, Philippe. I'll now review three of our late lead oncology programs moving toward candidate nomination. The first, highlighted on slide 26, is a novel tumor-specific anti-glycan antibody.
Speaker 4: that were advancing as an antibody drug conjugate or ADC, referred subsequently to as antibody 444.
Speaker 4: 444 is one of a growing number of anti-glycan antibodies that we are uncovering with our platform. This is exciting as the baryon glycosylation has long been recognized as a hallmark of cancer but this class of targets has been difficult to address through standard methods.
Speaker 4: As I'll show you, 454 displays uniform and selective binding on tumors with high prevalence on colorectal cancer and is active as an ADC both in vitro and in vivo. We're currently optimizing both the antibody portion of the molecule and the linker drug portion to yield a candidate, a clinical candidate that we expect to nominate by year end with an IND target for late 2024.
Speaker 4: The bar plot in the top left of slide 27 shows why we're so excited about this antibody. Morpho4 exhibits strong immunoreactivity, i.e. 2 plus and 3 plus staining in greater than 70% of colorectal cancer.
Speaker 4: And I hope you can appreciate that this staining is very uniform in the images to the right where essentially all tumor cells are positive for the epitope. We also see high prevalence in gastric cancer with lower prevalence in several indications including uterine, pancreatic, ophthalpageal, and lung cancer. Importantly, we did not detect membranous immunoreactivity on 27 normal, fresh-broken tissues.
Speaker 4: The highest signal in normal tissue is moderate cytoplasmic staining in the stomach, which we suspect from data that I'll share in the coming slides is not accessible to the antibody.
Speaker 4: On slide 28, you can see that consistent with the abundant immunoreactivity in colorectal and gastric cancer, 444 binds to cell lines derived from these tissues, highlighted in blue, and not to those derived from other tissues.
Speaker 4: We screen for ADC activity shown on the right. 444 leads to cited toxicity in cells that express high and low to moderate levels of target in the case of Lovo and NUGC4 respectively.
Speaker 4: On slide 29, you can see that 444 before any affinity maturation, when formatted as an ADC using XymWorx, XymLink, or a statin-based linker payload, leads to dose-responsive anti-tumor activity after a single dose in a low-vosinograph model.
Speaker 4: This model expresses a relatively high level of target, but as shown to the right, the level of staining is comparable to what can be found in human cancer and therefore is a relevant model system. Importantly, 444 has been tolerated in both single and multiple dose studies in mice without body weight loss or histopathologic findings. 444 as an ADC has also been explored in initial PK tolerability assessment in the...
Speaker 4: to the ADC. Moving now to slide 30. At this point in the project, we had a very interesting antibody with tumor specific expression and intriguing anti-tumor activity, but we didn't know the target. Attempts to de-orphanize the antibody using standard approaches such as commercial protein or glycan arrays had failed to this point.
Speaker 4: As Tito mentioned, we have now enabled whole genome CRISPR screens in-house and 444 was one of the first antibodies we assayed with this approach. Using a CRISPR knockout approach, we knocked out genes individually and assessed which genes were essential for 444 binding to a flow-positive cell line. Three genes were identified as being required for 444 binding, two glycosylsial transtrations, and two glycosylsial transtations.
Speaker 4: Beta-4 gallon T3 and FUT-4 as well as the Fucose transporter. The Fucose transporter makes sense in the context of FUT-4 which requires Fucose as a substrate.
Speaker 4: Interestingly, when one looks at the expression of the two glycosylsial transferases at the RNA level in normal tissue, they're largely not co-expressed, a feature that helps explain the near absence of immunoreactivity in normal tissues. We validated that these two enzymes were required by expressing them in a cell line that did not express the target for 444.
Speaker 4: Upon co-expression, a dramatic right shift in the flow cytometry plot shown to the right suggests that these enzymes are required to present the glycan on the cell surface, at least in this context. Based on the substrate specificity of these two enzymes, we understand what glycan structure is likely required for binding and are confirming this through biochemical means. Advancing to slide 31.
Speaker 4: I alluded to the fact that 444 is one of a growing number of anti-glycan antibodies being discovered by our platform. In fact, half of the antibodies for which we have identified the target are anti-glycan antibodies.
