Shattuck Labs Inc (STTK) 2022 Q3 法說會逐字稿

Good afternoon, and welcome to the Shattuck Labs third-quarter 2022 earnings conference call. (Operator Instructions) As a reminder, this conference is being recorded. I will now turn the call over to your host, Conor Richardson, Senior Director of Finance and Investor Relations at Shattuck Labs. Conor, please go ahead.

Thank you, operator. Good afternoon, everyone, and welcome to the Shattuck Labs conference call regarding our third-quarter 2022 financial results and recent business update. The press release reporting our financial results was issued after market close this afternoon and can be found on the Events and Presentations section of our website, shattucklabs.com.

In this afternoon's call, the Shattuck leadership team will provide a business overview of the third quarter of 2022, including clinical development updates from SL-172154, our lead program, and SL-279252. We will refer to these as 154 and 252 throughout today's earnings call.

With me on today's call will be our Chief Executive Officer and scientific Co-founder, Dr. Taylor Schreiber, who will review our pipeline progress and upcoming key milestones; followed by our Chief Medical Officer, Dr. Lini Pandite, who will provide an update on our clinical activities; and then our Chief Financial Officer, Andrew Neill, will review our third-quarter 2022 financial results and financial guidance.

We will then open the call for questions after Dr. Schreiber makes some closing remarks.

Before we begin, I would like to remind you that today's webcast contains forward-looking statements within the meaning of the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995. Such statements represent management's judgment as of today, and they involve risks and uncertainties that could cause actual results to differ materially from those expressed in or implied by these statements.

For more information on these risks and uncertainties, please refer to our most recent annual report on Form 10-K for the year ended December 31, 2021, and our other filings with the SEC, which are available from the SEC's website or on our corporate website, shattucklabs.com. Any forward-looking statements represent our views as of today, November 8, 2022.

With that, I will now turn the call over to Dr. Schreiber, our Chief Executive Officer. Taylor?

Thank you, Conor. Good afternoon, everyone, and thank you for joining us today. 2022 has been an operationally focused year for Shattuck, and our clinical team has done an excellent job of advancing 154, our lead clinical-stage agonist redirected checkpoint or ARC compounds.

As a reminder, 154 is a SIRPα-Fc-CD40L bifunctional fusion protein, which serves to both block the macrophage checkpoint molecule known as CD47 and also activates an important immune stimulatory receptor known as CD40.

Linking these two functions within a single therapeutic differentiates 154 from all other CD47 inhibitors in clinical development. As you will hear from Dr. Pandite in a moment, our clinical team has made excellent progress, and we completed enrollment in the monotherapy dose escalation portion of our Phase 1 trial for patients with advanced platinum-resistant ovarian cancer in the second quarter of this year.

154 reached a maximum administered dose of 10 milligrams per kilogram, which was the highest-anticipated dose level in the study. In the third quarter, we began enrolling patients in the first chemotherapy combination cohort in ovarian cancer, and we have selected 3 milligrams per kilogram as the starting dose level for 154 in this combination cohort.

As for the chemotherapy combination agent, we selected the combination with liposomal doxorubicin because preclinical studies demonstrated that ovarian cancer cells express prophagocytic or eat-me proteins on their surface following exposure to liposomal doxorubicin. These eat-me signals are essential to initiating an anti-tumor response in the setting of CD47 inhibition.

In addition, several decades of clinical experience in the platinum-resistant ovarian cancer setting has established a single-agent response rate in the range of 10% to 12% for liposomal doxorubicin Thus, this trial design allows us to decipher the contribution of components with a relatively small number of patients.

In addition to our clinical development program in solid tumors, we began a clinical study for 154 for patients with acute myeloid leukemia and high-risk myelodysplastic syndrome in the second quarter of this year. And we expect to enroll patients in the first combination cohort with azacitidine in the fourth quarter of this year.

Patients enrolled in the dose-escalation cohorts will primarily have relapsed refractory disease, and any complete responses in this patient population would differentiate 154 from other CD47 inhibitors in this patient population.

The subsequent planned expansion cohorts will then enroll patients in the frontline setting where the activity of first-generation CD47 inhibitors has narrowed in recent updates and left significant room for improvement. We believe that one platform may differentiate with the addition of CD40 agonism to CD47 blockade, which may lead to improved response rates and increased durability.

Our second clinical stage compound, 252, a PD1-Fc-OX40L bifunctional fusion protein is in Phase 1 development for patients with advanced solid tumors and lymphomas. We are continuing to enroll patients with primarily PD-L1 selected tumors at the top-dose level of 24 milligrams per kilogram and top-line data from the Phase 1 dose escalation trial are anticipated in the first quarter of 2023.

