Thank you for standing by and welcome to Calithera 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. Please be advised that today's call is being recorded.

I would now like to hand the call over to Stephanie Wong, Chief Financial Officer. Please go ahead. .

Thank you, operator. Good afternoon everyone. Welcome to our fourth quarter and full year 2021 conference call. Joining me today are Susan Molineaux, Founder, President and CEO; and Emil Kuriakose, 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 calithera.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, any 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. .

Thanks Stephanie. Good afternoon, everyone, and thank you for joining us for today's conference call.

2021 was a transformational year at Calithera as we took several critical steps to transition the company's focus and core programs to developing therapies for biomarker specific patient population, while continuing to leverage the company's deep expertise in clinical development for targeted small molecule cancer therapy.

In October, we announced the acquisition of two clinical stage assets from Takeda, Mivavotinib and Sapanisertib. Mivavotinib is a spleen tyrosine kinase or SYK inhibitor that targets the constitutively activated B-cell receptor pathway in diffuse large B-cell lymphoma and other non-Hodgkin lymphoma.

In completed Phase 1/2 clinical trial, Mivavotinib showed promising single-agent responses with deep and durable activity in unselected patients with DLBCL. Our initial development will be an ABC or activated B-cell DLBCL where BCR signaling and SYK activation are central drivers.

Mivavotinib showed a substantially higher response rate in ABC compared to GCB DLBCL with a 53% ORR or overall response rate in ABC, compared to a 22% ORR in GCB. DLBCL in a retrospective analysis of completed trials had this data.

And in addition recent preclinical studies have shown enhanced SYK activity and sensitivity to SYK inhibition in DLBCL and other non-Hodgkin lymphomas harboring mutations in MyD88 and/or CD79. They comprise a distinct genetic subset of ABC DLBCL known to have poor outcomes with standard of care therapy.

Approximately 50% of all ABC DLBCL tumors have one or both of these new patients. Mivavotinib has the potential to be the first-to-market therapy for patients with a genetically defined subset of DLBCL.

The compelling single agent overall response rate in ABC DLBCL and potential for further enrichment of single-agent activity in a genetically defined subset of ABC DLBCL with MyD88 or CD79 mutations, we believe provides a well-defined, efficient development path to potential single-agent accelerated approval in these populations.

Sapanisertib is a dual mTORC1/2 inhibitor that targets a key survival mechanism in T1 or NRF2 mutated tumors. Sapanisertib 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 mTORC inhibitors and is the only inhibitor to have strong single agent activity in NRF2-mutated squamous non-small cell lung cancer xenograft. NRF2 mutations occur in approximately 15% of squamous non-small cell lung cancer and confer a poorer prognosis for these patients.

We believe sapanisertib 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 cancer. We plan to initiate Phase 2 studies of both sapanisertib and mivavotinib in the first half of 2022.

We also presented data from our Phase 1b trial of CB-280 for the treatment of cystic fibrosis at the North American Cystic Fibrosis Conference in November of last year. The data showed that CB-280 was well tolerated demonstrated linear pharmacokinetics and showed complete and continuous target inhibition in plasma at doses at or above 100 milligrams.

CB-280 also demonstrated robust pharmacodynamic effects with rapid and significant dose proportional increases in plasma arginine, a key driver of nitric oxide production. Enrollment and analysis of all four cohort 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 gene and loss of one or the other paralog in cancer cells is synthetically lethal.

Our VPS4 program is the most advanced synthetically 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 mivavotinib and sapanisertib in biomarker-defined population. By focusing on well-characterized genetic vulnerability with molecules that have already shown single-agent activity, we believe we will be able to generate Phase 2 data with targeted efficient study design.

We plan to share data from these studies by the first quarter of 2023..

Thank you, Susan. I'd like to start today by providing some additional detail around our planned Phase 2 trials with mivavotinib in patients with relapsed/refractory ABC DLBCL with and without MyD88 or CD79b mutations as well as sapanisertib in patients with relapsed/refractory NRF2-mutated squamous non-small cell lung cancer.

Starting with mivavotinib, we plan to initiate a Phase 2 trial in relapsed or refractory non-GCB DLBCL, as defined by the Hans algorithm, which captures all ABC DLBCL. And we will enrich the MyD88 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 MyD88/CD79b-mutated DLBCL.

With the primary endpoint of overall response rate such a study would target an accelerated approval pathway for mivavotinib 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 mivavotinib has shown compelling single-agent responses in previously completed trials.

Now turning to sapanisertib, we plan to initiate a Phase 2 study of sapanisertib monotherapy in patients with NRF2-mutated squamous non-small cell lung cancer, harboring either wild type or mutated NRF2 as detected by next-generation sequencing.

This study will strengthen the existing data on sapanisertib as a monotherapy in patients with squamous non-small cell 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 2a 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 mutation as a selection biomarker.

We believe that if Phase 2a is successful, it would enable us to initiate Phase 2b which could be a registrational study in NRF2-mutated squamous non-small cell lung cancer.

Subsequent development in squamous non-small cell lung cancer could involve monotherapy and/or combinations with standard of care therapies in earlier lines of treatment within the biomarker-defined population, including both NRF2 and KEAP1 mutant tumors.

