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spk01: Ladies and gentlemen, thank you for standing by and welcome to the Calithera Biosciences, a third quarter earnings conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one on your telephone keypad. If you require any further assistance, please press star zero. I would now like to hand the conference over to your speaker today, Stephanie Wong. Thank you. Please go ahead, ma'am.
spk06: Thank you, Operator. Good afternoon, everyone. Welcome to our third quarter 2021 conference call. Joining me today are Susan Molyneux, Founder, President, and CEO, and Emil Curiaco, Chief Medical Officer. Earlier this afternoon, we issued a press release which included an overview of our third quarter 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 provision 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 factor section of our periodic filings with the SEC. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representative 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 today on our third quarter 2021 conference call. And a special welcome today to Emeril Kriakos, who is joining us in his new role as Chief Medical Officer. and we'll be presenting later in this call. We could not be more excited to embark on this next chapter with Emil. Speaking of the next chapter, last month we strengthened our precision oncology pipeline with the acquisition of Sipanacertib and Mivivotinib from Takeda. As a reminder, Sipanacertib is a dual TORC1-2 inhibitor that targets a key survival mechanism in KEEP1 Nrf2 mutated tumors. which has the potential to be the first treatment for nerve-mutated squamous non-small cell lung cancer. As a next-generation TORC inhibitor, Sipanacertib provides dual inhibition of the TORC1 and TORC2 complexes and has demonstrated durable single-agent responses and clinical benefit in patients with relapsed refractory nerve-2-mutated squamous non-small cell lung cancer with a well-tolerated safety profile. Myvovotinib is a sick inhibitor with the potential to be a best-in-class drug in non-Hodgkin's lymphoma, as well as a first-to-market therapy for patients with DLBCL whose tumors harbor MyD88 or CD79 mutations. Myvovotinib has shown compelling single-agent activity in relapsed refractory NHL patients in completed Phase I-II studies. We plan to initiate Phase II studies of both cipanacertib and migravotinib in the first quarter of 2022. Additionally, last week we announced the decision to discontinue the keepsake trial of teloglanostat in non-squamous, non-small-cell lung cancer following an interim analysis of 40 patients. We have no plans to continue the development of teloglanostat internally at this time. We remain committed to developing targeted therapies for patients with difficult-to-treat cancers with the advancement of both cipanacertib and libivotinib in biomarker-defined populations of squamous non-small-cell lung cancer and diffuse large B-cell lymphoma, respectively. Last week, at the North American Cystic Fibrosis Conference, we presented interim data from the Phase Ib study of CB2AB, our arginase inhibitor. In the presentation, we reported that CB280 was well-tolerated and showed linear pharmacokinetics and robust dose-related pharmacodynamic effects. Additionally, we saw encouraging trends in disease biomarkers, including increased fractional exhaled nitric oxide, or pheno, and decreased sweat chloride. The current data substantiates the proposed mechanism as a rational approach for treating CF. The poster can be found on our website. Finally, as we disclosed on Friday, we have promoted Emil Cariacos from Vice President and Head of Clinical Development to succeed Keith Orford as CMO. In addition, we have strengthened our Board of Directors with the addition of Keith. I would like to take this opportunity to thank Keith for his contributions over the last seven years and to congratulate Emil on his promotion. Emil has been a part of our team for the last four years, and was an integral part of the diligence team that evaluated Sipanacertib and Mivivotinib prior to our acquisition of these assets. This has been a transformational year for Califera. As we prepare to close out 2021 and enter 2022, we look forward to exciting times ahead. We will begin the new year with a keen focus on precision oncology and two new, highly compelling clinical development programs. We plan to initiate the phase two studies of cipanacertib and mizovotinib in the first quarter and look forward to updating all of you on our progress. And with that, I will pass the call over to Emil for additional details on our clinical self-program.