As per Shattuck's preclinical pipeline, we've made tremendous progress over the past quarter with multiple publications on our preclinical ARC and GADLEN programs in the Journal of Immunology, which can be found on our website.

Interest in harnessing the activity of gamma delta T cells in cancer has continued to build, and we believe our GADLEN platform is truly distinct from all other approaches currently in development due to its unique design features.

Our team has uncovered and published some of the key aspects of gamma delta T cell biology, which will guide our clinical strategy, and additional preclinical data will be presented at the Society for Immunotherapy of Cancer annual conference later this week in Boston.

The GADLEN platform is highly modular and is amenable to monospecific, bispecific, and biparatopic design, and data from two separate product candidates, one targeting the CD20 antigen and another targeting the B7-H3 antigen, will be included in the SITC presentation.

The CD20 GADLEN has completed a dose range-finding toxicology study in nonhuman primates and is being considered as a non-Ig-based B-cell depleting therapy for antibody-driven autoimmune diseases.

The B7-H3 GADLEN is being considered for a variety of solid-tumor indications where single agent efficacy would be expected. We look forward to sharing more data as the gamma delta T cell therapy space continues to advance.

With that, I will now turn the call over to Dr. Pandite, our Chief Medical Officer. Lini?

Thanks, Taylor, and good afternoon. I'm extremely pleased with the execution of our clinical programs and the progress we have made throughout the year.

Let's turn first to 154, our differentiated CD47 inhibitor and CD40 agonist. Our first clinical trial of 154 is a multicenter open-label dose escalation trial intended to assess the safety, tolerability, pharmacokinetics, anti-tumor activity, and pharmacodynamic effects of intravenous administration of 154 as monotherapy in patients with platinum-resistant ovarian cancer.

Initial clinical data from this trial presented at SITC 2021, demonstrated a favorable safety profile, high-target occupancy, and on-target pharmacodynamic activity driven by CD40 activation. As you will recall from the last quarter, we announced that we had completed enrollment in the maximum-administered dose level of 10 milligrams per kilogram.

To date, we have not observed any evidence of destructive anemia, which we attribute to the design of the Fc portion of154 and the absence of binding to Fc gamma receptors. We believe that the current safety profile at 154 provides us with a therapeutic window in which we can potentially maximize the biology of CD40 while reaching near-100% target occupancy of CD47.

We expect to report the full data from the dose escalation portion of this trial mid-year 2023.

Enabled by our progress in the Phase 1 trial, I'm pleased to say that in the third quarter of this year, we dosed our first patient in a Phase 1b clinical trial of 154 in combination with liposomal doxorubicin in patients with platinum-resistant ovarian cancer.

This multicenter open-label trial is intended to evaluate the safety, tolerability, pharmacokinetics, anti-tumor activity, and pharmacodynamics of 154 in combination with liposomal doxorubicin. We expect to report initial combination data from this trial mid-year 2023.

Now let us turn our attention to our 154 clinical trials in hematologic malignancies, where I'd like to highlight the progress we have made in our Phase 1a/1b clinical trial in AML and high-risk MDS. In this trial, we are evaluating the safety, tolerability, pharmacokinetics, anti-tumor activity, and pharmacodynamics effects of 154 as both monotherapy and in combination with azacitidine.

As a reminder, the first part of this trial is a parallel staggered monotherapy and combination dose escalation in heavily pretreated relapsed/refractory patient population where few, if any, agents have consistently led to complete responses. As Taylor alluded to, this is an area where any complete responses could be a differentiating signal, particularly compared to other CD47 agents.

I'm pleased to report that enrollment in the monotherapy cohorts of this trial has progressed nicely, and as a result, enrollment in the azacitidine combination cohort is expected to begin in the fourth quarter of 2022. Initial dose escalation data from the monotherapy and azacitidine combination are expected in the first half of 2023.

Our second clinical candidate, 252, is in a multicenter open-label clinical trial evaluating the safety, tolerability, pharmacokinetics, anti-tumor activity, and pharmacodynamics of 252 in patients with advanced solid tumors and lymphoma.

As you will recall, we have previously reported initial data to6 milligrams per kilogram from the ongoing Phase 1 dose escalation clinical trials, demonstrating evidence of anti-tumor activity and dose-dependent pharmacodynamic activity.

We have completed enrollment in the 12-milligrams-per-kilogram cohort and anticipate completing enrollment in the 24-milligram-per-kilogram cohort in the fourth quarter of this year. As a result and to allow for response assessments in these patients, we expect to share top-line data from the additional cohort in the first quarter of 2023.

