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spk01: Thank you for standing by and welcome to Calathera Biosciences' fourth quarter 2021 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. To ask a question during the session, you will need to press star 1 on your telephone. Please be advised that today's call is being recorded. Should you require any further assistance, please press star 0. I would now like to hand the call over to Stephanie Wong, Chief Financial Officer. Please go ahead.
spk03: Thank you, Operator. Good afternoon, everyone. Welcome to our fourth quarter and full year 2021 conference call. Joining me today are Susan Molyneux, Founder, President, and CEO, and Emil Kuryakov, Chief Medical Officer. Earlier this afternoon, we issued a press release which included an overview of our fourth quarter and full year 2021 financial and operational results which can be accessed through our website at calathera.com. Before we begin, I would like to remind you that today's discussion will include statements about our future expectations, plans, and prospects that constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors including those discussed in the risk factors section of our periodic filings with the SEC. In addition, forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our views change. Please note that this call is being recorded. And with that, I'll turn the call over to Susan.
spk02: Thanks, Stephanie. Good afternoon, everyone, and thank you for joining us for today's conference call. 2021 was a transformational year at CalFERA as we took several critical steps to transition the company's focus and core programs to developing therapies for biomarker-specific patient populations while continuing to leverage the company's deep expertise in clinical development for targeted small molecule cancer therapies. In October, we announced the acquisition of two clinical stage assets from Takeda, Myvovotinib and Cepanasertib. Myvovotinib is a spleen tyrosine kinase, or SICK, inhibitor that targets the constitutively activated B-cell receptor pathway in diffuse large B-cell lymphoma and other Nod Hodgkin's lymphomas. In completed Phase I-II clinical trials, Myvovotinib showed promising single-agent responses with deep and durable activity in unselected patients with DL-BCL. Our initial development will be in ABC, or activated B cell, DL-BCL, where BCR signaling and sick activation are central drivers. Myvovotinib showed a substantially higher response rate in ABC compared to GCB-DL-BCL, with a 53% ORR, or overall response rate, in ABC compared to a 22% ORR in GCB. DL-BCL, in a retrospective analysis of completed trials, had this data, and in addition, recent preclinical studies have shown enhanced sick activity and sensitivity to sick inhibition in DL-BCL and other non-Hodgkin's lymphomas harboring mutations in MITEI-88 and or CD79. They comprise a distinct genetic subset of ABC-DL-BCL known to have poor outcomes with standard of care therapy. Approximately 50% of all ABC-DL-BCL tumors have one or both of these mutations. Myvovotinib has the potential to be the first to market therapy for patients with a genetically defined subset of DL-BCL. The compelling single agent overall response rate in ABC-DL-BCL and potential for further enrichment of single-agent activity in the genetically defined subset of ABCDL-BCL with MiD88 or CD79 mutations, we believe provides a well-defined, efficient development path to a potential single-agent accelerated approval in these populations. Sipanacertib is a dual mTORC12 inhibitor that targets a key survival mechanism in KEEP1 or Nrf2-mutated tumors. Cipanacertib has demonstrated promising single-agent activity in patients with relapsed or refractory Nrf2-mutated squamous non-small-cell lung cancer. It is a differentiated molecule from other mTOR inhibitors and is the only inhibitor to have strong single-agent activity in Nrf2-mutated squamous non-small-cell lung cancer venagraft. Nrf2 mutations occur in approximately 15% of squamous non-small cell lung cancer and confer a poorer prognosis for these patients. We believe Cepamacertib has the potential to address a substantial underserved patient population and has the potential to be the first treatment for Nrf2-mutated squamous non-small cell lung cancers. We plan to initiate Phase II studies of both the Panacertib and Mivivotinib in the first half of 2022. We also presented data from our Phase Ib trial of CB280 for the treatment of cystic fibrosis at the North American Cystic Fibrosis Conference in November of last year. The data showed that CB280 was well tolerated, demonstrated linear pharmacokinetics, and showed complete and continuous target inhibition in plasma at doses at or above 100 milligrams. CD280 also demonstrated robust pharmacodynamic effects with rapid and significant dose proportional increases in plasma arginine, the key driver of nitric oxide production. Enrollment and analysis of all four cohorts is now complete, and evaluation of next steps is ongoing. Turning to our preclinical pipeline, we have continued to advance our internally discovered preclinical pipeline of synthetic lethality targets. VPS4A and VPS4B are paralog genes, and loss of one or the other paralog in cancer cells is synthetically lethal. Our VPS4 program is the most advanced synthetic lethality program we have, and we recently announced that we will be presenting a poster on the discovery of novel VPS4A small molecule inhibitors at the upcoming AACR meeting in April. I will pass the call over to Emil now to go into additional details on our clinical program. We're excited to realize the potential of Mivovotinib and Sabanacertib in biomarker-defined populations. By focusing on well-characterized genetic vulnerabilities with molecules that have already shown single-agent activity, we believe we will be able to generate Phase II data with targeted, efficient study designs. We plan to share data from these studies by the first quarter of 2023. Thank you, Susan.