Speaker 4: Our platform appears uniquely positioned to help uncover the potential of this underexploited class of antibodies. The platform, of course, also identifies antibodies to protein targets. And one thing that has emerged is the mislocalization of normal intracellular targets to the cell surface. A good example of this is our next late lead asset, 958, highlighted on slide 32. 958 recognizes an RNA binding protein that is normally sequestered in the nucleus.
Speaker 4: Similar to the anti-glycan antibody 444, the native antibody of 958 straight from the patient shows preclinical activity. In this case, however, we formatted the antibody as a T cell engager using Zencore's xMAB CD3 by a specific platform.
Speaker 4: As shown on the left, the 958 bispecific leads to tumor stasis in a target positive prostate cancer xenograft model in the blue line. We're currently optimizing the antibody to further enhance the potency to match or beat the positive control T cell bispecific used in this study, which is directed against...
Speaker 4: a well-known prostate cancer target, PSMA, shown in orange. On the right, you can see that 958 leads to the expected pharmacodynamic effects for molecules with this mechanism of action, including robust immune activation, as evidenced by an increase in interferon gamma levels in plasma, and expansion of CD8-positive T cells in blood. 958 is the first molecule to advance as part of our collaboration with Zencor, the details of which are described in this video.
Speaker 4: While each company will lead one of the joint programs, the agreement allows each partner to pursue up to two programs independently.
Speaker 4: The last oncology lead I will review is highlighted on slide 35. 597 is our anti-FA2 antibody which targets a novel, well-conserved membrane proximal epitope on FA2, a validated oncology target that is overexpressed in a range of tumor types. We have generated a series of antibody variants with a range of affinities to have a...
Speaker 4: share our excitement about the molecules I highlighted for you today. We are equally excited about molecules coming from the platform which are at an earlier stage. As Tito mentioned at the beginning of the presentation, we believe investments we have made across our platform, especially around target identification with the implementation of CRISPR screening, and
Speaker 4: have eliminated common bottlenecks and made the platform even more productive. We believe ATREKA is well positioned to capitalize on the discovery and development of novel oncology targets.
Speaker 4: Finally, while not an internal pipeline molecule, we wish to highlight another exciting asset that triggers anti-malaria antibody, ATRC501, on slide 37.
Speaker 4: ATRC 501 is an engineered version of an ATRECA discovered antibody designed to prevent malaria infection. The antibody is licensed to the Gates Medical Research Institute, which is preparing to file an IND this year. ATRECA retains rights in the US, Europe , and parts of Asia with potential product development opportunities.
Speaker 4: including prophylaxis for those traveling to malaria endemic regions. And with that, I'll hand it back over to John to discuss our upcoming milestones and provide an overview of our financials and IPs. Thank you, Stephen. This slide on slide 39 is an overview of our upcoming milestones.
Speaker 3: As Felipe noted, we are planning to provide updated data and a go-no-go decision for Phase II development of ATRC-101 later this year and potentially begin Phase II studies next year.
Speaker 3: On the preclinical side, we expect to nominate clinical candidates in the 444 and 958 programs later this year and are targeting INDs in late 2024 and early 2025 respectively. And behind those, our early stage discovery and lead generation efforts are ongoing. Finally, Gates MRI continues to advance ATRC 501.
Speaker 3: through the end of this year. We have a strong IP position with patents issued covering critical aspects of a trait discovery platform, as well as ATRC 101 and related antibodies with pending applications covering other pipeline assets.
Speaker 3: That concludes today's prepared remarks. We'd like to thank our trial participants and their families, as well as investigators and research staff at our clinical sites. Thanks again to everyone who joined the conference call and webcast today. With that, operator, could you please open the line for Q&A? As a reminder, to ask a question, you will need to press star.
Speaker 2: on the line of Divya Rao of Cohen. Your question, please, Divya.
Speaker 6: Hi guys, thanks for taking our questions. Just based on your experience.
Speaker 6: When you're trying to enrich for high H-score patients, what would you say is the percent of patients that fit that eligibility criteria? And then I guess as a followup, how does that change in terms of indications that maybe you're not seeing?
Speaker 5: as many patients enrolled in. Yes, well thank you. So as you know, in the preclinical assessment of the program, we had done some prevalence assessments in my coral rays, so these are tumors.