spk05: Thank you, Susan, and thank you for the kind words. I'm truly honored to accept the role of CMO and want to express my sincere gratitude to Keith for his leadership and mentorship over the last several years. I'm thrilled to continue our partnership at Going Forward as he joins the Board of Directors. I'm happy to update you today on our clinical programs and look forward to meeting all of you over the next several months. I'd like to start today by providing some additional detail around the data we presented last week on CB280, our novel oral largeny inhibitor for the treatment of cystic fibrosis. Last week at the North American CF Conference, we presented data on the first 24 subjects in the ongoing Phase 1b dose escalation trial in adults with CF. These 24 subjects were enrolled across the first three dose levels, 50 mg, 100 mg, and 200 mg BID, with 18 receiving CB280 and 6 receiving placebo. The study population comprised a broad spectrum of CFTR genotypes, including subjects with nonsense mutations. Notably, 91% of the subjects were already on CFTR modulator therapy with Trikafta or Calodeco. CB280 had a well-tolerated safety profile across all three dose levels, and all 18 subjects receiving CB280 completed treatment without interruptions or premature discontinuation. Changes in force expiratory volume in one second, or FEV1, were assessed as a safety endpoint, and a pooled analysis of treatment versus placebo showed a positive trend in FEV1 compared to placebo. CB280 demonstrated linear pharmacokinetics with plasma exposure increasing proportionally with dose, Complete and continuous target inhibition in plasma was achieved at the 100 milligram dose and above. CB280 also demonstrated robust pharmacodynamic effects with rapid and significant dose proportional increases in plasma arginine, which is a key driver of airway nitric oxide production. Increased airway NO production was reflected by a trend showing an increase in fractional Xcel nitric oxide, or PHENO, in subjects treated with CB280. Sweat chloride, a marker of CFTR function, showed a trend towards decreasing in CB280-treated subjects, which is consistent with previously reported preclinical data showing that arginine inhibition enhances CFTR function in human bronchial epithelial cells. Together, these pharmacodynamic and biomarker data substantiate the overall mechanistic rationale for CB280 in CF. Turning to our newly acquired programs, We plan to initiate a Phase II study in the first quarter of 2022 that will strengthen the existing data on saponocertib as a monotherapy in patients with relapsed or refractory squamous non-small cell lung cancer harboring a Nrf2 mutation and further evaluate its monotherapy activity in KEEP1 mutated and Nrf2 or KEEP1 wild-type squamous non-small cell lung cancer. Also in the first quarter of 2022, We plan to start a Phase II study of the sick inhibitor, mitovotinib, as monotherapy in patients with relapsed olfactory DLBCL, both with and without the MITEI 88 or CD79 mutation. The efficacy data that will be generated from these studies over the course of the next 12 to 18 months are intended to inform and support the initiation of registrational trials in both of these molecules in the specific biomarker-defined populations of non-small cell lung cancer and DLBCL that we're interested in. With that, I'll pass it over to Stephanie for an update on our financials.
spk06: Thank you, Emil, and good afternoon, everyone. Detailed financial results for the current quarter were included in today's press release. I will briefly review our results on this call. Revenue was $6.8 million for the three months ended September 30th, 2021, and represents the milestone payment received in September under our in-site collaboration agreement. R&D expenses were $11.6 million in the third quarter of 2021. compared to 18.2 million in the third quarter of 2020. The decrease was primarily driven by decreases in the Teleglenostat on 1158 programs, partially offset by investments in early stage research. G&A expenses were 6.3 million in the third quarter of 2021, compared to 4.7 million in 2020. The increase was primarily related to increased legal expenses. Net loss for the third quarter of 2021 was 11.2 million. Cash and investments totaled $84.5 million at September 30, 2021, or $74.5 million after the upfront cash payment to Cicada in October. As mentioned during the keepsake data call on Friday, we expect the discontinuation of the keepsake study to result in cost savings between $10 and $15 million. We also expect our cash and investments will be sufficient to meet our current operating plan into 2023. And with that, I will now return the call back 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 keypad. Again, everyone, if you have questions, please press star one on your telephone keypad. Please stand by, we'll compile the Q&A roster. Your first question comes in the line of Roger Song from Jefferies. Your line is now open.
spk03: Great. Thank you for taking the question. A couple from me. The first one is, so besides those two phase two plans for the two new assets, would you conduct an additional kind of mechanistic or pre-communicable work to better characterize their MOA and the unique properties for the best in class potential in the targeted indications?
