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spk10: Good morning, ladies and gentlemen, and welcome to the Chimerics Third Quarter 2023 Earnings Conference Call. I would now like to introduce you to your host for today's call, Michelle Laspaludo, Vice President of Strategic Planning and Investor Relations at Chimerics. Please proceed.
spk01: Thank you, John. Good morning, everyone, and welcome to the Chimerics Third Quarter 2023 Financial and Operating Results Conference Call. This morning, we issued a press release related to our third quarter earnings update. You can access the press release in our investor section of our website. With me on today's call are President and Chief Executive Officer Mike Andreol, Chief Medical Officer Alan Melamed, and our Chief Technology Officer Josh Allen. Before we begin, I would like to remind you that the statements made on today's call include forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and are subject to risks and uncertainties and other factors. These risks and uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. Please refer to our filings with the SEC for a more complete disclosure of these risks and uncertainties. At this time, I would now like to turn the call over to our President and Chief Executive Officer, Mike Andreuil.
spk07: Thank you, Michelle, and good morning, everyone. The third quarter was marked by continued execution across our pipeline. including continued enrollment in our global phase three action study of ONC201 and phase one dose escalation studies for our second generation compound, ONC206. I'll start with ONC201 and the action study. We now have 113 sites open across 12 countries and tracking ahead of our prior guidance of activating 100 sites by September 30th. Enrollment is progressing with site activation and we continue to expect first and second interim overall survival data as well as PFS data in 2025. Geographically, we now have about an equal number of sites activated in Europe as the U.S. This past September, we participated in the European Association for Neuro-Oncology Conference, also known as IANO, in the Netherlands. And at that conference, we hosted a symposium on the current diagnosis, treatment strategies, and clinical trials for H3K27M mutant glioma, and engage with the neuro-oncology community broadly to drive ongoing awareness and interest in the action study. I was very pleased with the level of enthusiasm across the European community for this program and the degree of support from so many investigators who recognize the very high unmet need in this patient population. I was also reminded of the value to our industry of being back in person at medical conferences following the pandemic as attendance at IANA was at a new record high and we have seen a nice increase in site activity across Europe in the weeks since that conference ended. That increase is in addition to already strong engagement prior to IANO. Turning to North America, the annual meeting for the Society for Neuro-Oncology, also known as SNOW, will occur in Vancouver, Canada in just a couple weeks, where we are also planning a large presence. I'll let Josh comment on our plans around this conference, but we're looking forward to seeing many of our investigators in the action study as well as other program collaborators later this month. Our efforts in enrolling the action study are also underpinned by a robust publication strategy that includes a recently published manuscript in Cancer Discovery this quarter, which focused on frontline ONC201 survival data and further explained its mechanism of action. The data from this peer-reviewed publication further strengthens our confidence in the action trial and also further supports its enrollment. I'll let Josh speak. more to the details included in this recent manuscript. As we continue to enroll the action study, we're also simultaneously preparing the company and the market for ARN201's potential commercialization. To that end, we're in the process of finalizing recruitment of a chief commercial officer, and I'm excited that that process is nearing completion. In fact, I expect to announce the hiring of that individual before the end of the year. Turning briefly to ARN206, The protocol amendments for each of our dose escalation studies have been approved as expected during the third quarter. These amendments allow for a more intense dose and schedule that includes twice-a-day dosing up to three consecutive days weekly in order to increase the duration of therapeutic exposure. We expect the continual 72-hour exposure of ARK206 to potentially generate additional monotherapy activity both in CNS tumors and potentially tumors outside of the CNS based on emergent in vivo data. The PNOC and NIH studies are enrolling at the more frequent dose levels, and we expect dosing to be complete in the first half of 2024. As you may recall, we previously reported a GBM response on the once-a-week schedule starting at dose level two, and that patient's response remains ongoing as the patient's dose level has increased. Since these studies began enrolling again, I'm also happy to report we have observed no dose-limiting toxicities thus far. Before I turn the call over to Josh, I'd like to reiterate our deliberate and disciplined approach to capital allocation. We ended the quarter with $217 million in cash and equivalents, which is on plan to meet our previous guidance of approximately $200 million in cash at the end of the year. We continue to expect our cash balance to be sufficient to support operations into the end of 2026 and through each of the expected action clinical endpoints. For more details on our third quarter balance sheet and income statement, please refer to the press release, which we released earlier today. With that, I'll turn the call over to Josh to provide additional color on our recent publication on cancer discovery and our recent engagements with the neuro-oncology community. Josh?