spk04: I'd like to start today by providing some additional detail around our planned Phase II trials of Mivivotinib in patients with relapsed refractory ABC-DLBCL with and without MITEI-88 or CD79B mutations, as well as the panacertib in patients with relapsed refractory Nrf2-mutated squamous non-small cell lung cancer. Starting with Mivivotanib, we plan to initiate a Phase II trial in relapsed or refractory non-GCB-DLBCL as defined by the Hans algorithm, which captures all ABC-DLBCL, and we will enrich for MITEI-88 and CD79B mutated tumors using liquid NGS testing. Patients will be randomized to either a standard dosing schedule with 100 milligrams Q daily or an induction dosing schedule, which is 120 milligrams Q daily for 14 days, followed by 80 milligrams Q daily. Efficacy data from this study could position the company to initiate a registrational study, which would potentially enroll cohorts comprised of patients with non-GCB DLBCL and or MITEI 88 slash CD79B mutated DLBCL. With the primary endpoint of overall response rate, such a study would target an accelerated approval pathway for myovotinib as a single agent in these biomarker-defined subsets. We plan to rapidly pursue combination strategies with novel and or standard-of-care therapies to further expand development into earlier lines of therapy in DLBCL. Additional paths for monotherapy and combination development include Waldenstrom's macroglobulinemia and other indolent lymphomas where myovotinib has shown compelling single-agent responses in previously completed trials. Now, turning to cipanacertib, we plan to initiate a Phase II study of cipanacertib monotherapy in patients with Nrf2-mutated squamous non-chromosal lung cancer, harboring either wild-type or mutated Nrf2 as detected by next-generation sequencing. This study will strengthen the existing data on cipanacertib as a monotherapy in patients with squamous non-chromosal lung cancer with the Nrf2 mutation and also evaluate its activity in Nrf2 wild-type squamous non-small cell lung cancer. The objectives of this Phase IIa study will be dose refinement and confirmation of the selective activity in Nrf2 mutated tumors compared to wild-type tumors in order to validate Nrf2 mutations as a selection biomarker. We believe that if Phase IIa is successful, it would enable us to initiate Phase IIb, which could be a registrational study in Nrf2 mutated squamous non-small cell lung cancer. Subsequent development in squamous non-multi-lung cancer could involve monotherapy and or combinations with standard of care therapies in earlier lines of treatment within the biomarker-defined populations, including both Nrf2 and KEEP1 mutant tumors. Nrf2 and KEEP1 mutations have been detected across several tumor types, providing additional indications for development of saponocertib as monotherapy and in combination beyond squamous non-multi-lung cancer. So with that summary, I'll pass it over to Stephanie for an update on our financials.
spk03: Thank you, Emil, and good afternoon, everyone. Detailed financial results were included in today's press release. I will briefly review our results on this call. Our cash and cash equivalents totaled $59.5 million at December 31, 2021, which we expect, together with proceeds from our recently priced $10 million public offering, will be sufficient to meet our operating plan through the second quarter of 2023. R&D expenses for the full year 2021 were $53.4 million compared to $71 million in the prior year. The decrease was primarily due to the telequinestep program. R&D expenses for the fourth quarter 2021 were $13.7 million compared to $17.1 million for the same period last year. R&D expenses related to asset acquisition for the full year 2021 were $50.9 million due to our acquisition of Sopan Assertive and Ligavotamin in the fourth quarter, which was comprised of a cash payment of $10 million and $40.9 million attributed to the value of the preferred stock we issued. G&A expenses for the full year 2021 were $20.9 million compared to $20.4 million in the prior year. G&A expenses for the fourth quarter of 2021 were $4.6 million compared to $5.6 million for the same period last year. Net loss for three months and year-end at December 31, 2021, was $69.2 million and $115.1 million, respectively. And with that, I will now return the call back over to Susan.