As we have discussed before, the PD-1 landscape has evolved in such a way that enrolling patients that are both PD-1 naive and at a high likelihood of responding to PD-1 inhibition is extremely difficult in nearly all geographies around the world.

As such, the clinical part of 252 would first be in PD-1 relapse/refractory patients. We will need to see a 20% or greater overall response rate in the additional patient cohort to see a viable path forward for 252.

With that, I will now turn the call over to Mr. Neill to discuss our financial update. Andrew?

Thank you, Lini. Good afternoon, everyone. As Conor mentioned at the outset of our call, the full financial results for the third quarter of 2022 are available in our earnings press release and in our forthcoming 10-Q.

Today, I would like to focus on a few key points from our disclosures. We continue to be well positioned financially. As of September 30, 2022, we have cash and cash equivalents and investments of approximately $185.1 million. In the third quarter of 2022, our research and development expenses were $18.9 million compared to $15.1 million for the third quarter of 2021.

In the third quarter of 2022, our general and administrative expenses were $6.6 million compared to $4.3 million for the third quarter of 2021. Our net loss for the third quarter of 2022 was $24.6 million or a loss of $0.58 per basic and diluted share compared to a net loss of $17.4 million for the third quarter of 2021 or $0.41 per basic and diluted share.

Based on our current operating and development plans, we reiterate our financial guidance for 2022 and beyond. We expect our existing cash and cash equivalents and investments to be sufficient to fund our planned operations into the second half of 2024. We continue to operate with strong financial discipline across our entire company, including in our ongoing clinical programs.

And given our projected rate of cash burn, we are in a healthy position as it relates to our balance sheet and expected clinical data readout for our 154 and 252 clinical trials. With that, I'll hand the call back to Dr. Schreiber for final comments. Taylor?

Thank you, Andrew. As you've just heard, 2022 has been a year in which we have kept our heads down to focus both on clinical execution with the ARC platform and further broadening our pipeline with the GADLEN platform. Both of those opportunities are now ripening quickly, and we are pleased to be approaching key clinical data in 2023.

As you heard from Lini, clinical updates from the 154 program, including complete data from the monotherapy dose escalation study in platinum-resistant ovarian cancer patients and initial data in combination with liposomal doxorubicin, also in ovarian cancer patients, are expected mid-year 2023.

Additionally, initial data from our study in patients with relapsed/refractory AML and high-risk MDS are expected in the first half of 2023.

I want to thank everyone for participating in today's call. We believe the combination of our experienced team, transformational science and protein engineering, as well as financial resources, puts us in an incredibly strong position to move beyond our next set of milestones. We will keep you apprised of our progress as we continue to execute our strategic and corporate objectives.

With that, we would now like to open the call for your questions. Operator?

(Operator Instructions) Marc Frahm, Cowen

Thanks for taking my questions. Last quarter, the last time you guys spoke on an earnings call, you talked about the 3-milligram dose being advanced into the doxo combo trial, and it seems unlikely that the 10-milligram, while still being pursued in the monotherapy, was going to need to be ported over.

Do you have enough data now from that cohort in the monotherapy to confirm whether you think you will or will not be using the 10-milligram dose in the combo at all?

Hey, Marc, thanks for the question. Let me ask Lini to take that.

Marc, all our PK/PD analyses support the 3-milligram-per-kilogram dose being evaluated in the combination. Protocol allows us to go up on the dose, but the 3 milligram is a very solid dose for evaluation in combination.

Okay, that's helpful. And then also, in the early experience with monotherapy, there were some infusion reactions, and you extended the dosing time to help with that. Can you update us on how that's got to continue to evolve? And can you confirm, are you using the longer infusion time in the combo trials?

Yes, we are using the longer infusion time, which is 2 hours -- over 2 hours instead of over 1 hour.

Okay. Thank you.

Thanks, Mark.

Jon Miller, Evercore ISI.

Hi, this is Eric here asking on for John Miller. On SL-154, looking at a monotherapy trial in platinum-resistant ovarian cancer (technical difficulty)

This is Taylor. You've trailed off there. Could you repeat the question? Operator, maybe we can go to the next question and come back to Evercore?

Gil Blum, Needham & Company.

Hi. Good afternoon, everyone. Just a quick question on the 10-milligram-per-kilogram dose, was there any sign of toxicity at that dose? Or purely, this is a decision based on PK/PD?

Hey, Gil. I'll turn that over to Lini as well.