Speaker 5: in microarrays looking at the presence of targets on these tumors. And we had assessed that somewhere in the neighborhood of between 30 to 50% of the tumors that we were looking across all the indications were expressing the target.
Speaker 5: What we're observing in the clinical trial is similar to that. It's consistent with that prevalence data that we had generated previously. And depending which indication we're looking, for the most part, we're seeing about 50% of the tumors expressing the target.
Speaker 6: That's helpful. Congrats on all of the data.
Speaker 6: That's helpful. Congrats on all of the data. Well, thank you very much.
Speaker 2: Thank you. Our next question comes from the line of Roger Song of Jefferies. Your question, please, Roger.
Speaker 7: Great. Thanks for the data update and taking our questions. A couple of fun. So the first one is, you know.
Speaker 7: For this enrolled patient, you have medium five prior lines. Can you just help us to conceptualize what is the expected ORR or PFS in this population from standard of care or whatever the therapy available to those patients?
Speaker 5: Yes, so, Roger, it depends which education you're looking at. For some patients, as you may be aware, such as lung cancer, breast cancer would be another example. As you begin to exhaust into the care, the expected...
Speaker 5: progression-free survival gets shorter and shorter with subsequent lines of therapy. There are some other indications of where you can observe from time to time, indolent disease. I would think some coronal rectal cancers are like that. And as you know with Melomona as well, we have seen with the advent of...
Speaker 5: immunotherapy individuals now having longer period where you see progression-free survival occurring. I think with, for the most part in our study, with the patients that we are looking at, they come in already heavily pretreated. They tend to have an e-calc performance status of 1, which also predicts...
Speaker 5: were cellcom for these individuals. And so for them, I think looking at the data, I think it's important to note anyone that would go past the six month mark. I think the PFS at six months is an important landmark.
Speaker 3: The PFS at four months for some of those indications may also be equally interesting to look at. Yeah, I'd probably just add to that, Roger, that I think, you know, given the heterogeneity of these patients, different tumor types and the sort of open label.
Speaker 3: of the trial, I think we certainly need to have more patients before we could really draw conclusions about the efficacy or the activity that we're seeing and how it...
Speaker 3: compares with standard care. I think we are encouraged by the fact that where we do see more disease control and where we have seen responses is primarily in the context of patients who are expressing targets. So that does give us you know some encouragement that what we're seeing is real.
Speaker 3: and a function of AHRQ-101. But clearly we'll need more patients and that's why we're continuing to enroll, adding additional centers, and hope to have efficient data by the end of this year, really make a decision about whether and where to go to phase two for AHRQ-101.
Speaker 7: Okay, great. Maybe just that leads to my next question. Regarding the additional patient, about 40 to 50 patients, would you expect those patients will be slightly different from what you have enrolled in terms of the tumor type and the prior line of therapy?
Speaker 7: And just to remind us, what is the breakdown between the monotherapy versus the combination therapy? And when you make the go-no-go decision, what will be the key efficacy endpoint you were looking at, like the disease control or ORR or PFS? Sorry for the alarm.
Speaker 5: No questions here. So I'll try to address all the questions and points that you have raised.
Speaker 5: I think for the patients that are going to be enrolling, the 30 to 40 patients that we expect to enroll that will be new, and with the changes that we have made going to centers that are more adept to enrolling.
Speaker 5: Phase II patients as opposed to Phase I, as you know, Phase I units are highly specialized. And here what we have done is gone to centers that are hybrid between academic centers and community centers where we're seeing...
Speaker 5: patients, a greater number of patients that would be eligible for our trial. So that's one point to make. And what we expect to see there is a distribution across the various tumor types that we're seeking to enroll into. Some of the centers are more likely to enroll individuals.
Speaker 5: at this point and we're looking to try to supplement those underrepresented patient populations. And the goal for that is really to, for us to be able to look at where our strongest signal comes from. And there we'll be looking at, I think, response rates, obviously responders.
Speaker 5: As you know, we have the lung cancer and the melanoma patient that have been durable. I think that's notable. But what is new with the data that we're presenting today is really this notion of disease control and the ability to see patients staying on study for longer periods of time. So we'll be incorporating...
Speaker 5: a component of disease control into our decision algorithm. And we plan to update you at some point about how we're gonna approach that. And base it of course on sound analytic principles. So with regards to the type of patients that we're planning to see the eligibility criteria.