spk05: Sure. Yeah. Thanks for the question. Yeah. So I think the answer is yes, in the sense that for both of these molecules, I think the key theme is that the clinical data are already there and compelling in terms of the fact that they both have single agent activity demonstrated in these specific populations. I would say the mechanistic, the overall mechanism for the SICK inhibitor is probably much clearer in terms of the fact that it's the well-characterized signal transduction pathway in lymphoma that's been well-studied, both the MI-88 and PD79B. There have been published reports on the connection between Nrf2 and TORC1-2 in squamous non-small cell lungs specifically. Although the exact details of the mechanism are not known, but there's clearly rationale supporting that TORC1-2 is activated and upregulated in the context of NERF2 activation in squam. So, yes, we will do some further characterization of that, but I think the fact that we're running a clinical trial also allows us to do translational work in that regard and corroborate the mechanism and the hypotheses using that work as well.
spk03: That's great. Thanks for the comments. And maybe just for the CF data, so I understand you have kind of promising initial Phase I data. Maybe just what are the key elements you will be looking for from the full Phase I data to make the go-no-go decision for CF programs?
spk05: No, great question. So I think the data so far are very encouraging and that the molecule has a very well-tolerated safety profile. And from a PKPD standpoint, it's behaving very nicely. And lastly, from a biomarker standpoint, where these are the key downstream biomarkers of the pharmacodynamic effect, they're all headed in the right direction. So the mechanistic rationale, I think, is so far corroborated by the data. As far as next steps, obviously, you know, we're continuing dose escalation. The current cohort, which is cohort four, 300 milligrams is enrolling and expected to complete by the end of the year. Per protocol, we have the option to go to another dose level, go up another dose level per the dose escalation design. And so the idea is we want to get a full characterization of the molecule PKPD profile and define the entire dose range in terms of safety PKPD and biomarker. Once we do that, the next step would be a more dose finding type study where we would pick doses from dose escalation where we think, you know, they're both safe and therapeutic in order to define what the dose would potentially be for full development. And we do have the option to increase the dosing duration to 28 days and look at efficacy in a more robust fashion. So that would be the next step that would be planned.
spk03: Got it. So for the full data, mostly for the safety and the PKPD, not necessary for the efficacy. And the next step, you will start to looking at the efficacy for the full development?
spk05: Correct.
spk03: Okay. Got it. Okay. Maybe just one last question. So Susan, I think you mentioned you also tried to discover some kind of synthetic v-solid compounds. Maybe just tell us about what is the history of that discovery platform and any synergy with previous focused glutaminase or the metabolism pathway internal discovery.
spk02: Sure. No problem. So our synthetically salady targets are not specifically designed to be in metabolisms. we've really moved away from metabolism and looked at a whole series of parallel genes. So we're interested in targeting pairs of genes where one gene is deleted in the tumor and inhibition of the activity of the other gene is the basis for a drug. And so we've ranged pretty far from where we started and it really puts more to the drugs that we've just brought in. Myvovotinib and Sipanacertib, where it's clear that they play roles in signal transduction pathways, for example, that are important and important in specific biomarker-defined populations. So, paralog genes is like boiling it down to the simplest case. You have gene A and you have gene B. If gene B is missing and you inhibit gene A, then you know that they're very related and this tumor can't survive without gene A. So that's the basis for where we've gone in synthetic lethality, and we expect to discuss some of where we're going, some of the targets, in 2022. Got it.
spk03: That's very helpful. Okay, so that's all from me. Thank you for taking my questions. Thank you.
spk04: Thank you.
spk01: Your next question comes in the line of Nick Abbott from Wells Fargo. Your line is now open.
spk04: Great, thank you. Thanks for taking my questions. Maybe a couple on CB280 to start off with. I think the original dosing plan was to go from 200 milligrams to 400 milligrams, but the data you reported last week was at 300 milligrams. So, you know, what was the rationale to go to 300? And, you know, given that you reported continuous plasma inhibition of arginase at 100 milligram or higher, you know, what do you hope to achieve by going above 300?