Yes, it's a decision based on PK/PD. We did an analysis across all the dose -- the entire dose range, and the 3-milligrams-per-kilogram dose gives full receptor occupancy, gives on-target pharmacodynamic activity, and it is a very good dose actually to take forward. And there is not much that you gain from going up to 10 milligrams.

Okay, that's very helpful. And maybe a speculative one. Do you guys have any view on the abstracts that were published for magrolimab ahead of ASH? I mean, I'm sure you guys looked at it. It doesn't look like there's not much more benefit for CD47 in the high-risk MDS. I would appreciate any thoughts you guys have.

Yes, so I'll start, and Lini may want to chime in with some additional comments. I think, recently, we've seen some updated abstracts both from ALX and [for magro] heading into ASH. And with both, I guess what I would say to caveat my response is that there's not quite enough detail in the abstracts to make a full assessment of the patients that were studied in each trial and what it necessarily means.

And the other statement that I would make is that I think the trend toward the activity of CD47 inhibitors, at least single-acting CD47 inhibitors, being most convincing in the TP53 mutant AML population is where we believe the field will continue to evolve.

And the activity of azacitidine alone in the non-TP53 mutant HR-MDS patients and then the combo between [aza] and then the non-TP53 mutant AML, I think it's -- so far, the data we've seen is really on the margins as to whether a single-acting CD47 inhibitor add something beyond what you would expect from that chemotherapy-only backbone.

All right. I appreciate the color. I'll step back in the queue. Thank you.

Thanks, Gil.

Yigal Nochomovitz, Citi.

Hi, this is Carly on for Yigal. Thanks so much for taking our questions. I just have one on the 154 update for AML and MDS in the first half of next year. I guess, can you comment at this point on roughly how many patients we should expect for both the monotherapy and the combination cohort?

And I know you mentioned in the prepared remarks that any complete responses in this population would be meaningful, but can you elaborate a bit on what you're looking to see with the azacitidine combo, specifically on efficacy? Thank you.

Great, thanks. I'll ask Lini to take that also.

Yes, so the dose escalation part -- so there's a monotherapy dose escalation, and then there's a combination with azacitidine dose escalation. And so, we anticipate anything from between 10 and 20 patients across the dose escalation.

And then your second question regarding the complete remissions. So in the relapse/refractory patient population, it's usually -- it's unusual to see complete remissions in that patient population. So if we were to see any complete remissions, that would be differentiating for this agent.

Okay, that's helpful. Thank you. And then, we just have one quick clarification question also. I think, previously, you were also planning to do a combination with venetoclax with azacitidine, but it looks like now you might be just doing azacitidine. Could you just clarify if there was a change and what the reason was?

Yes, so the dose escalation is with azacitidine. Once we get to a dose of azacitidine and 154, then there is expansion cohort in combination with azacitidine, SL, and venetoclax. [So there is a safety run-in], followed by an expansion. It's a safety run-in followed by an expansion.

Okay, great. Thank you very much.

Thank you.

(Operator Instructions) Kaveri Pohlman, BTIG.

Yes, good afternoon. Thank you for the update. For 154, can you talk about how the approach is different from ILT4 targeting, which also repolarizes macrophages? I believe Merck has expanded its effort into this space with multiple tumor types, including ovarian cancer.

Sure. So this is -- the CD47 axis addresses a particular aspect of macrophage biology, which enables macrophages to consume or phagocytose tumor cells that are in their proximity. And so, that activity in and of itself is not an activity that is directly addressed by something like an ILT4-specific agent.

There are a number of agents -- a number of ways to influence the polarization of macrophages. Some macrophages can be immune inhibitory. Some macrophages can be immune stimulatory, and certainly, ILT4 for can play a role in that [phage] decision.

Interestingly, CD40 does as well. And when you stimulate CD40 on a macrophage, it helps guide that cell toward that immune-stimulating M1 phenotype. And so, I believe that an agent like 154 addresses, on the CD40 side, a somewhat similar aspect of macrophage biology as some of the ILT4 agents, whereas the CD47 inhibitory part is purely a prophagocytic function.

That's very helpful. Thank you. And for AML, any thoughts on combining it with cytarabine because based on the ovarian cancer data, the safety profile looked benign enough, or is cytarabine also immunosuppressive?

So the dose of cytarabine matters also. It is immunosuppressive, just as you said, so you could actually deplete the cells that you're trying to activate.

Got it. And then maybe last one on GALDEN. So you have multiple programs or ARC assets. And for GALDEN, a target like B7-H3 could be used for several indications. I guess, my question is, is GALDEN a potential partnering opportunity, or do you ultimately have aspirations to really independently develop both ARC and GALDEN assets?