Speaker 5: We think that these patients will be similar to the ones that we've enrolled to date. We're continuing to enrich for Target as of today. And those patients are getting enrolled at the 30 milligrams per kilogram dose cohort. And in terms of I think what we objectively need.
Speaker 3: in terms of our response rate or durability of either responses or disease control or generally, I think it depends also on the tumor type, right? As Philippe alluded to, some of these are tumor types where it's not entirely uncommon.
Speaker 3: to see patients with, you know, indolent disease. And then there are other settings, so if we take our, you know, our response with a 50% tumor reduction in lung cancer, that's, you know, fifth line lung cancer, that's a setting where we wouldn't expect to see indolent disease. But then we have to overlay on top of that.
Speaker 3: What's the unmet need? What would the regulatory hurdle be? Because the whole point of that randomized phase two trial to really set up what could be a potential registration. So I think it'll be taking all of those things into consideration and applying relatively high bar particularly.
Speaker 3: in any setting where there's a well-established standard of care.
Speaker 7: Thanks for the thorough answer. Just to clarify, what is the breakdown between the model therapy and the combination therapy for the new 3240 patients in your old mind?
Speaker 5: So this will be obviously considered would be eligibility criteria. So for patients that would be considered to continue on PAMBRO or to receive a PAMBRO containing a regimen.
Speaker 5: Those indications are, as you know, based on the PAMBRO label. So there we have some differences with the monotherapy. And the monotherapy, as you know, was based on our earlier data showing that there was a high prevalence of target in these various tumor types.
Speaker 5: So if the physician thinks that PEMBRO is not indicated or the patient had already received PD-1 or PD-L1 agents and unlikely to respond, it is likely that they'll be brought on to the monotherapy if they meet eligibility. And for those for whom the physician believes that continuing.
subset of breast cancer, the triple negative breast cancers, and the hepatocellular carcinoma would be indications that we would see in the combination arm that would not be appropriate for the monotherapy arm based on eligibility criteria.
Yeah, and I think even in the setting where we have cohorts open for monotherapy and...
combo with pembrolyzumab. I think we would likely need to show more suggestion of single agent activity for the FDA anyway. So to some extent we'd like to see more combination patients but to some extent we also benefit from more.
because I think that's something that, you know, that individual contribution is something that probably the FDA would want us to answer. But at this point, those centers, most of them would have basically the choice and use their own discretion.
At least we're very in. Gotcha, yeah, let me send. Okay, thank you.
for breast lung, ovarian, colorectal. Gotcha, yep, that makes sense. Okay, thank you. Thank you, Roger.
Thank you. Our next question comes from the line of John Newman of Canaccord. Your question please, John .
Hi guys, thanks for taking my question. Just wondering with the currently ongoing Phase 1 study for 101.
How much follow-up time will be allotted? Just wondering if you'll be able to follow the study longer term for...
things like overall survival where perhaps there's a signal that shows up that doesn't initially show up in the response rate. Thanks.
Yes, so right now the data that is being collected obviously is response rates and we're looking at progression pre-intervals. Survival is collected when that event occurs for patients that are on study during the period of follow-up. That we are not, there's some instruments that canbe verified whether you are in hospital or in four-year hospital or whether you're in field care or physical therapy as well.
following patients once they come off study. So the overall survival data would not be something that we would expect to report on with this trial.
I think what we're looking at is for response rate and disease control to give us an idea of the signal and help us prioritize which indication is most likely to be...
seeing or deriving some kind of benefit from being treated with ATRC 101. And that sets the stage really for the phase two study that John was talking about where there in a more formal way and ideally in the controlled fashion with an appropriate control we would be assessing.
what a true treatment effect would be for phase three in order to appropriately design the phase three trial. And that phase two could include collecting survival data. Okay, great. Thanks.
effect would be for phase three in order to appropriately design the phase three trial. And that phase two could include collecting survival data. Okay, great. Thanks. Thanks, John .
Thank you.
Thank you. Our next question.
It comes from the line of Tony Butler of EF Hutton. The line is open, Tony.