spk02: Thank you, Stephanie. And with that, operator, we're happy to open the line for questions.
spk01: As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from the line of Jonathan Chang of SVB-Lyrinc. Your line is open.
spk06: Hi, guys. Thanks for taking my questions. First question, can you provide more color on the status of the planned Phase II studies for myvavatinib and cipanacertib? What are the remaining steps to get those studies started?
spk04: Yes, Jonathan, I can answer that. So the study activation is proceeding really well. We have essentially parallel tracking both the transfer of these programs from Takeda as well as the study startup process over the last several months. Both are progressing very smoothly. Both are complete. And we've essentially, the transfer process as well as regulatory reviews of both studies have been completed and we're well underway to get the sites activated. So it's really just straight ahead shot through to site activation and patient enrollment, which is why we're still guiding to the data in 1Q23.
spk06: Got it. And second question, just following up on the last part of your comment. Can you discuss reasons for confidence in the clinical execution of both of these programs, such that data for both will be available by first quarter 23? Thank you.
spk04: Sure, yeah. And that confidence really arises from the fact that these are very clean biomarker-defined subpopulations which are well characterized, and these patients, in terms of the clinician's knowledge of their genetics or their biomarker status is well known. specifically with regard to the squamous lung cancer Nrf2 mutant subset. All these patients get tumor sequencing very in the front line. And so in terms of identifying patients for the relapsed pharycary study, we're working with sites that have very robust curated local databases, NGS databases for their patients that can allow for rapid identification of both mutant and wild-type patients. And we are leveraging our prior experience running the keepsake trial and including relationships with the various, you know, NGS vendors and infrastructure that we developed in that study to really hit the ground running. So that gives us a lot of confidence in terms of getting to that. With Mivovotinib, it's a similar story. ABCDLBCL is a distinction that is known from diagnosis onwards, and so in terms of finding these patients, It's well known from their clinical history, whether they fit the non-GCP slash ADC label. And the fact that we're using liquid NGS, again, to enrich for MITEI-88, CD790 mutant patients, again, from a timing and efficiency standpoint, allows for rapid identification of those patients as well. We're working with very well-experienced sites in terms of lymphoma physicians who have either already used the drug in previous studies and very large centers where they know we have high volumes of patients that are also characterized genetically at the local level. So the selection of sites in both studies was streamlined in order to make sure that we have a high yield of patients from every site that we picked.
spk06: Got it. Thanks for taking the questions.
spk01: Sure. Thank you. Our next question comes from Roger Song of Jefferies. Your question, please.
spk07: Great. Thank you. Maybe just quickly follow up on this two phase two trials. In the initial data in one cue, what should we expect? Kind of how much data we're going to see from that initial readout? Also, what kind of data, the phase two data ultimately will trigger you to move forward into the registration or trial, as you mentioned?
spk04: Right. So the benefit we have here is that both of these molecules already have pre-existing data showing that they're both clearly active as a single agent. And we know the numbers with regard to response rates in those prior studies that gave us the confidence to get them in the first place. I mean, in terms of the fact that this is an overall response endpoint study that's open labeled and we'll be seeing the data in real time give us a lot of flexibility in terms of, you know, the type of data that we'll see. So I think in terms of the fact that this is rapid time to responses for both molecules, specifically in myovivotinib, we know that responses tend to happen very quickly within the first one to two cycles. And the same thing is actually seen for in previous studies. So the time from a patient enrolling to meaningful efficacy data for each patient is pretty short. And so that being said, and given that the numerator in terms of ORR is already fairly high, especially for the lymphoma in the DLVCL setting, give us a lot of confidence that we could have a meaningful data set by the first quarter of 23. Got it.
spk07: Okay. Maybe just to quickly touch on the CB280. So you have finished the full cohort and doing the data analysis. Would you announce the data this year? And what could be the path forward as you evaluate the next steps for this compound?