spk06: Thank you, Mike. So we continue to see benefit from our connections to the global neuro-oncology community. As Mike mentioned, over the last quarter, we held a symposium at the European Association for Neuro-Oncology Conference in the Netherlands. There, we met with leading neuro-oncologists and active clinical trial investigators, in addition to holding a symposium for presentations by thought leaders related to H3K27 and mutant glioma, including the action study. Later this month, we will be similarly present at the annual Society for Neuro-Oncology meeting in Vancouver, where we are planning a large presence, including a symposium on future directions and the diagnosis and treatment of H3K27 and mutant glioma, as well as supporting our collaborators who will be making a series of oral presentations on preclinical and clinical studies of ONC201 in different treatment settings. We're looking forward to seeing many of our investigators and collaborators in person as we drive continued engagement in the action study and keep a close eye on emerging treatment strategies in molecularly defined gliomas. In addition to these larger neuro-oncology conferences, we also remain actively engaged on the scientific front including presentation of non-clinical data that reflect our deepening understanding of the novel mechanism of action of the mipridones at the AACR Special Conference in Cancer Research for Brain Cancer held in Minneapolis just a few weeks ago. As Mike mentioned, a research manuscript co-authored by numerous academic investigators and chimerics recently published in the journal Cancer Discovery that reflects several years of clinical, translational, and mechanistic investigations of OCTO-01 as a first-in-class therapy for H3K27M mutant glioma. The manuscript describes data that support a range of important conclusions for OCTO-01 and H3K27M mutant glioma that span its mechanism of action, its biological activity within patient tumors, and its clinical activity that extends beyond the prior efficacy analyses in the recurrent setting. Starting with the mechanistic findings, The data provide a step-by-step understanding of why ARF201 is uniquely poised to address this disease that starts with the engagement of its ClpB binding target in the mitochondria and ends with reversal of the H3K27 trimethyl loss event in the nucleus. Reversal of this epigenetic hallmark is remarkable. as it is the direct consequence of the H3K27M mutation and is thought to be the pathophysiological driver of the disease. These findings were consistent across disease models, and importantly, reversal of H3K27 trimethyl loss was robustly evident across all tumor biopsies obtained from Onc201-treated patients. Turning to clinical outcomes, the survival of H3K27-immutant glioma patients who received Onc201 in the frontline setting following radiotherapy, which I'll note is the same setting as the action trial, was reported as 21.7 months from diagnosis in contrast to 12 months for patients who did not receive R201. Favorable survival outcomes among R201-treated patients were consistently observed across a variety of sensitivity and subgroup analyses. It is worth noting that while the previously disclosed results for ARC-201 in the recurrent setting were skewed towards adult patients and thalamic primary tumor locations, this frontline data set described in the manuscript were skewed towards pediatric patients and brain stem tumor locations. Aggregately, these findings demonstrate that ARC-201 is a first-in-class therapy for H3K27N mutant glioma that consistently reverses the major driver of the disease pathology and appears to be associated with compelling outcomes in uncontrolled trials across multiple clinical settings. These findings boost our confidence in the prospective randomized controlled evaluation of OG201 in the ongoing action study, which is further strengthened by inclusion of dose intensification to twice-weekly dosing. With that, I'll turn the call back over to Mike for closing remarks.
spk07: Thanks, Josh. During the third quarter, we've continued to execute our plan with a focus on bringing Onc201 to patients as soon as possible. We're beginning to prepare our organization to potentially launch Onc201, and we're excited about the promise to further broaden our pipeline in the future by advancing Onc206 and or through business development.
spk11: With that, operator, we'll open the call up to questions. Thank you.
spk10: At this time, if you would like to ask a question, Please press star followed by the number one on your telephone keypad. We will pause for just a moment to compile the Q&A roster.