Yes, thanks very much. If I understand correctly.
preclinical work had demonstrated that HRC-101 actually remodeled the tumor microenvironment, if I'm correct in that. If that's true, one of the questions that comes to mind is.
this notion of combination where is, I think you stated, utilizing PIMBO with 101 was really related to those indications where PIMBO was already indicated. If that's true, that's fine, and I'm respectful of that, but the real...
combination where, as I think you stated, utilizing PIMBO with 101 was really related to those indications where PIMBO was already indicated. If that's true, that's fine, and I'm respectful of that, but the real question is, is PIMBO
In cold tumors, for example, in CRC and or ovarian where Pembro just has no effect
there may be, if in fact you do get TME remodeling, there may be some really decent signals here where in those tumors, that combination could then therefore be advantageous. And so for example, it wouldn't take a lot from a response rate to really demonstrate in the late line CRC patient that you really have something of benefit.
I am respectful that in monotherapy you may have modest benefit, but yet certainly in combination there is at least a question here that.
Chief, if you could show anything better than, you know, we're graphing it, you really have an opportunity set. And I'm just throwing this out as a thought, if it's directionally correct, or maybe what you think about it. Thank you. Yeah, maybe you want to address that from the preclinical side and then I don't know.
Maybe we've had some further thoughts. Thanks for the question, Tony. Yeah, Tony. So, you know, you are right, you know, in the sense that if the mechanism
is directed towards the innate immune system, then that upstream of agents that act on T cells, like an orange frames in the blood cells,
anti PD-1 or PD-L1 checkpoint inhibitors. And so, yes, in principle that converting tumors that normally don't have much of a, you know, an immune response, you know,
with ATRC1 as possible. And we all know that as you point out, TRC is one of those tumor types. Yeah, from a clinical end, you raise a, I think a very provocative thought and question that I think would be at some point worth addressing, you know, in the clinical setting.
I think the individuals with mismatch repair or MSI high colon cancer are more likely to have a response with pambrolizumab or PD-1 or PD-L1 agents. And I think this concept of cold...
and converting a cold tumor to something that is more likely to respond is something that is worth investigating for sure.
converting a cold tumor to something that is more likely to respond is something that is worth investigating for sure.
Thanks very much. Good suggestion, Tony. Thank you for raising your.
Thanks very much. Good suggestion, Tony. Thank you for raising your. Thank you. Our next question.
Come from the line of Stephen Willie of Steve. Your question please. Steve. Yeah, good afternoon. Thanks for taking the question.
I think I've asked you this before, but I'm going to ask it again. Just curious if in this incremental patient data set you were able to somehow look at longitudinal H-score expression, just as a way to assess the stability of target expression over time.
So, thank you for the question. We are collecting biopsies, well-owned studies for patients that consent to it.
and we are planning to do some analysis longitudinally for those matched biopsies that we've obtained. As you know, these are...
There are studies that are not that easy to conduct, and with small numbers we have to be careful with inferences. To date, what we have is the baseline data. We've batched the specimens and plan to analyze this with the final analysis. So we have not looked at the serial biopsies yet for those.
for the patients whom have given us permission to go ahead and sample again. And just for clarity, we do it during a baseline. We do it during the first cycle, and we do it also at the disease progression.
Okay, and then I think eligibility for the combo cohort.
required either progression on a PD-1 or L-1 targeting map and or stable disease on a PD-1 or L-1 targeting map. And just curious if you know offhand if the incremental patients enrolled into the combo cohort.
that either fit the progression definition or if there were some patients in there who also fit the stable disease definition. Yes, so I think the eligibility criteria is worded slightly differently. It's a unsatisfactory response.
while on PD-1 or PD-L1 agent and or his progression. So there in the opinion of the physician, the response that was obtained while on the PD-1 or PD-L1 would have to be unsatisfactory and require the institution of new therapy.
What we have is, for the most part, looking at those nine individuals, the reason for the last therapy was really a lack of efficacy and progressive disease. So looking at those individuals, I would say that most of them would have had progressive disease. Okay. And just with respect to the...
Goal of enrolling an additional 30 to 40 patients before the end of this year. I know you've kind of talked about some of the the headwinds that a lot of these phase 1 sites are facing and we've heard that from other companies as well, but I guess would you still
Is the 30 to 40 incremental amount of patient data, is that requisite for making a no-go decision before year-end? Or is that something that is a little bit fungible in terms of timelines?