NRF2 and KEAP1 mutations have been detected across several tumor types, providing additional indications for development of Sapanisertib as monotherapy and in combination beyond squamous non-small cell lung cancer. So with that summary, I'll pass it over to Stephanie for an update on our financials..

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 a telaglenastat 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 of 2021 were $50.9 million due to our acquisition of Sapanisertib and Mivavotinib 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 the three months and year ended 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..

Thank you, Stephanie. And with that, operator, we're happy to open the line for questions..

Our first question comes from the line of Jonathan Chang of SVB Leerink. Your line is open..

Hi, guys. Thanks for taking my questions.

First question, can you provide more color on the status of the planned Phase 2 studies for Mivavotinib and Sapanisertib? What are the remaining steps to get those studies started?.

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 start-up 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 this site activation and patient enrollment, which is why we're still guiding to the data in 1Q 2023..

Got it. And second question, just following up on your -- 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 2023? Thank you..

Sure. Yes.

And that confidence really arises from the fact that these are very clean biomarker-defined populations, which are well characterized and these patients, in terms of their -- the clinician's knowledge of their genetic or their biomarker status is well known, specifically, with regard to the squamous lung cancer nerve-to-mutant subset, all these patients get tumor sequencing in the front line.

And so, in terms of identifying patients for the relapsed refractory 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 KEAPSAKE trial and including relationships with the various NGS vendors and infrastructure that we develop in that study to really hit the ground running. So that gives us a lot of confidence in terms of getting to that.

With mivavotinib, it's a similar story ABC DLBCL 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-GCB/ABC label, and the fact that we're using liquid NGS again to enrich for MyD88 and CD79 mutant patients again from a timing and efficiency standpoint allow 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 use 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..

Got it. Thanks for taking the questions..

Sure..

Thank you. Our next question comes from Roger Song of Jefferies. Your question please..

Great. Thank you. Maybe just quickly follow-up on this two Phase 2 trials.

In the initial data in 1Q, 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 2 data often today will trigger you to move forward into the registrational trial as you mentioned?.

Right. So the benefit we have here is that, both of these molecules already have preexisting 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 label and we'll be seeing the data in real time give us a lot of flexibility in terms of 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 mivavotinib, we know that responses tend to happen very quickly within the first one to two cycles. And the same thing is actually seen for sapanisertib in previous studies.

So the time from a patient enrolling to meaningful efficacy data for each patient is pretty short. And so with that being said, and given the numerator in terms of ORR is already fairly high, especially for the lymphoma on the DLBCL setting give us a lot of confidence that we could have a meaningful data set by the first quarter of 2023..

Got it. Okay. Maybe just to quickly touch on the CB-280.

So you have finished the four cohort and during 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?.

Right. So with that molecule again, the dose escalation was completed. In terms of the data from the final cohort, we analyze 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, we – there is the option to present that data at a later time point.

We're continuing discussions with our advisers 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 Phase 2 dose-finding type study. And those discussions are ongoing right now..

Got it. Thank you. Thank you for taking the question..

Thanks, Roger..

Thank you. Our next question comes from Arthur He of H.C. Wainwright. Please go ahead..

Hi. Good morning, everyone. This is Arthur in for RK. So I just wanted to follow-up on those two Phase 2 studies you guys are going to initiate.

Could you repeat the optimization of dosing regimen for mivavotinib? And I wonder is a similar dose optimization strategy going to apply to the sapanisertib for this study?.

Yeah, so great question. So yes, both studies do have an element of dose refinement included. For mivavotinib, 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 mivavotinib, the two dose levels the 100 milligrams Q daily is the previously established recommended Phase 2 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 molecules PK properties, namely that it has 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 concentration 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, is 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 taking advantage of the fact that the molecule properties already make it amenable to evaluating that. For sapanisertib, it's a similar sort of fine-tuning that we're doing. The 3-milligram Q daily dose is the dose that was previously studied and actually showed the efficacy signal in NRF2 mutant claim patients.

Again, based on the molecule PK property namely a shorter half-life with a tox profile where we know that more of the GI toxicities are ever more emasculated and that you might be able to get to a higher cumulative exposure by using a lower BID dose schedule, namely two BID could get you improved the efficacy with the -- maintaining the very good tolerability profile that we already see at three milligrams Q daily dose.

So those are the rationale for why we're doing what we're doing with regard to dose refinement. But again, we think that it's -- 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..

Oh, thank you. Thank you. That's really helpful. And so for your new VPS4A inhibitor program could you give us more color regarding the prevalence of the VPS4B deletion in different cancer type. And also how soon could we expect this program to advance into the clinic? 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 incidents approximately two-thirds of specifically colorectal cancer and pancreatic cancer see heterozygous deletions.

And there is evidence to show that the dependence -- the increased dependence on VPS4A is still high in the heterozygous deletion of VPS4B giving you a substantial opportunity to evaluate a very large set of tumors and a large subset of colorectal and pancreatic. I'm going to let Susan, answer your second part of your question..

Well, we're presenting our early data at AACR next week. And we do have VPS4 inhibitors 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 on when we might be in the clinic..

Awesome. Thank you for taking my question..

Sure..

Thank you.

At this time I'd like to turn the call over to Susan Molineaux for closing remarks, Ma'am?.

Thank you and thanks all for joining us today. And have a good evening..

This concludes today's conference call. Thank you for participating. You may now disconnect..