spk05: Great, great question. So I think that's a two-part question. So in regards to the decision to go to 300 instead of going straight to 400, being that we were at the top end of the dose range, despite the fact that we haven't seen any DLTs or safety-related, we and the Data Safety Monitoring Committee together decided that it would be better to get to 400 in two steps rather than one. And I think that's primarily driven by, you know, the idea that preclinically The key on target task, which is urea cycle inhibition that's measured by this marker called urinotic acid, could have sort of a more nonlinear profile. And while we have not seen clinically relevant urea cycle inhibition or disruption in this study, we just thought it was the best approach in order to do that in two steps. And that also gives you the opportunity to better, more granular, get a granular characterization of the PKPD profile. So that was the reason we decided to go 300 and then 400. With regard to your second question around why go higher than the dose where you see full plasma target inhibition, the main reason is there's two reasons. One is that we continue to see the PD effect with regard to arginine increases occurring even above doses where we're saturating the target in the plasma. And given that arginine is the key driver of NO production, the thinking is as long as you're getting dose-related improvements in arginine that are expected to drive up NO production, you could continue to go up as long as your safety is okay. And the second reason is that plasma inhibition doesn't necessarily translate to inhibition within the airways. And so the assumption is that you're driving up systemic arginine levels, but you might need higher doses to make sure that site of action in the airways is achieved at higher doses. And that's reflected by the fact that we're seeing trends in phenol, which is a reflection of inhibition of the target within the lung. And so that's the other thing we're targeting.
spk04: Right. So as you, you know, just following up on that then, do you think you would see a plateau of the effect on phenome?
spk05: That's a good question. I don't know if we know the answer to that yet. You know, we know that these patients at baseline have diminished NO production. Their baseline phenols are lower than the normal population. And so, you know, we are clearly seeing a trend in phenol going up. And phenol has a wide dynamic range, and it's also highly, it's a variable readout. So I don't think we know the answer to that. But again, I think we could get more data on that as we continue to recalculate.
spk04: Okay. And then I know collection of sputum was affected by COVID. In this trial, is there anything you can say or will be able to say about microbial burden in these patients?
spk05: Yeah, that's a great question. And we do have an exploratory endpoint looking at quantitative sputum colonization. The yield of samples has been relatively poor. I think it was primarily impacted by the fact that the study was enrolling during COVID, and there were a lot of site-level restrictions on induced sputum collection in these patients. And so, unfortunately, the level of student data we have is not there. But I think what's reflective of the benefit is, number one, again, the trend in pheno and that we're seeing a positive trend in FEV1 as well. And, you know, even with mechanism being primarily antimicrobial, that's a reflection of the fact that, you know, when you do eliminate pathogens in the airway and reduce the inflammation, you do see benefits with regard to airway function. So we're all encouraged by the fact that we're seeing these biomarkers heading the right direction.
spk04: And then maybe just a couple of quick questions on the new program. So, for Sipanacertib, so I understood that there's a KEAP-2 trial, but then I think you also mentioned continue to evaluate, I'm sorry, a NERF-2 and then continue to evaluate NERF-2 and KEAP. So, are those two separate cohorts or two separate trials?
spk05: No, they are two separate. So, we'll evaluate those patients separately. as separate groups in the same study. And the idea here is that the data we already have from the CTEP study that was completed showed, you know, there was a pretty compelling differentiated signal in Nrf2 and, you know, evidence of a moderate signal in TEEF1. And so we want to, number one, look at the Nrf2 population individually. look at KEEP1 separately and also look at the question of whether wild-type patients also have that, would respond. So we'll be looking at all of those in the context of this study.
spk04: Okay, great. And then for mevavantinib, you're looking at patients who have those mutations and wild-type or patients who don't have those mutations, will that be split evenly? And then just in relation to 79B of my D88, Do those mutations tend to co-occur with other genetic abnormalities seen in double or triple hip lymphoma?
spk05: Right. So the first question, answer to the first question is yes. We will be looking at both of those in an equal number across two separate cohorts is the idea because we think, number one, the existing data already show that there's a signal potentially even outside of that MyD883D79B mutation, and there's strong preclinical data indicating a an increased probability of single-agent response within that mutational subset, as well as early trends in the clinical data. And so your second question with regard to commutations, I think, sorry, can you repeat that second question specifically?
spk04: Yeah, exactly. Commutation, too, because we often hear about double and triple-hit lymphomas. Oh, right, right, yeah.
spk05: So the MITEI-88-CD79 do not overlap strongly with the double-hit phenotypes. So the double-hit lymphomas are predominantly in the GCB cell of origin classification, whereas the MITEI-88, CD79, for the most part, are in the ABC classification. So there's very little overlap, and that's published based on published data.
spk04: Okay, terrific. Thank you very much. Sure.
spk01: I am showing no further questions at this time. I would now like to turn the conference back to Susan Molyneux.
spk02: Thank you, Operator, and thanks all for joining us today.
spk01: Have a good evening. This concludes today's conference call. Thank you all for your participation. You may now disconnect.
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