So as you know, the trial is currently set up as an assignment two-stage study with criteria for expansion within specific indications. I think like early phase one studies, as you learn about your drug and you begin to collect information....
Adapting your approach and incorporating what you're learning along the way is something that is done by most company and certainly encouraged even by health authorities. So, early in trial development, we tend to be. You will report to adapt.
as we learn more about our drug, either on the safety side or on the activity side or even sometimes with pharmacokinetics, we can certainly modify the way we approach looking at these data. What is new with today's presentation?
is the notion of disease control or stabilization of disease or durability of response. And I think that's a very important new information that we have today. If we think about a higher bar for making decisions, I think applying a bar that not only looks at response rate but...
as we had planned earlier. And we can probably make those decisions based on sound analytic principles using data and statistics with fewer patients in each one of the categories.
Okay, and then maybe just lastly, just in terms of, I thought it was interesting that you disclosed that about half of the antibodies that you're disclosing are actually against these glycan targets, which I know from...
As you mentioned, kind of the conventional immunization perspective have been really hard. These are carbohydrates
Just curious as to kind of where you think your progress puts you from a collaborative position, just kind of given the amount of interest there has been around this target class historically. So yes, I want to start with me as as it is currently the moment upon which
Hi Steven, so I'll take that one. So we've, we're in a number of discussions about programs, obviously. The profile of 444, as Steven described it, is proving to be quite attractive and garnering a great deal of interest. You have something that's binding it to the
there are a couple of anti-glycan antibodies that have reached commercial stage. And part of the problem there, if huge black box warnings is they're not specific to tumor. They attack peripheral nerve, for example. And what I believe you're hearing today in Steven's presentation, part of the presentation.
is that our platform is delivering what you might expect. It's glycans that you can't really find through molecular biology tricks. You just can't do it that easily with glycans. And they are fairly specific. And as you point out, we have a very nice IgG antibody recognizing that glycan simultaneously. Great, thanks for taking the questions, guys.
is delivering what you might expect. It's glycans that you can't really find through molecular biology tricks. You just can't do it that easily with glycans. And they are fairly specific. And as you point out, we have a very nice IgG antibody recognizing that glycan simultaneously. Great. Thanks for taking the questions, you guys. Thank you.
We have time for one more question. Yes, sir. Our final question comes from the line of Kemp Dolliver of Brookline. Your line is open, Kemp. Thank you. I have a couple questions there. Some of them are pointed and quick. I'll be respectful of your time, but quickly with regard to the incremental enrollment. What would be the assumed data cutoff to make a decision in the timeframe you're thinking?
So, yeah, obviously, we're going to enroll and collect data until the study comes to fruition. I think we will report on the, you know, when it's appropriate, by the end of the year, what are most coming out of the first half of July , 16? Yes.
up to date results would be. And I think, you know, the data cut off for that typically requires, you know, a few weeks for us to be able to analyze that data and put it together. But, yeah, I think maybe one of the challenges you might be alluding to, and I think it's, you know, it's an important one, is
having sufficient follow-up, you know to be able to assess durability of response So I think it might be a little bit easier in a way to make a no-go decision than it is a go decision The no-go decision would be based on you know, not seeing a level of activity or a given indication or program overall that that would lead you to not move forward in phase two
It goes to phase two decisions, clinical decisions, it's also a business decision, and I think that you could imagine a scenario where you've got responders or long-term stable disease and you want to give a little bit more time before making the decision to pull the trigger on an expensive phase two program. But I think our commitment is really to try to provide fairly regular updates and get to a crisp decision that you want to make through your next decision.
by the end of this year plus minus when we basically don't want to leave the study just open enrolling patients without making a decision to go to phase two, or possibly end the program. I think we all feel pretty encouraged by the data that we're seeing, the durability of the responses, the PFS that.
you know, seems to favor patients who express target, but I also think it's important for us to get to a decision because there's an opportunity cost here when you look at the other molecules that we have that are going to, you know, IND in the next 18 months. I will stop there. Thank you.
Okay, great. Well, thanks a lot. Much appreciated, Kemp. Thanks, everyone, for your questions today and for joining the call. And I look forward to additional updates in the future. Thank you. This concludes today's conference call. Thank you for participating.
You you sol.