spk11: Thank you. Your first question comes from the line of Maury Raycroft from Jefferies.
spk10: Please go ahead.
spk09: Hi, this is James. Congrats on the progress and thanks for taking our question. Can you talk more about the progress on site initiation, enrollment, feedback from investigators specifically in Western Europe and also Canada? And can you bookend timeframes for when you could reach full enrollment of the 450 patients needed for the study?
spk07: Sure. Thanks for the question, James. Engagement in Western Europe, actually across all of Europe, has been strong. I think it's evidenced by the speed of site activations to date in that part of the world. I'd say Canada has been a little bit slower, but from a regulatory perspective, that's not entirely unusual. But engagement at sites with investigators has been has been quite strong in both geographies. In terms of when we would expect full enrollment in the study, we haven't given that guidance, but continue to reinforce our guidance to have first interim efficacy overall survival data in the first half of 2025. So you might expect it would be a similar timeframe if you just look at the number of events required to hit that in timelines.
spk09: Got it. Thanks. And where are you in enrollment for the consecutive dosing phase cohorts with Onc206? Do you anticipate that you would press release that data in an earnings call, have a separate event for that, or would you present that data at an upcoming medical conference?
spk07: Yeah, good question. You know, we've got two separate arms, pediatric and or recurrent and frontline in the pediatric PNOC study and then a separate, obviously, study with the NIH. So there are three different, in a way, arms ongoing with that phase one studies, James. And so we're not going to give a play-by-play on where we are with each one, but all three are enrolling and we continue to expect that we'll have enrollment completed in the first half of 24. I think that we'll likely top line the safety data. To the extent that there's efficacy insights that we can gather from that, we'll do that at that time. But I want to probably set expectations that if you look at at least the parent compound on 201 and the recurrence setting, there was an 8.3 month time to onset of response. And so there's a natural lag between the maturity of those patients into a response and when we might have safety data. So there's probably a two-step process in terms of identifying safety data and additional insights from an efficacy responder perspective. The other insight I'll make is some of those patients who will qualify for those studies may have seen OCTO-01 previously, and so they could have resistance mechanisms built in that would make assessing response more difficult. We also have some patients in the PNOC study that are in the frontline setting and therefore confounding a response assessment, really making them unevaluable for a response. And so we're really focused on the recurrence setting in patients who are naive to the imipridone class in assessing response. So we'll look at the totality of the data at the time, but I think it's likely to be top line safety data first, that we would press release and then followed perhaps by maturing efficacy data.
spk11: Great. Thank you for taking our questions. I'll hop back in the queue. Sure.
spk10: Your next question comes from the line of Norit Kibria with Capital One. Please go ahead.
spk04: Hi. Good morning. Thanks for taking my question. I guess I'll start first with ONG206, the patient respond, the GBM patient responder. Is the patient still on study? You know, how long has the patient been on therapy? And can you comment on what dose, you know, how many doses they've received? The different levels.
spk07: Yeah, the patient's been on, yeah, Noreen, the patient's been, well, first, thanks for the question, Noreen. That patient's been on study for about a year and a half at this point, so it's been quite some time, a very durable response. They have continued to dose escalate. Last I heard, I'll ask Alan or Josh to weigh in on this, but my understanding is they graduated to dose level four. That was the last piece of information I had on that patient. I don't know. Josh, do you have other insights?
spk06: Not much to add. I know that that patient has dose escalated at least twice since the initial dose level at 100 milligrams. I know the investigators reported a deepening of the response as that dose escalation has occurred in that patient, which is very encouraging. But overall, I think that the macro messages, we're compelled by this idea that Octo six continues at the Preclinical level to show signs of efficacy outside of H, three K, twenty seven and mutant glioma. Clearly that was a strong indication that that can translate at least in that patient is Mike has pointed to. We, we look forward to continuing execution at this intensified dose schedule and taking a careful look within the response to valuable population in the study. to see what the path forward looks like outside of H3K27. So great news for that one patient. We look forward to seeing more of that.
spk04: Great. Thanks, Josh. And maybe this one's for you or Alan. Can you comment on what type of data on this patient and any of the preclinical type of data that will be presented at the upcoming SNOW conference?