I mean, certainly could. The GALDEN platform is quite broad, and B7-H3 is just one of the agents that we have in our pipeline these days. And we think it's a compelling one. B7-H3 is a tumor antigen that's widely expressed.

Daiichi Sankyo has recently shown some interesting data with one of their programs targeting B7-H3, and I think a gamma delta engager could offer something that's distinct from what an antibody drug conjugate-type molecule can offer in a number of tumor types.

So two tumors that are interesting from a B7-H3 expression standpoint, where gamma delta T cells are also relatively abundant, include tumors like melanoma and non-small cell lung cancer, bladder cancer, a number of others. And so, for now, we're proceeding along with the development of this agent toward IND. I'll just leave it at that for now.

Makes sense. Thanks for taking my question.

Thanks, Kaveri.

Zhiqiang Shu, Berenberg.

Great. Thanks for taking my question. I have a few. So first one on 154, are you willing to discuss in more detail around the 3-milligram-per-kilogram dose and 10-milligram-per-kilogram dose, the [KPD] dynamics there? I wonder, since you did a call last year around this time, a lot of things have changed. If you're willing to discuss a little more this time?

Sure. [Hi Zhi]. So I'll start, and then Lini can fill in any gaps if I miss them.

So the thing you might remember from our prior conversation that what we were hoping to achieve over the course of the monotherapy dose escalation study was to identify a dose where 154 was well tolerated, where CD47 was fully saturated, where CD40 was fully saturated, and where the pharmacodynamic effects that we attributed to CD40 biology were maximal and had achieved the maximal plateau.

We shared some of that data in the SITC presentation, and the types of things that we see as a consequence of CD40 finding included the rapid migration of CD40 expressing T-cells and monocytes out of the blood within an hour of infusion, as well as pretty impressive inductions of a number of CD40-driven cytokines in the peripheral blood.

And when we moved from the 3-milligram to the 10-milligram-per-kilogram dose, we were fundamental -- we knew that we were at saturation of CD40 and CD47, and we are starting to see large spikes in those cytokines and near-maximal margination of CD40-expressing cells by 3 milligrams per kilogram.

And so, fundamentally, what we're asking is when we go to 10 milligrams, do we see a further potentiation of those pharmacodynamic effects as stabilization and a maximal plateau of those effects, or a reduction in some of those pharmacodynamic effects?

Many of you likely are aware that with other CD40 agents, you see this odd bell-shaped dose response curve that indicates that it might be tough to maximally drug the pathway. And what we saw from 3 milligrams to 10 milligrams is that all of those pharmacodynamic effects remained at a maximal plateau.

And so, as Lini alluded to before, in looking at between that 3-milligram and 10-milligram-per-kilogram dose, there wasn't any discernible benefit based on those endpoints to continue with the 10-milligram-per-kilogram dose.

Great. And that's helpful. And then, second question is around the combination with folate receptor ADC. I think it was disclosed last time. It was posted on clinicaltrials.gov. Given your update today, I'm wondering if you're willing to discuss the plans there?

Sure. So first of all, we're eagerly awaiting, hopefully, an accelerated approval for mirvetuximab by ImmunoGen any day now. I think it's an exciting opportunity for patients with platinum-resistant ovarian cancer that haven't had a new therapy available to them for quite a long time.

And one of the interesting things about mirvetuximab is that the label is expected to be at least initially in patients that express very high levels of folate receptor alpha on their tumor, 75% or greater. But along the way, ImmunoGen has seen tumor shrinkage in about 80% of patients or so with lower levels of folate receptor alpha expression starting in about 25%.

And it really begs the question, could the durability -- could that initial tumor shrinkage lead to greater durability if it was combined with something that potentiated that initial tumor-killing signal that mirvetuximab clearly delivers?

And that's exactly where we see an opportunity for a drug like 154. And I think I need to leave it there until we hopefully get news of the accelerated approval, and then we'd love to continue that conversation.

Great. Just a final question on 252. You're still dose escalating the drug and will provide an update in [first quarter of 2023]. I wonder, should we still operate under the assumption that if we are not seeing 20%, this program will [wind down]?

Yes, that should be your operating assumption.

Okay, great. Thanks very much.

Thanks, Zhi.

Thank you. That concludes the question-and-answer session, and I turn the call back over to Taylor Schreiber, the Chief Executive Officer of Shattuck Labs.

Thank you. This concludes the Q&A session of the call. Thank you, operator, and thank you all for joining Shattuck Labs' third-quarter financial results and business updates conference call. We appreciate your continued interest in Shattuck, and we look forward to updating you on our milestones throughout the remainder of 2022. Thank you.