spk04: Right. So with that molecule, again, the dose escalation was completed. In terms of the data from the final cohort, we analyzed the trends that we saw. and reported on in the first three dose levels with regard to pharmacodynamic effects, arginine increases, as well as trends in FeNO and FeV1 were essentially maintained in that final dose level. So again, the overall trends continue to stay consistent, and definitely there is the option to present that data at a later time point. We're continuing discussions with our advisors in the Cystic Fibrosis Foundation as well as the therapeutic development network in terms of how these data could best inform the design of a potential, you know, phase two dose finding type study. And those discussions are ongoing right now.
spk07: Got it. Thank you. Thank you for taking the question.
spk01: Thanks, Raj. Thank you. Again, to ask a question, please press star one on your touchtone telephone. Again, that's star one on your touchtone telephone to ask a question. Our next question comes from Arthur of HC Wainwright. Please go ahead.
spk05: Hey, good afternoon, everyone. This is Arthur for RK. So I just want to follow up on those two Phase II studies you guys are going to initiate. Could you repeat the optimization of dosing regimen for imaviravatinib, and I wonder, Is the similar dose optimization strategy going to apply to the Ceponetrazib for these study?
spk04: Yeah, so great question. So, yes, both studies do have an element of dose refinement included. For Mivivotinib, again, the fact that both these molecules have had extensive dose schedule work done previously through Takeda's studies, gave us a really good starting point. And this is really more of a fine-tuning, especially because we're going in a biomarker-defined population. So for Mivovotinib, the two-dose level is 100 milligrams per day, is the previously established recommended phase two dose from prior dose escalation expansion trials. We see an opportunity to explore a further dosing strategy, specifically an induction dosing strategy. And that's really taking advantage of the molecule's PK properties, namely that it has you know, pretty long half-life. It has a very high volume of distribution. And considering that we, based on our analysis of this molecule, it has a tendency to accumulate in tissue and specifically tumor in large concentrations, that gives you an opportunity to evaluate a strategy where you get a large bolus of drug in quickly in these aggressive tumors to get rapid disease control. And once you get to a response, back off to a still active but more tolerable long-term dosing strategy to maintain that response. And this is not unusual in the context of lymphoma. Specifically, other approved drugs use a very similar approach. So we wanted to explore that, you know, taking advantage of the fact that the molecule's properties already make it amenable to evaluating that. For Sipanacertib, it's a similar sort of fine-tuning that we're doing. The three milligram Q-day dose is the dose that was previously studied and actually showed the ecstasy signal in Nrf2 mutants claim patients. Again, based on the molecule's pre-PK property, namely a shorter half-life with a tox profile where we know that more of the GI toxicities are more CMAS-related and that you might be able to get to a higher cumulative exposure by using a lower BID dose schedule, namely 2BID, could get you improved efficacy with maintaining the very good tolerability profile that we already see at 3 mg per daily dose. So those are the rationales for why we're doing what we're doing with regard to dose refinement. But again, we think that because it's a fine-tuning and not repeating, for example, a full-dose escalation, it can happen very quickly and in parallel with getting the efficacy data.
spk05: Thank you. Thank you. That's really helpful. So for your new VPS for A inhibitor program, could you give us more color regarding the prevalence of the VPS for B deletion in different cancer type? And also, how soon could we expect this program to advance into the clinic?
spk04: Thank you. I could give you the prevalence. So in the homozygous deletion of VPS4B occurs in 1% to 3% of all solid tumors. However, heterozygous deletion is much more prevalent and the higher incidence approximately two-thirds of specifically colorectal cancer and pancreatic cancer see heterozygous deletion. And there's evidence to show that the dependence, the increased dependence on VPS4A is still high in the heterozygous deletions of VPS4B, giving you a substantial opportunity to evaluate a very large, you know, set of tumors and a large subset of colorectal and pancreatic. I'm going to let Susan answer your second part of your question.
spk02: Well, we're presenting our early data at ACR next week, And we do have a VPS4 inhibitor, and we're moving those molecules forward. So we're in lead optimization, and we hope to continue to advance this program and can give you future guidance when we might be in the clinic.
spk05: Awesome. Thank you. Thank you for taking my question.
spk01: Sure. Thank you. At this time, I'd like to turn the call over to Susan Molyneux for closing remarks. Ma'am?
spk02: Thank you, and thanks all for joining us today, and have a good evening.
spk01: This concludes today's conference call. Thank you for participating. You may now disconnect.
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