spk11: Go ahead, Josh.
spk07: I think you're closest to that.
spk06: Go ahead. I'll start with snow, Noreen, and just mention that we expect at least three oral presentations to occur at snow on OCTO-01. Two of them are related to positioning OCTO-01 as a combinatorial backbone in DMGs, right, given the signal as a monotherapy that this drug has produced. its safety profile, its oral administration, et cetera, really physicians that is an ideal backbone therapy. So some of the mechanistic data, preclinical rationale, and then available emerging clinical safety and outcomes associated with Noctua as a backbone therapy will be presented at Snow. I think that's going to be the subject of a couple of those studies. So you'll expect to see more of that at Snow.
spk04: Terrific. Okay, and just one more. Can you just remind me, with the ONG206 trials that are ongoing, the dose escalation, is it just post-radiation, or do they receive a little bit of temozolomide as well?
spk07: There are arms that are in the frontline setting post-radiation and also arms that are at recurrence. I believe temozolomide is allowed prior to initiation of 206.
spk02: Mike, this is Al. Mike, and this is a phase one study. It's a little more open on the inclusion criteria as we are trying to get safety for the patient population. I think the bonus is if we do see some signs of activity, we need to evaluate where we've seen this activity, and that will help us decide where to go for future
spk11: Okay, thanks so much.
spk10: Your next question comes from the line of Samit Roy with Jones Research. Please go ahead.
spk03: Good morning, everyone, and congratulations on all the progress. On ONC206, excuse me, could you remind us the dose escalation is going to be with 100 milligram dose level twice weekly and how much dose exposure increase do you expect from the prior schema yeah assuming i'll have josh perhaps contribute to this too but we have a slide in our deck that essentially lays out the the dose frequency and schedule so
spk07: The next two dose levels following reactivation of this new protocol are evaluating essentially similar exposures and dose levels that were given once a week, but doing it fractionated over three days and then escalating up from there. Big picture, we'll end up at about four times the dose on a weekly basis if we make it all the way to dose level 11. Josh, anything to add?
spk11: No, I think you covered it. Okay.
spk03: So, and with the time to respond being about eight months or so, and I'm expecting these patients just got the dose escalation part just got initiated. So, the data is most likely we are thinking end of 24. Is that a correct assumption, the efficacy data?
spk11: I think, yeah.
spk07: To the extent that we have evaluable efficacy data, it will come in likely after completion of the safety analysis, right, Shumit? And so we'd expect that, as we've said, in the first half or middle part of next year. And we'll share what efficacy insights, response insights we have at that time. And we'll update that during the course of the year as those patients continue to be followed.
spk03: Got it. And one last question. In terms of the location of the tumor itself, we should expect a broad range, right, between anything between the POM, GIPG, stem?
spk07: Yeah, this is looking at primary CNS tumors, so it's going to be a fairly heterogeneous patient population.
spk02: Got it. The only exception is, this is Alan, the only exception is we are excluding patients that you typically see with H2K7M. We're looking outside of that. but otherwise it's broader for a CNS disease.
spk11: Thank you so much and congrats again on the progress. Thank you, Matt. Your next question comes from the line of Joel Beatty from Baird.
spk10: Please go ahead.
spk08: Good morning. Hi, this is Ben on for Joel. Thanks for taking our questions. First question is what expense trajectory to expect over the next few quarters?
spk11: Hi, Ben. I'm sorry to clarify, was that expense trajectory you asked?
spk07: Yes, sir. Yeah, it'll be similar, I would expect. If you look at our first half run rate in terms of cash burn in 2023 and this latest quarter, we're averaging $15, $16, $17 million a quarter. I would expect that to continue over the next couple quarters. Yeah, I was just going to add, as we begin to prepare for commercialization, you might see an uptick in expense, but I would say in the grand scheme of things, it would be just at the margin.
spk11: Great. That's super helpful.
spk08: And then I guess on the identification of biomarkers for ONC206 for future efficacy studies, Would you expect the biomarkers to be similar to the biomarkers you showed for 201 in the cancer discovery publication or something different?
spk07: Yeah, really good question, Ben. I'll let Josh weigh in on that. Josh?
spk06: Yeah, Ben, great question. And as you would expect from, you know, we've been working on OCTO-01 and this platform for a number of years now, and we're expecting to leverage all of that molecular information we've gathered from those efforts and pour it into the OCTO-06 program. So what I'll say is we're really excited about what we're seeing with OCTO-06. We've been working hard in the lab ourselves and with collaborators and have generated a you know, a growing body of compelling in vitro and in vivo efficacy that we're excited about. As we've mentioned, the potency increase and the alternative engagement of additional target engagement interactions that we've seen with OCTO-6 relative to OCTO-1, while that may not be a meaningful opportunity for H3K27M mutant glioma, given that OCTO-1 is having on-target saturation there, We think there's a lot of other opportunities outside of H3K27M, both within the CNS and outside of the CNS, that can be addressed by OCTO6. So we're seeing signs of that in preclinical studies. Clearly, we've reported on this one responder early in dose escalation in the phase one for OCTO6 that endorses that hypothesis. And what we're looking to do now is take some of these molecular biomarkers, some of which you're pointing to, but good ideas can come from anywhere. So we're trying to take all of those ideas we have for specific molecular driver alterations in cancer that could be associated with OCT206 heightened activity and test some of those hypotheses against the compelling preclinical activity we're seeing so that we can run towards, you know, actionable alterations and follow-on trials if that's appropriate. So good question, good thinking, and we're hard at work testing a lot of these theories that include what we've learned from OCTO-01 and OCTO-06 over the years.
spk11: Great. Thanks for the insights. I'll start from us.
spk10: Your final question comes from the line of Troy Langford from TD Cowen. Please go ahead.
spk05: Hi. Congrats on all the progress this quarter, and thanks for taking our questions. First one's just on ONC206. So, with respect to the Phase I justice escalation work, do you currently expect the Phase I work for both the NIH-sponsored study and the PNANC-sponsored study to complete around the same time? And if not, would you need to wait for both of those to finish before you move forward with the program?
spk07: Yeah, good question, Troy. We do expect them, based on what we know right now, to complete around the same time. I don't think we have any insight that they would be materially different. Of course, as we get closer to the final dose levels, assuming that we don't have a safety event that would stop us earlier at a particular dose level, we right now are planning for them to complete around the same time if If that should change, then, of course, we'll update you accordingly. Alan, any additional thoughts on that? I was just going to ask Alan any additional thoughts.
spk02: No, the only thing I would add is the demand for the Ong 206 is high. So it's really how quick we can fill the cohort, close the cohort, and then open a new cohort. So there's high demand here.
spk05: Okay, great. And then just one other one on Ong 206. So with respect to some of the expansion opportunities for that compound, do you want to just provide any color around how you think about balancing investment into some of those other areas with the need to preserve the cash runway for the action study?
spk07: Yeah, great question. And so as we think about capital allocation, we have earmarked some capital on balance sheet for Phase 2 studies. That could be on 206. It could be another compound maybe that could be in-licensed. As we've said in prior quarters, Troy, the bar for business development continues to be high because we continue to see early preclinical and clinical data with 206 that continues to raise the bar for anything else we would pull in and allocate capital to. Clearly, the more substantial of a Phase 2 study we might run with ONC 206 would shorten the runway, and we'll evaluate that when we make that decision, to what extent would we shorten the runway, what are our access to other dilutive or non-dilutive capital, and in particular, any additional insight we might have on milestone payments that might be forthcoming from emergent biosolutions with respect to the Tembexa divestiture we made last year, all factor into that calculus. But it starts with how much conviction do we have in the data to date on OCTO-06, both preclinically and clinically, and sharing that data with the market, making sure that that conviction is shared externally as well.
spk11: Great. Thanks for all the extra color. That's all for me. Sure. I will now turn the call back over to Mike Andreol for closing remarks. Thanks, John.
spk07: Thank you, everyone, for your time this morning. For those of you attending the snow conference this month, please stop by our booth. Otherwise, we look forward to updating you again in the coming months.
spk11: Ladies and gentlemen, that concludes today's call. Thank you all for joining. You may now disconnect.
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